Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
instance,adecreasedriskwith inertintrauterinedevices(IUDs)suggeststhatimmune
factorsrelatedtothelow-gradeinflammation thatoccurs withIUDsmay playarole,
andincreasedriskwithinsulinresistance,amongnonobesewomenorwomenwiththe
same BMI, suggests that insulin is important to endometrial cancer development
(66–68).Insulinandinsulin-likegrowthfactor1havebeenshowntoincreaseproliferation
anddecreaseapoptosisinendometrialcancercellsthroughthe β-cateninandRaspathways
(69,70) suggesting a nonhormonal mechanism through which obesity may increase
endometrialcancerrisk.
OvarianCancer
Ovariancancerisa diverseset of cancers that include germ celltumors, sex-cord stromal
tumors, epithelial tumors, and other rarer types. In adult women, about 90% of ovarian
tumors are epithelial, including: serous, mucinous, endometrioid, clear cell and,
undifferentiated. Epithelial tumors may be further subdivided by grade with tumors of
borderlinemalignancy orlow malignantpotential beinganimportantsubset.These tumors
areusuallynotcountedinnationalstatisticsonovariancancerbutareofteninepidemiologic
studies.Ifincluded,borderlinetumorsshouldbeevaluatedseparately.
Invasiveserousisthemostcommontypeofovariancancerandusuallypresentsasahighgrade tumor. With the recent observation that some (if not the majority) of high-grade
serousovariancancersmay arisefromthefimbriated endofthe fallopiantube,some
pathologistshaveproposedaTypeI/IIanalogysimilartoendometrialcancer(71–74).TypeI
cancers are those arising within the ovary and include low-grade serous, mucinous,
endometrioid,and clearcell tumors, while TypeII cancers are the high-grade serous
andpossiblyhigh-gradeendometrioidcancers,whicharelikelytocomefromthetube.
Recently, these authors suggested that lumping the Type I cancers together may be too
simplisticandthattheyshouldbesubdividedintoatleastthreesubtypes:(i)endometriosisrelated cancers including endometrioid, clear cell, and seromucinous carcinomas, (ii) lowgradeserouscarcinomas,and(iii)mucinouscarcinomasandmalignantBrennertumors(75).
Consistently observed risk factors for epithelial ovarian cancer include a protective
effect of pregnancy, breast-feeding, and oral contraceptive use. A popular theory to
accountforthesefindingsisthattheseeventsleadtoabreakinmonthlyovulationsand,
therefore, repeated disruption and healing of the surface of the ovary (incessant
ovulation),leadingtoovariancancer(76).Withthenewappreciationfortheimportanceof
thefallopiantubes,theeffectofovulation onfimbriae,including exposuretothe cytokinerichfollicularfluid,mustbeconsidered(73).
An alternative theory to incessant ovulation is that ovarian cancer may arise from
excessivegonadotropinstimulationoftheovary(77). Classicanimal models forovarian
cancer have involved disruption of ovarian–pituitary feedback, either by prematurely
destroyingoocytesusingradiationorchemicaltoxinsorbytransplantingtheanimal’sovary
to its spleen, leading to enhanced metabolism of ovarian hormones before they can exert
feedback inhibition (78–80). A role for gonadotropins was indicated by observations that
ovarian tumors did not develop in rodents who were hypophysectomized before the
experimentaltreatment,orwho were given estrogen, which inhibited gonadotropin release
(81,82).Gonadalstromaltumorsinvariablydevelopedinmicewithatargeteddeletionofthe
geneforthegonadotropindownregulator,α-inhibin,unlessthemicewerealsoincapableof
secretinggonadotropins(83,84).
