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AngelitoDLMagno,M.D.,FPOGS,FSGOP,FPSCPCDeLaSalleHealthScienceInstitute
March24,2017
� MostcommonmalignancyofthefemalegenitaltractintheUSandotherdevelopedcountries
� PerimenopausalandPostmenopausalage(50-65yearsold)
� 10-15%-youngerthan50years� 5%-womenlessthan40yearsold
Normal Hyperplasia Cancer
UnopposedEstrogen
� Anabnormal,non-invasiveproliferationoftheendometriumresultingfromglandularandstromalalterations
� abnormallyhigh,prolongedlevelofestrogenicstimulationwithdiminutionorabsenceofprogestationalactivity
� Occursmostcommonlyaroundmenopauseorinassociationwithpersistentanovulationinyoungerwomen
WHOClassificationSimplehyperplasiawithoutatypia
ComplexhyperplasiawithoutatypiaSimplehyperplasiawithatypia
Complexhyperplasiawithoutatypia
� anendometriumwithdilatedglandswithsomeoutpouchingandabundantendometrialstroma
� weaklypremalignant
• Glandsarenotoverlycrowded,butmayshowmarkedvariationinsize
• Glandularepitheliummaybepseudostratifiedtomodestlystratified
• Stromaisuniformlycellularandcontainsmultiplebloodvessels
� Glandsarecrowded,� Verylittleendometrialstroma� Verycomplexglandpatternandoutpouchingformations
� alowmalignantpotential
• glandsthataremarkedlyvariableinsizeandshape,withsidebudsandoutpouchings
� hyperplasiathatcontainsglandswithcytologicatypia
� Highlypremalignant� Increasednuclear-to-cytoplasmicratio,withirregularityinthesizeandshapeofthenuclei
� Cytologicatypiaoccursprimarilywithcomplexhyperplasia
� Simplehyperplasiawithatypiaisrarelyseen
� cellulardyspolarity� irregularstratification� anisocytosis,accompaniedbynuclearrounding(ascomparedwiththeuniformcolumnarnucleiofhyperplasiaswithoutatypia),
� Nucleomegaly� hyperchromatism,� chromatinclumping� enlargednucleoli
� Cellulardispolarity,irregularstratificationandanisocytosis
� Nuclearrounding,nucleomegaly,hyperchromatism,chromatinclumping
� Simplehyperplasiawithatypiaisrarelyseen
� Endometrialproliferationanddifferentiationdependsonestrogenandprogesteroneeffects
� Regulatedbythequalityofthemenstrualcyclefunctionandotherfactors.
• Unopposedestrogenstimulatesendometrialcellgrowthbybindingtoestrogenreceptors
EarlyMenarche
� Obesityisastrongriskfactorforendometrialhyperplasiaandcancer
� BMI>30:2-3xincreasedrisk� Androstenedioneconversiontoestrogeninadiposetissueincreasedestrogenlevels
� decreasedsexhormone-bindingglobulin� insulinresistance
� 4-8xincreasedriskforawomanusingestrogenaloneformenopausalreplacementtherapy
� Associatedwithhigherdose(>0.625mgconjugatedestrogens),andmoreprolongeduse
� Markedlyreducedwiththeuseofprogestin� Combined(progestin-containing)oralcontraceptivesdecreasetherisk
� Relativeriskreductiontoapproximately0.5� Theprotectionbeginsafter1yearofuseandlastsapproximately15yearsafterdiscontinu-ation.
� Otherconditionsleadingtolong-termestrogenstimulationoftheendometrium
� Polycysticovarysyndrome(Stein-Leventhalsyndrome)–chronicanovulation
� Rarefeminizingovariantumors,likeGranulosacelltumor-estrogenproducingtumors
� SelectiveEstrogenReceptorModulator(SERM)� Anti-estrogenreceptorinthebreastbutnotintheendometrium
� 7.5-foldincreasedrisk� Riskincreasedwithdurationofuse� Endometrioidhistologyandlowendometrialcarcinomagradeandendometrialcarcinomastage
� Transvaginalultrasound:8mm(higherthanthepostmenopausalageendometrialthicknesscutoffof5mm
� Highfalse-positiveratebecausetamoxifencausessubendometrialcystformation,whichmakestheendometrialstripeappearabnormallythick
� Routineofficeendometrialsamplingonlyyieldedveryfewendometrialcancer
� Endometrialsamplingisonlyrecommendedtouserswithuterinebleeding
� Nulliparity:2xincreasedrisk-continuousestrogenstimulation
� Diabetes:2.8xincreasedrisk-lowsex-hormonebingdingglobulin
� HereditaryNonPolyposisColorectalCancersyndrome(HNPCC)
� AutosomaldominanthereditarycancersusceptibilitysyndromecausedbyagermlinedefectinaDNAmismatchrepairgene(MLH1,MSH2,orMSH6).
