in Ulaanbaatar, Mongolia Human papillomavirus genotyping among women with cervicalabnormalities International Journal of Infectious Diseases

Human papillomavirus genotyping among women with cervical abnormalities in Ulaanbaatar, Mongolia

Batchimeg Tsedenbal

, Tomomi Yoshida

*, Bayarmaa Enkhbat

, Uyanga Gotov

, Enkhtuya Sharkhuu

, Masanao Saio

, Toshio Fukuda

aGraduateSchoolofHealthSciences,GunmaUniversity,3-39-22Showa-machi,Maebashi,Gunma371-8514,Japan

bMongolianNationalUniversityofMedicalSciences,JamyanSt3,SukhbaatarDistrict,Ulaanbaatar14210,Mongolia

cNationalCenterforPathology,MinistryofHealth,1stKhoroo,SukhbaatarDistrict,Ulaanbaatar14210,Mongolia

dMongolianAssociationofHistopathologyandCytopathology,NamYanJuStreet,BayanzurkhDistrict,Ulaanbaatar13374,Mongolia

ARTICLE INFO Articlehistory:

Received29January2018

Receivedinrevisedform14September2018 Accepted20September2018

CorrespondingEditor:EskildPetersen,Aar- hus,Denmark

Keywords:

Cervicalcancer

Humanpapillomavirus(HPV) Genotyping

Cervicalcytology Mongolia

ABSTRACT

Objectives:Fewstudiesonhumanpapillomavirus(HPV)havebeenconductedinMongolia.Thisstudywas performed to evaluate the prevalent HPV genotypes and their associations with cytology and demographicandbehavioralcharacteristicsinMongolianwomenwithcervicalabnormalities.

Methods:Exfoliatedcellsamplesof100womenwhohadaprevioushistoryofcervicalabnormalitywere collected.CytologicalinterpretationwasconductedmicroscopicallyandHPVgenotypingwasperformed usingtheRocheLinearArraytest.Studyquestionnaireswerecompleted.

Results:Overall,25HPVgenotypesweredetectedin47%ofparticipants,andthemostprevalentwereHPV 16,52,58,and33.Cytologicalexaminationrevealed12%ofparticipantshadatypicalsquamouscellsof undeterminedsignificance(ASC-US),8%hadlow-gradesquamousintraepitheliallesions(LSIL),7%had high-gradesquamousintraepitheliallesions(HSIL),and14%hadsquamouscellcarcinoma(SCC),while 59%ofwomenhadanormalcytology.HPV16wasthemostcommontypeamongwomenwithanormal cytologyandcervicalcancer.However,womenwithcervicalabnormalitiesincludingLSILandHSILwere predominantlyinfectedwithHPV52.Moreover,womenaged<35yearshadasignificantlyhigherriskof HPVinfectionthanthoseintheotheragegroups(p<0.05).

Conclusions:TheprevalenttrendofHPVgenotypesobservedinthiscohortdiffersfromthatreported previouslyinMongolia.Thesedatamaycontributetodevelopinganeffectivestrategyforcervicalcancer preventioninMongolia.

©2018TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.

ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by- nc-nd/4.0/).

Introduction

Mongolia isa landlockedcountrywitha total populationof threemillion.Abouttwo-thirdsofthepopulationliveinthecapital cityUlaanbaatar(Pezzuloetal.,2017);remoteareasaresparsely populated. Mongolia has undergone significant socioeconomic changes accompanied by an unstable government and poor systemic policy. Thus, a large number of the population has migratedabroadoverthelasttwodecades(Tsilaajavetal.,2013;

Kohrtetal.,2004).

Cervicalcanceristhefourthmostcommoncancerinwomen and the seventh most common cancer overall worldwide.

ComparedwithJapanand othercountries, Mongoliahasoneof thehighestage-adjustedcervicalcancerratesinAsia(Organization WH, 2014). The current situation in Mongolia indicates that cervicalcanceristhefourthmostcommoncancerintheoverall populationandthesecondmostcommoncancerinwomen(Ferlay etal.,2013).Accordingtostatisticaldatafor2015,cervicalcancer morbidityandmortalityrateswere29.8per100000womenand 13.6 per 100000 women, respectively; 51.1% of patients were diagnosed in the late stage and the 5-year survival rate was estimatedas44.2%(NationalCenterforCancer,2015).