Thereissomesupportingepidemiologicdata,includingthatovariancancerincidencerises
sharply between the ages of 45 and 54, and remainselevated for the remainderof a
woman’s life, paralleling gonadotropin levels over this period. In addition, the strong
protectiveassociationbetweenoralcontraceptivesandovariancancerduplicatestheeffectof
exogenousestrogenintheanimalmodels(85).However,thetumorsintheseanimalmodels
were stromal, not epithelial, and there does not appear to be a strong and consistent
associationbetween use of fertility drugs and ovariancanceras might be predicted by the
gonadotropintheory(86–88).Finally,cohortstudies donot suggestthatlow anti-mullerian
hormone levels (a signal of decreased ovarian reserve) increase the risk of ovarian cancer
(89).
Anothertheory gaining credibility is that ovarian cancer may relate to inflammatory
processesinvolvingtheovary(90). Apostulateofthis theory is thatpelvicinflammatory
disease(PID)shouldincreasetheriskforovariancancer,and,indeedameta-analysisof13
case-controlledstudiessuggestedthatPIDmayincreasetheriskforborderlineovarian
tumors(91). Becauserecall biascould haveaffectedtheconclusion fromthe case–control
studies,cohortstudiesareimportant.Atleasttwocohortstudiessuggestedanincreasedrisk
forovariancancer(92,93)forwomenwithPID,whileathirddidnot(94).BesidesPID,other
causes of ovarian inflammation may result from incessant ovulation or vaginal or uterine
contaminants that reach the ovary. One such contaminant might be talc used in genital
hygiene,whichhasbeenfairlyconsistentlyidentifiedasariskfactorforovariancancer
(95,96).TalcusedingenitalhygienewasdeclaredapossiblecarcinogenbytheInternational
AgencyforResearchonCancer(97–99).
Besidestalc,anotherpelvic“contaminant”mightbemenstrualproducts,whicharebelieved
toflowoutofthefallopiantubesduringmenstruationtoexplainendometriosis(100).Indeed,
priorendometriosisisariskfactorforovariancancer,especiallytheendometrioidand
clearcelltypes(101,102).Thepelviccontaminationtheorymightexplainwhytuballigation
decreasestheriskofovariancancer(103).
Thetheorythatchronicinflammationmaybethepathwaytoovarian(andothercancers)has
prompted interest in anti-inflammatory drugs as a means of possible prevention. There is
reasonable evidence that aspirin use may reduce ovarian cancer risk (104,105). Risk
may also be decreased by statin use, another drug with possible anti-inflammatory effects
(106).
Anothertheorysuggestedisandrogenexcessandprogesteronedeficiency,butthisdoesnot
explaintheobservationsontalc,tuballigation,oranti-inflammatorydruguse(107).Noneof
thesetheoriesaccommodatetheobservationfromearlierstudiesthatahistoryofchildhood
mumps decreases the risk for ovarian cancer, or the recent observation that puerperal
mastitis may lower the risk (108,109). This observation, as well as other described risk
factors,areaccommodatedby a theory involvingimmuneeffectsrelatedto the surface
glycoprotein and tumor marker, human mucin 1 (MUC1) (110). MUC1 is a high–
molecular-weight protein expressed in a highly glycosylated form at low levels by many
types of normal epithelial cells, and in an underglycosylated form at high levels by most
epithelialadenocarcinomas,includingendometrial,breast,andovariancancer(111).
In cancer patients, anti-MUC1 antibodies may correlate with a more favorable prognosis
(112,113).Interestingly,anti-MUC1antibodiesarefoundinhealthyindividuals,especiallyin
womenduringpregnancyandlactation,leadingtothehypothesisthatanaturalimmunity
againsttumorMUC1mightdevelopandaccountforthelong-termprotectiveeffectof
pregnancyorbreast-feedingontheriskofbreastcancer(114).Thishasledtothebroader
theory that women who develop ovarian cancer may have had relatively fewer acute
inflammatoryevents,suchasmumps,atuballigation,mastitis,andothersthatmaylead to
anti-MUC1antibodies.They mayalsohavehadan excessof chronicinflammatoryevents,
such as incessant ovulation, endometriosis, and talc use that may downregulate MUC1
immunity,therebyleadingtotheemergenceofaMUC1-expressingcancersuchasovarian.
