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.