Cervicalscreeningsystemsarebecomingmorecomplex.The conventionalPapanicolaou(Pap)testwasamajorleapforwardin cervicalcancerscreeningandcontinuestobeusedefficientlyin many countries. However, the liquid-based cytology test has increasedsensitivityand specificitycompared withthePaptest

*Correspondingauthor.

E-mailaddresses:[email protected](B.Tsedenbal),

[email protected](T.Yoshida),[email protected](B.Enkhbat), [email protected](U.Gotov),[email protected](E.Sharkhuu), [email protected](M.Saio),[email protected](T.Fukuda).

https://doi.org/10.1016/j.ijid.2018.09.018

1201-9712/©2018TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International Journal of Infectious Diseases

j o u r n a lh o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j i d

(Azizetal.,2006).Moreover,theintroductionofnewtechnologyto testforhumanpapillomavirus(HPV),whichhasahighsensitivity (>90%)and high negativepredictive value compared toliquid- based cytologyand thePap test, is now recommended by the WorldHealthOrganization(WHO)forcervicalcancerscreening.

HPVinfectionistheleadingcauseofcervicalcancerprogression andissexuallytransmitted(Castellsagué,2008).HPVinfectioncan occuratthebeginningofawoman’ssexuallifeandtakeseveral decadestoadvanceintocervicalcancer(Franceschietal.,2006;

Woodman et al., 2007). However, most HPV infections are transientand only persistent HPVinfections, particularly those withhigh-riskHPV(HR-HPV)genotypes,progressintohigh-grade lesions or cancer. Individuals with low-risk HPV (LR-HPV) genotypes are likely to develop genital warts. About 15 HPV genotypes(16, 18,31,33,35,39,45,51,52,56,58,59,68,73,and82) havebeen classified ashaving high oncogenicpotentialamong

>100HPVgenotypes(Muñozetal.,2003).

Since2012,HPVDNAtestinghasplayedanimportantroleinthe investigationofabnormalcytologyfindingstoclarifyrisktypes.

Indeed,highlydevelopedcountrieshaveincludedHPVDNAtesting asapartoftheirtriagesysteminguidelinesfortheearlydetection ofcervical cancer(Saslowet al.,2002).In2011, theMongolian Ministry of Health approved clinical guidelines for a uterine cervicalcancerpreventionprogramforwomenwiththetargetage of 30–60 years. Since 2012,a uterinecervical cancerscreening programhasbeenimplemented in Mongoliaforwomen in the targetagegroup,whichgenerallyconsistsofa Paptestevery3 years (Chimeddamba et al.,2015; Ministryof Health Mongolia, 2007).Unfortunately,liquid-basedcytologyandHPVtestsarenot accessible because of theirhigh costs. Moreover, data on HPV prevalenceandthetypedistributioninMongoliaareoutdatedand scarce.Accordingtoa2008study,HPV16wasthemostcommon type(54%)amongMongolianwomen,followedbyHPV58,18,and 33 (Dondog et al., 2008). Recently, many studies on the implementationofvaccination for HPVinfections withtheaim ofpreventingcervicallesionsrelatedtoHPVinfectionorrepeated infectionhavebeenstarted.TheMongolianMinistryofHealthand the Millennium Challenge Corporation (Washington DC, USA) organizedapilotHPVvaccineintroductionprogramforschoolgirls aged11–15yearsin2012.However,concernsaboutthesideeffects oftheHPVvaccinesledtotheinterruptionofthepilotprogramin thesameyear(Tohetal.,2017).

The primary aim of this study was to determine the most prevalent HPVgenotypesand theirassociations withabnormal cervical cytology in Mongolian women. It was also sought to analyze the relationships between HPV infection and cervical abnormalities, demographic data, and behavioral changes. The resultsofthispilotstudymaycontributetofutureapproachesfor cervicalcancerscreeningandHPVpreventionandvaccinationin Mongolia.