The observation that anti-MUC16 (CA125) antibodies may be raised by mastitis suggests
thatimmuneeventsrelatedtoCA125shouldbeconsidered(109).
Finally,thereareseveralgeneticriskfactorsemergingforovariancancer.Havingamotheror
sister with the disease increases a woman’srisk for ovarian cancer approximately two- to
threefold(115).SpecificgeneticfactorsincludemutationsoftheBRCA1andBRCA2and
theDNAmismatchgenes(116).Althoughthesegeneticfactorsaremorelikelytobefound
infamiliesinwhichanumberofrelativeswereaffectedwithbreastorovariancancer,they
maybefoundinupto44%ofwomenwithnosignificantfamilyhistory(117,118).Genome-
wide association studies (GWAS) have found small but significant increases in risk with
genetic variants located at 9p22 (in the BNC2 gene), 8q24, 2q31, 3q25, and 17q21
(16,119,120).
OtherGynecologicNeoplasms
Other than clear cell adenocarcinomas of the vagina associated with maternal use of
diethylstilbestrol,vaginalcarcinomaisprimarilyadiseaseofwomenolderthan50yearsof
age. Vulvar cancer has an age-incidence distribution similar to vaginal cancer. HPV
infection appears to play a role in both vaginal and vulvar cancers (121–124). In a
population-based case–control study, HPV was detected in more than 80% of the tumor
blocksfrompatientswithinsituvaginalcancerandin60%ofthosefrominvasivevaginal
cancers(122). For vulvar cancer, two types have been defined (121,122,124). The first,
whichaffectsyoungerwomen,isassociatedwithHPVandhasapreinvasivestage.The
second type occurs in older women and arises in areas with nonneoplastic epithelial
disorders such as lichen sclerosis. Risk factors known to exist for cervical neoplasms
also pertain to vulvar and vaginal neoplasms, including sexual history and smoking
(122,125–127). Dietary studies suggest that alcohol may increase the risk while vegetable
intakemaydecreasetherisk,butvalidationofthesestudiesisneeded(128,129).
Trophoblasticneoplasmsincludecomplete and partialhydatidiformmoles, invasive moles,
andchoriocarcinoma.Theepidemiologyofhydatidiformmoleisprobablybetterunderstood
than that of other trophoblastic diseases, and it is likely to be relevant because of the
associationbetweenmolarpregnancyandsubsequentinvasivemoleorchoriocarcinoma.The
prevalenceofmolarpregnancyis10timesmorecommoninAsia,Indonesia,andother
developing countries than in the United States (130). The risk of having a molar
pregnancyincreaseswith maternal age, but it is less certain whether adolescents are at
increased risk (131–133). A previous hydatidiform mole is a strong risk factor and
subsequent pregnancies have a 1% risk of being a choriocarcinoma (134). The peculiar
cytogeneticpatternsofcompleteandpartialhydatidiformmolesarediscussedinChapter15
andmayindicatetheimportanceofaberrantgermcellsintheoriginofthesedisorders.
Berkowitzetal.(135)suggestedthatdeficiencyofthevitaminAprecursor,carotene,orof
animalfatsnecessaryforitsabsorption,mightbeafactorinthecauseofthisdisease.
VitaminAdeficiencycausesfetalwastageandaberrancyofepithelialdevelopmentinfemale
animals,anddegenerationofseminiferousepitheliumwithpoorgametedevelopmentinmale
animals (136–138). Geographic regions where molar pregnancy is common have a high
incidenceofnightblindness(139).
Paternal blood group combinations may influence the risk of a molar pregnancy.