� 40%to60%lifetimeriskfordevelopingendometrialcancer
� 40%to60%lifetimeriskofdevelopingcoloncancer� 12%lifetimeriskofdevelopingovariancancer.
� Abnormalvaginalbleedingisthemostfrequentsymptomofendometrialhyperplasia
� oligomenorrheaoramenorrheaduringanovulation
� Premenopausalwomenwithirregularvaginalbleeding
� Post-menopausalwomenwithanyvaginalbleeding� Officesamplinginstruments,suchasathinplasticpipelle
� Threshold:Endometrialthickness
� Reproductiveage� Proliferativephase:8mm� Secretoryphase:upto1.4cm
� Postmenopausalage:<5mm
� NotausefultoolforasymptomaticTamoxifenusers
� Endometrialstripe:<4mmhasa100%negativepredictivevalue
� However,persistentvaginalbleedingshouldleadtoendometrialsampling,regardlessoftheultrasoundfindings.
� Endometrialablationhasnoroleinunevaluatedendometrialpathology
HYSTEROSALPINGOGRAPHY� Laifer-Narin,et.al(2001)
� Sensitivity:98.9%� Specificity:76.4%
HYSTEROSCOPY� Togetherwithbiopsy,consideredthegoldstandardfortheinvestigationofwomenwithsymptomsofendometrialpathology
� Protective effect lies in its anti-estrogen effect � Reducing the estrogen receptor content � Inhibition of the increased conversion of estradiol
• Progesteronereducesnumberofestrogenreceptors
• increasestherateofconversionofestradiol(ac7veestrogen)toestrone(inac7ve)
• increasesac7vityofestradioldehydrogenase
� Medroxyprogesterone acetate (Provera) � Use of MPA 10 mg daily cyclically during 11 to 14 days for 3 to 6
months and 10 mg daily continuously for 3 months and cyclically thereafter in cases of hyperplasia with atypia.
� Regression to normal: 86% � Recurrence:10% � In atypical hyperplasia:
-50% persisted
� Norethisterone � 15 mg/day for 10 days per cycle � Pafumi, et.al (2002)
� reduced the incidence of bleeding and spotting with a sufficient endometrial protection from hyperplasia
� Megestrol acetate � 40-160 mg daily � prevent and reverse endometrial hyperplasia
� 19-nortestosterone derivative leading to atrophy and inactivation of the endometrial lining
� Released at a rate of 20 ug daily � Varma et.al.: 90% regression by
24 months
� Formedicallyunstablepatients(hysterectomyisnotadvisable)
� Periodicsamplingoftheendometriumisalsoperformed(every3months)
� Periodicprogestintreatmentororalcontraceptionforwomennotdesirousofpregnancy
� Inductionofovulationwithclomiphenecitrate(Clomid)
� Weightreductionforveryobesepatientsisalsoadvised
� Resistant to medical management (no change after 3 months of medical treatment)
� Standard of treatment for atypical hyperplasia
TYPE %REGRESSION
%PERSISTENCE %PROGRESSION
Simple 80 19 1
Simplewithatypia 69 23 8
Complex 80 17 3
Complexwithatypia 57 14 29
Alllesionswithatypia 58 19 23
� Complexatypicalhyperplasiashadthehighestriskofprogressiontocarcinoma
� Simplehyperplasiahada1%rateofprogressiontocancer
� Complexhyperplasiawithoutatypiahada3%rateofprogressiontocancer,
� Complexatypicalhyperplasiahada29%rateofprogressiontocancer
� GynecologicOncologyGroup(GOG)study� 40%ofwomenwithcomplexatypicalhyperplasiahaveendometrialcancerintheirhysterectomyspecimen
� Forwomendiagnosedwithendometrialhyperplasiabybiopsy,exclusionofaconcurrentendometrialmalignancyshouldbedone.
� Endometrialhyperplasiaisarelativecontraindicationtoendometrialablation.Itisparamounttoexcludehyperplasiaorcancerbeforeablatingtheendometrium.
� itisrecommendedtoperformultrasoundandendometrialsamplingafter3monthsofhormonaltreatment,preferablyperformedafterwithdrawalofthetreatingdrugandcompletionofawithdrawalbleed.
� Thereisnodefiniteoptimaltreatmentdosesanddurationforhormonaltherapyofendometrialhyperplasia.