Methods

Studypopulationandsamplecollection

Thiswasahospital-based,cross-sectionalstudyinvolving100 women who visited the gynecological outpatient clinic of the NationalCenterforCancerinMongoliaduringMarchtoMay2017.

Women aged 18–65 years (meanstandard deviation 4510 years)whohad aprevioushistoryofcervicalabnormalitiesand wereattendingagynecologicalexaminationinordertoconfirm whethertherewasan abnormalityornot wereeligiblefor this study. However, pregnant women, women who had received radiationtherapyorahysterectomy,andwomenwithanymental illness/diseasehistory whocouldnot makedecisions forthem- selveswereexcluded fromthisstudy.Allparticipantssignedan

informedconsentformafterbeingprovidedwithanexplanationof the study purpose. Theyalso answered a socioeconomic back- groundquestionnaire.Womenwithanabnormalcytologyclassi- fiedashigh-gradesquamousintraepitheliallesion(HSIL)ormore were advised to undergo colposcopy and/or biopsy; however, womenwithatypicalsquamouscellsofundeterminedsignificance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) were advised to undergo a repeat cervical smear test after 6 months;allpatientsweretreatedinaccordancewiththeguide- linesformanagementstandardizedbytheMinistryofHealthin Mongolia.Cervicalsampleswerecollectedbyagynecologistusing Cervex-Brush Combi (Rovers Medical Devices B.V., Oss, The Netherlands).ThebrushheadwasdirectlysuspendedinaTACAS GYNVial(Medical&BiologicalLaboratoriesCo.,Ltd,Tokyo,Japan) andkeptinarefrigeratorat4Cuntiltransportedtothelaboratory atGunmaUniversity.

Ethicalconsiderations

This study was conducted under cooperation between the MongolianNationalUniversityofMedicalSciences,Mongoliaand GunmaUniversity,Japan.Thestudywasapprovedbytheethics and research committees of the Graduate School of Health Sciences,GunmaUniversity(number2016/020)andtheMongo- lianNationalUniversityofMedicalSciences(numberB/191).Study approvalwasalsoobtainedfromtheEthicsReviewBoardofthe MinistryofHealth,Mongolia.

HPVDNAgenotypingandcytologicalexaminationofsamples

HPVDNAtestingwasperformedusingexfoliatedcervicalcells from the TACAS GYN Vial before any procedure to minimize contamination. The Linear Array HPV Genotyping Test (Roche MolecularSystems,Branchburg,NJ,USA)wasusedtodetectthe37 HPV genotypesin this study. Three specific kits (the Amplicor LinearArrayExtractionKit,LinearArrayHPVGenotypingKit,and LinearArrayDetectionKit)wereusedforthefollowingprocesses:

specimenpreparation,DNAextraction,PCRamplificationoftarget DNA using HPV primers, and hybridization of the amplified products tooligonucleotideprobesand detection ofthe probe- boundamplifiedproductsbycolorimetricdeterminationaccord- ingtothemanufacturer’sinstructions(Jamisonetal.,2009).Final colorprecipitationoftestingstripsallowedformanualreadingof genotypedetectionbycomparisonwithareferencecard.Residual cellsamplesinthevialweremanuallyprocessedaccordingtothe protocoloftheTACASsystem.Processedcytologicalsmearswere dyedwithPapanicolaoustainandinterpretedbyseniorandjunior cytopathologists accordingtothePaptestandBethesda System 2014(NayarandWilbur,2015).

Statisticalanalysis

StatisticalanalyseswereconductedusingIBMSPSSStatistics version23.0(IBMCorp.,Armonk,NY,USA).Statisticalmeans,p- values, and odds ratios (OR) were determined. Associations betweendemographic/behavioralcharacteristicsandHPVpositiv- ity and cytological abnormalities were analyzed by logistic regressionanalysis.Alltestswereconsideredstatisticallysignifi- cantatthelevelofp<0.05.

Results

Cytologicaldiagnosisofallparticipants

Amongthe100womenwhoparticipatedinthisstudy,thePap testrevealedthat12%hadASC-US,8%hadLSIL,7%hadHSIL,and

14%had squamous cellcarcinoma(SCC). Theremaining59% of participantshad normal cytological results (negative for intra- epitheliallesionormalignancy,NILM)(Table1).