MotherswithgroupAbloodandfatherswithgroupAor0haveanincreasedriskcompared
with all other blood group combinations (140–142). Oral contraceptives are associated
withanincreasedrisk of hydatidiform mole that increases with duration of use. Tenor
moreyearsofuseareassociatedwithamorethantwofoldincreaseinrisk(143).Smoking
doublesthe riskofhydatidiform mole andquadruplesthe risk with 10 or moreyearsof
smoking (140,144,145). The roles of alcohol, asbestos, and infections (HPV, adenoassociatedvirusandtuberculosis)havealsobeenconsidered(146,147).
CancerPrevention
Cancerpreventionmayoccuratthelevelofprimaryprevention(theidentificationand
modification of risk factors for disease), secondary prevention (the detection of the
diseaseatearlier,moretreatablestages),ortertiaryprevention(effectivetreatmentof
clinicaldisease).Thissectionaddressesprimaryandsecondarymeasuresofprevention.
Methods of primary prevention are by no means certain, but suggestions include the
following:
1. Forcervicalcancer,HPVvaccineshaveprovenbenefitsandshouldbeadministeredin
adolescenceorearlierinbothgirlsand boys. Use of barrier methods of contraception,
avoidance of tobacco, and maintenance of a diet high in folates, B vitamins, and βcarotenemaybebeneficial.
2. Forendometrialcancer,maintenanceofidealbodyweight,avoidanceofahigh-fatdiet,
andavoidanceofunopposedestrogentherapyduringmenopausemaybebeneficial.
3. For ovarian cancer, use of oral contraceptives, if not medically contraindicated,
breastfeeding,andavoidanceoftalcingenitalhygienemaybebeneficial.Womenknown
to carry a predisposing mutation should undergo prophylactic salpingo-oophorectomy
afterthey have completedchildbearing.Because of thelinkbetween tubal and ovarian
cancer, it has been proposed that women undergoing hysterectomy who would not
otherwiserequireoophorectomyshouldhavetheirtubesremoved(148). Aclinicaltrial
hasbeeninitiatedtoevaluatewhetherwomenwhohaveaknowngeneticriskcansafely
delayoophorectomybyfirstundergoingbilateralsalpingectomy(149).
Table7.5MeasuresofValidityforaScreeningProcedure
SecondaryPrevention
Detecting disease at a stage when it is more curable may prevent cancer deaths.The
secondarypreventionofcervicalcancerissuccessful,and screeningprogramsforthe other
gynecologiccancersmayeventuallybedevised.
To be successful, a screening program must be directed at a “suitable” disease with a
“suitable”screeningtest(150).Asuitablediseasemustbeonethathasseriousconsequences,
as most cancers do. Treatment must be available so that when such therapy is applied to
screen-detected (preclinical) disease, it will be more effective than when applied after
symptomsof the diseasehave appeared. Thepreclinical phase ofthe disease mustbe long
enoughthat the chancesaregood thataperson will bescreened.There mustbea suitable
screeningtestasdefinedby simplicity,acceptabilitytopatients,lowcost,andhighvalidity
(definedbythemeasuresinTable7.5).
TestDefinitions
Sensitivity
The sensitivity of a test is defined as the proportion of people with a true positive
screeningresultofallthosewhohavethedisease.
Specificity
The specificity of a test is defined as the proportion of people with a true negative
screeningresultofallthosewhodonothavethedisease.
PredictiveValue
Thepredictivevalueofapositivetestisdefinedastheproportionoftruepositivesoutof
all those who screened positive. The alternate formula shown in Table 7.5 reveals that
predictivevalueisafunctionofsensitivity,specificity,anddiseaseprevalence.Thisfunction
implies that a positive screening test is more likely to indicate disease in a high-risk
populationthaninalow-riskpopulation.Positivepredictivevaluecannotbecalculatedfrom
a case–control study, because the ratio of cases to controls is set by design and does not
reflectdiseaseprevalenceinthegeneralpopulation.
ScreeningStrategies
Cervical cytology represents one of the most effective screening tests for cancer ever
developed;controversies relate to how to makeitmore efficient. Guidelines suggestedby
the American Cancer Society are that the interval between screenings may be safely
lengthenedto 3 years in women who have at least threeconsecutivenegative screens
and are at otherwise low risk (e.g., no history of immunosuppression) (151). Similar
guidelines were proposed by the American College of Obstetricians and Gynecologists in
2000,althoughthelessfrequentintervalsweretobeatthediscretionofthephysician(152).
Ananalysis of the potentialeffects ofextendingscreening intervals fromannuallyto once
every 3 years concluded that an average excess risk of three cases of cervical cancer per
100,000womenscreenedwouldresult(153).However,toavertoneadditionalcaseofcancer
byscreeningwomenannuallyfor3yearsratherthanonceevery3yearswouldnecessitate
approximately280,000additionalPaptestsand15,000colposcopicexaminations.
HPV testing, which involves detection of HPV DNA in a cervical swab, can greatly
improvethesensitivityofthetraditionalPaptesttoidentifyhigh-gradeCINinwomen
ages30to69years.Ina studyof10,154 womenaged30to69years,theHPVtesthada
muchhighersensitivity(95%)thanthePaptest(55%),andsimilarspecificity(95%forHPV
testingand97%forthePaptest).UsingHPVtestingtogetherwiththePaptestincreasesthe
sensitivity to 100% (154). A cost–benefit analysis revealed that the maximum number of
liveswouldbe saved when combined HPVand Pap test screening was performed every2
yearsuntildeath(155).FurtherdiscussionofthistopicisfoundinChapter8.
Screeningforendometrialcancerinasymptomaticwomeninthegeneralpopulationis
not justified, but endometrial biopsies or assessment of the endometrial stripe by
transvaginal ultrasound may be appropriate for perimenopausal or postmenopausal
womenat risk for endometrial cancer,including those who are obese, areexposed to
unopposed estrogen, use tamoxifen, or come from families with both colon and
endometrialcancer(i.e.,familieswithLynchsyndrome).
Thereisnoeffectivescreeningtestforovariancancer(156).Alargerandomizedtrialof
annual screening with CA125 with transvaginal ultrasound showed no benefit (157). A
similar trial in the United Kingdom showed no clinically meaningful benefit. Though the
searchforascreeningbiomarkerforovariancancerisongoing,nobiomarkerstodatehave
performed better than CA125 alone (158,159). However,new advances in proteomic and
metabolomicmeasurementwithbetterreproducibilityonsmallersamplevolumesthanbefore
opennewopportunitiesfordiscovery.
Acknowledgment
NaokoSasamotoforherassistanceinupdatingthefiguresandtables.
References
1. RosnerB.FundamentalsofBiostatistics,17thed,2010.
2. Rothman KJ, Lash TL, Greenland S. Modern epidemiology. In: Wilkins LW, ed. Modern Epidemiology. 3rd
(Reviseded.).Philadelphia,PA:WoltersKluwer;2012.
3. Howlader N, Noone AM, Krapcho M, et al., eds. SEER Cancer Statistics Review,1975–2016, National Cancer
Institute. Bethesda, MD. Available at https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data
submission,postedtotheSEERwebsite,April2019.
4. WartkoP,ShermanME,YangHP,etal.Recentchangesinendometrialcancertrendsamongmenopausal-ageU.S.
women.CancerEpidemiol2013;37(4):374–377.
5. TorreLA,TrabertB,DeSantisCE,etal.Ovariancancerstatistics,2018.CACancerJClin2018;68(4):284–296.
6. Chan JK, Cheung MK, Husain A, et al. Patterns and progress in ovarian cancer over 14 years. Obstet Gynecol
2006;108(3Pt1):521–258.
7. SopikV,IqbalJ,RosenB,etal.Whyhaveovariancancermortalityratesdeclined?PartI.Incidence.GynecolOncol
2015;138(3):741–749.