OverallHPVprevalenceandtypedistribution

Overall,HPVDNAwasdetectedin47%(47/100)ofparticipants, ofwhom32%wereinfectedwithsingleHPVinfectionsand68%

wereinfected withmultiple HPVinfections. Twenty-five geno- typesweredetectedincludingHPV16,18,31,33,35,39,45,51,52, 56,58,59,68,53,70,73,82,42,54,55,61,62,81,83,andCP6108 (Figure1).ThemostprevalentHR-HPVtypeswere16(21%,21/100) and52(14%,14/100),followedby58(6%,6/100),33(6%,6/100), and31(5%,5/100).HPV55(6%,6/100)and54(5%, 5/100)were dominant among LR-HPV types. The other genotypes had frequenciesof4%orless.

HPVprevalenceaccordingtocytologicalabnormalities

The prevalence of HPV-positive women among those with normalcervicalsmearswas32%(15/47),whereastheprevalence amongwomenwithASC-US,LSIL,HSIL,andSCCwere13%(6/47), 17%(8/47),13% (6/47), and 26% (12/47), respectively(Table 2).

SingleLR-HPVtypesweredetectedin13.3%(2/15)ofwomenwitha normalcytologyand 16.6%(1/6) ofwomenwithASC-US,while therewasnodetectioninwomenwithLSIL,HSIL,orSCC.SingleHR- HPVtypesweredetectedin20%(3/15)ofwomenwithanormal cytology,16.6%(1/6)ofwomenwithASC-US,33.3%(2/6)ofwomen withHSIL,and50%(6/12)ofwomenwithSCC.Theproportionsof multipleHPVinfectionsdetectedinwomenwithcytologicalNILM, ASC-US,LSIL,HSIL,andSCCwere66.7%(10/15),66.7%(4/6),100%

(8/8),66.7%(4/6),and50%(6/12),respectively(Table2).

RelevantHPVgenotypeswithindifferentcytologicalabnormalities

The prevalence and distribution of the most frequent HPV genotypesamongcytologicalabnormalitiesareshowninFigure2.

HPV16wasthemostprevalentgenotypedetectedinwomenwith SCC,followedbyHPV52,33,54, and31.HPV52was themost commongenotypeinwomenwithLSILandHSIL,followedbyHPV 58and59inLSILandHPV33,58,and82inHSIL.HPV16,52,and55 werethemostcommongenotypesinwomenwithASC-US,while womenwithanormalcytologywerefrequentlyinfectedwithHPV 16and45.

DemographicandbehavioralriskfactorsofwomenwithHPVinfection andcytologicalabnormalities

Multivariable analyses of demographic and behavioral risk factorsforHPVDNApositivityandcytologicalabnormalitiesare summarizedinTable 3.Womenaged between25 and34 years were4.1times(95%confidenceinterval1.0–16.8)aslikelytobe HPVDNA-positive as women aged 55 years (p<0.05). Other

variablesandriskfactorswithincytologicalabnormalitiesshowed nostatisticallysignificantdifferences.

Discussion

Consideringthecurrentwiderangeofinternationalcommuni- cation due totravel or immigration, changes in HPV genotype distributionincertainpopulationsarehighlyprobable.Thecurrent studyappearstobethefirsttoinvestigatethemostprevalentHPV genotypes and their relationships with cervical abnormalities amongMongolianwomen.

HPVDNAwasdetectedin47%ofstudyparticipants,andmore womenhadmultipleinfections(68%)thansingleinfections(32%).

Apreviousstudyconductedin2008showedthatoverallHPVDNA prevalence was 35% among 800 women in Ulaanbaatar city (Dondogetal.,2008).TheincreasedHPVDNAprevalenceinthis studymaybeattributedtothestudycohort,aswomenwhohada previoushistoryofabnormalcytologywereanalyzedinthisstudy.