8. LiaoCI,ChowS,ChenLM,etal.Trendsintheincidenceofserousfallopiantube,ovarian,andperitonealcancerin
theUS.GynecolOncol2018;149(2):318–323.
9. HennekensCH,BuringJ.EpidemiologyinMedicine.1sted.In:MayrentSL,ed.Boston/Toronto:Little,Brownand
Company;1987.
10. Colditz GA, Hankinson SE. The Nurses’ Health Study: lifestyle and health among women. Nat Rev Cancer
2005;5(5):388–396.
11. AltmanDG.PracticalStatisticsforMedicalResearch.LondonChapmanandHallCRC;1991.
12. RosnerB,ed.FundamentalsofBiostatistics.5thed.PacificGrove,CA:DuxburyThompsonLearning;2000.
13. HillAB.TheEnvironmentanddisease:Associationorcausation?ProcRSocMed1965;58:295–300.
14. CollaborativeGrouponEpidemiologicalStudiesofOvarianCancer;BeralV,DollR,HermonC,etal.Ovarian
cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257
womenwithovariancancerand87,303controls.Lancet2008;371(9609):303–314.
15. Muscat JE, Huncharek MS. Causation and disease: biomedical science in toxic tort litigation. J Occup Med
1989;31(12):997–1002.
16. BoltonKL,TyrerJ,SongH,etal.Commonvariantsat19p13areassociatedwithsusceptibilitytoovariancancer.Nat
Genet2010;42(10):880–884.
17. SingerA.Thecervicalepitheliumduringpubertyandadolescence.In:JordanJA,SingerA,eds.TheCervix.London:
WBSaunders;1976:87–104.
18. International Collaboration of Epidemiological Studies of Cervical Cancer. Cervical carcinoma and sexual
behavior: collaborative reanalysis of individual data on 15,461 women with cervical carcinoma and 29,164 women
without cervical carcinoma from 21 epidemiological studies. Cancer Epidemiol Biomarkers Prev2009;18(4):1060–
1069.
19. Oakeshott P, Aghaizu A, Reid F, et al. Frequency and risk factors for prevalent, incident, and persistent genital
carcinogenic human papillomavirus infection in sexually active women: community based cohort study. BMJ
2012;344:e4168.
20. RositchAF,BurkeAE, Viscidi RP,etal. Contributionsof recent and past sexual partnerships on incident human
papillomavirusdetection:acquisitionandreactivationinolderwomen.CancerRes2012;72(23):6183–6190.
21. SyrjanenK,HakamaM, SaarikoskiS,etal.Prevalence,incidence,andestimatedlife-time riskofcervicalhuman
papillomavirusinfectionsinanonselectedFinnishfemalepopulation.SexTransmDis1990;17(1):15–19.
22. DunneEF,UngerER,SternbergM,etal.PrevalenceofHPVinfectionamongfemalesintheUnitedStates.JAMA
2007;297(8):813–819.
23. SchiffmanM,DoorbarJ,WentzensenN,etal.Carcinogenichumanpapillomavirusinfection.NatRevDisPrimers
2016;2:16086.
24. KoutskyLA,AultKA,WheelerCM,etal.Acontrolledtrialofa humanpapillomavirustype16vaccine.NEnglJ
Med2002;347(21):1645–1651.
25. KahnJA,BurkRD.Papillomavirusvaccinesinperspective.Lancet2007;369(9580):2135–2137.
26. SavageL.ProposedHPVvaccinemandatesrilehealthexpertsacrossthecountry.JNatlCancerInst2007;99(9):665–
666.
27. JemalA,SimardEP,DorellC,etal.AnnualReporttotheNationontheStatusofCancer,1975–2009,featuringthe
burdenand trendsin human papillomavirus(HPV)-associated cancers and HPV vaccination coverage levels. JNatl
CancerInst2013;105(3):175–201.
28. KiviatNB,HawesSE,FengQ.ScreeningforcervicalcancerintheeraoftheHPVvaccine—theurgentneedforboth
newscreeningguidelinesandnewbiomarkers.JNatlCancerInst2008;100(5):290–291.
29. Barnabas RV, Laukkanen P,Koskela P, et al. Epidemiology of HPV 16 and cervical cancer in Finland and the
potentialimpactofvaccination:mathematicalmodellinganalyses.PLoSMed2006;3(5):e138.
30. ChoiYH,JitM,GayN,etal.Transmissiondynamicmodellingoftheimpactofhumanpapillomavirusvaccinationin
theUnitedKingdom.Vaccine2010;28(24):4091–4102.
31. Editorial.CheaperHPVvaccinesneeded.Lancet2008;371(9625):1638.
32. InternationalCollaborationofEpidemiologicalStudiesofCervicalCancer;ApplebyP, Beral V,Berringtonde
GonzalezA,etal.Carcinomaofthecervixandtobaccosmoking:collaborativereanalysisofindividualdataon13,541
women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological
studies.IntJCancer2006;118(6):1481–1495.
33. BrintonLA,BarrettRJ,BermanML,etal.Cigarettesmokingandtheriskofendometrialcancer.AmJEpidemiol
1993;137(3):281–291.
34. Schiffman MH, Haley NJ, Felton JS, et al. Biochemical epidemiology of cervical neoplasia: measuring cigarette
smokeconstituentsinthecervix.CancerRes1987;47(14):3886–3888.
35. Eldridge RC, Pawlita M, Wilson L, et al. Smoking and subsequent human papillomavirus infection: a mediation
analysis.AnnEpidemiol2017;27(11):724–730e1.
36. FerreraA,VelemaJP,FigueroaM,etal.Co-factorsrelatedtothecausalrelationshipbetweenhumanpapillomavirus
andinvasivecervicalcancerinHonduras.IntJEpidemiology2000;29:817–825.
37. VelemaJP,FerreraA,FigueroaM, et al.Burning wood inthe kitchen increasesthe risk ofcervical neoplasia in
HPV-infectedwomeninHonduras.IntJCancer2002;97(4):536–541.
38. ApplebyP,Beral V, Berrington de GonzalezA,etal. Cervical cancerand hormonal contraceptives:collaborative
reanalysisofindividualdatafor16,573womenwithcervicalcancerand35,509womenwithoutcervicalcancerfrom
24epidemiologicalstudies.Lancet2007;370(9599):1609–1621.
39. RouraE,TravierN,WaterboerT,etal.Theinfluenceofhormonalfactorsontheriskofdevelopingcervicalcancer
andpre-cancer:resultsfromtheEPICcohort.PLoSOne2016;11(1):e0147029.
40. ChihHJ,LeeAH,ColvilleL,etal.Areviewofdietarypreventionofhumanpapillomavirus-relatedinfectionofthe
cervixandcervicalintraepithelialneoplasia.NutrCancer2013;65(3):317–328.
41. GonzalezCA,TravierN,Lujan-BarrosoL,etal.Dietaryfactorsandinsituandinvasivecervicalcancerriskinthe
Europeanprospectiveinvestigationintocancerandnutritionstudy.IntJCancer2011;129(2):449–459.
42. Zhang X, Dai B, Zhang B, et al. Vitamin A and risk of cervical cancer: a meta-analysis. Gynecol Oncol
2012;124(2):366–373.
43. ChenD,Juko-PecirepI,HammerJ,etal.Genome-wideassociationstudyofsusceptibilitylociforcervicalcancer.J
NatlCancerInst2013;105(9):624–633.
44. MaimanM,FruchterR,SeldlisA,etal. Prevalence, risk factors, and accuracyofcytologicscreeningfor cervical
intraepithelialneoplasiainwomenwiththehumanimmunodeficiencyvirus.GynecolOncol1998;68:223–229.
45. ShiY,LiL, Hu Z, et al.Agenome-wideassociationstudyidentifies two new cervicalcancer susceptibility loci at
4q12and17q12.NatGenet2013;45(8):918–922.