ThepresentstudyalsofoundHPV16,52,58,33,and31tobethe dominantHR-HPVtypes,andHPV55and54tobethedominant LR-HPVtypesdistributedamongMongolianwomen.Theseresults aresimilartothosereportedfromAsiancountriessuchasJapan (HPV16,18,52,and58)andSouthKorea(HPV16,58,33,and52) (Onukietal.,2009;Takeharaetal.,2011;Soetal.,2016).Previous studies indicated that HPV 16 was the dominant genotype, followed by HPV 58, 18, 33, and 45 (Dondog et al., 2008;

Chimeddorjetal.,2008).However,thecurrentstudyrevealeda highprevalenceofHPV52andlowprevalenceofHPV18among Mongolianwomen.ThisminorchangeinHPVinfectionssuggests thatthesmallsamplesizeofthisstudycouldhaveledtoapossible bias,orthatstudyparticipantswithcervicalabnormalitiesmay haveaffectedthisdistributioninthepresentstudy.Furthermore, the previous HPV studies in this country, which has a small population, were performed almost 10 years ago. Increased migration of Mongolians throughout the world, especially to Asiancountries,andthepoorsocioeconomicconditionsoverthe last two decades, along with the development of tests, could explainthis distributiondifference in HPVinfections(Rousseau et al.,2001).Thus, weconsider it crucialthat newresearchbe performedwithincreasednumbersofstudyparticipantsandwith increasedreportingofdemographiccharacteristicsandriskfactors relatedtoHPVtypes.

Thedistributionofsingleandmultipleinfectionswasevaluated inparticipantswithanormalcytologyandASC-US(Table2).The overallmultipleinfectionrateforHPVDNApositivityinLSILwas high(100%)inthisstudy,andwassimilartoastudyinaLatino cohort(Zhouetal.,2014).HPV52,58,59,and16werethemost commontypesdetectedinLSIL.Themultipleinfectionrate(66.7%) for HPVDNA positivitywasalsohigher inHSILthan thesingle infectionrate(33.3%).HPVgenotypescommonlydetectedinHSIL were52,16,and33.However,therewasnodifferenceinsingleand multiple infection rates in participants with SCC. The most commonHPV genotypesdetected in SCCwereHPV16, 52,33, and31,whichdiffersfromthepreviousstudyinMongolia(HPV16, 35,31,and58)(Dondogetal.,2008).Thesefindingssuggestthat onlypersistentHPVgenotypesleadtocervicaldysplasia,regard- less of singleor multiple infections. Since the studyidentified probable high risk HPV types circulating in this country, it is important to formulate an appropriate, targeted strategy to preventHPVinfectionineachregion.

According to the demographic and behavioral risk factors questionnaire,Mongolianwomenaged<35yearsweremorelikely tohaveHPVDNApositivitythanwomenintheotheragegroups.

Thisfindingsupportsresultsfromapreviousstudythatshowed HPVinfectiontobehighestinwomenaged<25yearsinMongolia (Dondogetal.,2008).HPVinfectionsgenerallypeakatayoungage, Table1

Representationofcytologicalfindingsamongallparticipants(n=100).

Cytologicaldiagnosis n(%)

NILM 59(59)

ASC-US 12(12)

LSIL 8(8)

HSIL 7(7)

SCC 14(14)

NILM,negativeforintraepitheliallesionormalignancy;ASC-US,atypicalsquamous cells of undetermined significance; LSIL, low-grade squamous intraepithelial lesion;HSIL, high-grade squamous intraepithelial lesion; SCC, squamous cell carcinoma.

whichcorrespondstoawoman’sfirstsexualintercourse.However, mostinfectionsclearwithinafewyears(FrancoandHarper,2005;

Wang et al., 2015). Furthermore, no significant difference in cytologicalfindings according to agegroup was observed. This resultcanbeexplained bythefactthat thenumber ofwomen includedinthis studywas smalland HPVDNAtesting ismore sensitivethancytologytesting.Furthermore,thisfindingsuggests thatthetargetagerangeforthecervicalcancerscreeningprogram and primaryprevention systemshould bereconsidered for the younggenerationinMongolia.Otherfactorsincludingresidency, relationship status, contraceptive use, age at first sexual inter- course,numberoflifetimesexualpartners,andhistoryofinduced abortionwerenotsignificantlyassociatedwithHPVDNApositivity orabnormalcytologyresultsinthisstudy.Moreover,itwasnot possibletodetermineinformationregardingtheexactnumberof lifetimesexualpartnersoftheparticipants’partnersorhusbands, whichpreventsacompleteunderstandingofthehighincidenceof

multiple infection, but not significant risk factors of sexual behavior in participants.Further investigations are required to clarifythesefindingsbyincreasingthesamplesizeandincluding informationaboutpartnersandhusbands.

Thisstudyhassomelimitationsthatmustbediscussed.First, thenumberofstudyparticipantswassmall,andthusthedatado notdirectlyrepresentthewholepopulation.Second,this wasa cross-sectional study and whether the HPV infections were transientorpersistentremains uncertainduetotheabsenceof afollow-upsystem.Althoughprogressiontolesionorcancermay occurseveraldecadesafterinfection,it isnotpossibletodetect simultaneousorsequentialinfectionswitheachHPVgenotypeand potential combinatorial effects on cytological characteristics.

Third, there is a need for new research on demographic characteristics and risk factors associated with HPV types, increasingthenumberofsubjectsinthestudypopulation.Despite theselimitations,thestrengthsofthisstudyincludetheuseofthe Figure1.DistributionofHPVgenotypesdetectedinoverallparticipants.HPV,humanpapillomavirus;HR-HPV,high-riskHPV;LR-HPV,low-riskHPV.

Table2

FrequencyofHPVDNApositivityresultsaccordingtocytologicalabnormalities(n=47).

Cytologicaldiagnosis HPVDNApositivity(%) Singleinfection(%) Multipleinfections(%)

LR-HPV HR-HPV

NILM 15(32) 2(13.3) 3(20) 10(66.7)

ASC-US 6(13) 1(16.6) 1(16.6) 4(66.7)

LSIL 8(17) 0(0) 0(0) 8(100)

HSIL 6(13) 0(0) 2(33.3) 4(66.7)

SCC 12(26) 0(0) 6(50) 6(50)

Total 47(100) 3(6.4) 12(25.5) 32(68.1)

HPV,humanpapillomavirus;LR-HPV,low-riskHPV;HR-HPV,high-riskHPV;NILM,negativeforintraepitheliallesionormalignancy;ASC-US,atypicalsquamouscellsof undeterminedsignificance;LSIL,low-gradesquamousintraepitheliallesion;HSIL,high-gradesquamousintraepitheliallesion;SCC,squamouscellcarcinoma.

Figure2.MostfrequentHPVgenotypesaccordingtocytologicalabnormality.HPV,humanpapillomavirus;NILM,negativeforintraepitheliallesionormalignancy;ASC-US, atypicalsquamouscellsofundeterminedsignificance;LSIL,low-gradesquamousintraepitheliallesion;HSIL,high-gradesquamousintraepitheliallesion;SCC,squamouscell carcinoma.

relatively sensitive TACAS LBC test and the Linear Array HPV genotypingtest, which were repeated for inconclusive results.

Furthermore, this study described the probable relationship betweenHPVtypesanddemographicandbehavioralriskfactors.

In conclusion, this study revealed the prevalence of HPV genotypesamongMongolianwomenandthefrequencyincervical abnormalities.Evenwiththesmallpopulationsize,thesedataon themostprevalentHPVgenotypescouldformthebasisforfuture studies and may contribute to formulating prevention and vaccinationprogramsanda follow-upsystemfor HPVinfection inMongolia.

Acknowledgements

We would liketo express our gratitudeto all medical staff membersoftheMongolianNationalCenterforCancer,especially DrAmarsanaaE(headoftheobstetricsandgynecologyward)and DrSuvdmaaV(gynecologist)fortheirinvolvementinandsupport ofthis study.WealsothankChristinaCroney,PhD, fromEdanz Group (www.edanzediting.com/ac), for editing a draft of this manuscript.

Funding

This study did not receive any specific grant from funding agenciesinthepublic,commercial,ornot-for-profitsectors.

Ethicalapproval

Thisstudywasapprovedbytheethicsandresearchcommittees of the Graduate School of Health Sciences, Gunma University (number 2016/020) and the Mongolian National University of MedicalSciences(numberB/191).

Conflictofinterest

Allauthorsdeclarethattheyhavenoconflictsofinterest.

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