46. Key TJ, Pike MC. The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its
centralroleinexplainingandpredictingendometrialcancerrisk.BrJCancer1988;57(2):205–212.
47. ElwoodJM,ColeP,RothmanKJ,etal.Epidemiologyofendometrialcancer.JNatlCancerInst1977;59(4):1055–
1060.
48. EwertzM,SchouG,BoiceJDJr. The joint effect of risk factors onendometrialcancer.Eur JCancer Clin Oncol
1988;24(2):189–194.
49. KalandidiA,TzonouA,LipworthL,etal.A case-controlstudy of endometrial cancer in relation to reproductive,
somatometric,andlife-stylevariables.Oncology1996;53(5):354–359.
50. Kelsey JL, LiVolsi VA, Holford TR, et al. Acase-control study of cancer of the endometrium. Am J Epidemiol
1982;116(2):333–342.
51. KoumantakiY,TzonouA,KoumantakisE,etal.A case-control study of cancer of endometrium in Athens. Int J
Cancer1989;43(5):795–799.
52. KvaleG,HeuchI,UrsinG.Reproductivefactorsandriskofcanceroftheuterinecorpus:aprospectivestudy.Cancer
Res1988;48(21):6217–6221.
53. McPhersonCP,SellersTA,PotterJD,etal.Reproductivefactorsandriskofendometrialcancer.TheIowaWomen’s
HealthStudy.AmJEpidemiol1996;143(12):1195–1202.
54. CalleEE,KaaksR. Overweight, obesityandcancer: epidemiological evidence andproposedmechanisms. NatRev
Cancer2004;4(8):579–591.
55. MooreK,BrewerMA.EndometrialCancer:IsThisaNewDisease?AmSocClinOncolEducBook2017;37:435–442.
56. GradyD,GebretsadikT,KerlikowskeK,etal.Hormonereplacementtherapyandendometrialcancerrisk:ameta-
analysis.ObstetGynecol1995;85(2):304–313.
57. FisherB,CostantinoJP, Wickerham DL, etal.Tamoxifenforpreventionofbreast cancer: report of theNational
SurgicalAdjuvantBreastandBowelProjectP-1Study.JNatlCancerInst1998;90(18):1371–1388.
58. BeresfordSA,WeissNS,Voigt LF,etal.Riskofendometrialcancerin relationtouseofoestrogencombined with
cyclicprogestagentherapyinpostmenopausalwomen.Lancet1997;349(9050):458–461.
59. WeissNS,SayvetzTA. Incidence ofendometrialcancerinrelation to the use oforalcontraceptives.NEngl J Med
1980;302(10):551–554.
60. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal
Estrogen/ProgestinInterventions(PEPI)Trial.TheWritingGroupforthePEPITrial.JAMA1996;275(5):370–375.
61. JansenD,OstergaardE.Clinicalstudiesconcerningtherelationshipofestrogenstothedevelopmentofcancerofthe
corpusuteri.AmJObstetGynecol1954;67:1094–1102.
62. FrischRE,WyshakG,AlbrightNL,etal.Lowerprevalenceofbreastcancerandcancersofthereproductivesystem
amongformercollegeathletescomparedtonon-athletes.BrJCancer1985;52(6):885–891.
63. Patel UD, Grab J, Kosiborod M, et al. Impact of anemia on physical function and survival among patients with
coronaryarterydisease.ClinCardiol2008;31(11):546–550.
64. LeskoSM,RosenbergL,KaufmanDW,etal.Cigarettesmokingandtheriskofendometrialcancer.NEnglJMed
1985;313(10):593–596.
65. SpeertH.Endometrialcancerandhepaticcirrhosis.Cancer1949;2(4):597–603.
66. BenshusahnA, PaltielO, RojanksyN, et al. IUD use and the risk for endometrial cancer.EurJ Obstet Gynecol