病理学生殖系统疾病2015june liugy

ThediseasesofGenitalSystem

(生殖系统疾病）刘国元gyliu@PathologyDepartment,SchoolofBasicMedicalSciences,FudanUniversityFemaleGenitalSystemMaleGenitalSystemThecommondiseasesChronicCervicitis(慢性宫颈炎）CarcinomaoftheCervix(宫颈癌）GestationalTrophoblasticTumors(绒毛膜滋养细胞肿瘤）CarcinomaoftheBreast(乳腺癌)NodularhyperplasiaoftheProstate(前列腺结节状增生)CarcinomaoftheProstate(前列腺癌）一、DiseasesofCervix

ChroniccervicitisTumorsNormalcervixNormalcervixSchematicofthedevelopmentofthecervicaltransformationzone宫颈移行区在青春期或妊娠期，由于雌激素水平身高，子宫颈柱状上皮增生并外移,子宫颈被完整的柱状上皮所覆盖ChronicCervicitisChronicCervicitisEtiologyandTypesofchroniccervicitis1.Specific:tuberculosis,gonorrhea(淋病),HSV2.Nonspecific:manytypesofgermsandviruses3.Somedegreeofcervicalinflammationmaybefoundinvirtuallyallmultiparousandinmanynulliparousadultwomenwithlittleclinicalconsequence.Pathologicalclassifications糜烂型：最常见复层鳞状上皮脱落为单层柱状上皮增生下移所取代颗粒型：真性糜烂增生型：腺体腺瘤样增生囊泡型：Nabothian囊肿（纳博特囊肿）肥厚型：子宫脱垂肥厚增大2-3倍鳞状上皮和纤维结缔组织增生伴有：宫颈管上皮和腺体鳞状化生

宫颈息肉ChronicCervicitisErosiveectoandendocervicitisduetoHSVinfectionInflammatoryinfiltrate:polymorphonuclearleukocytesandmononuclearcells.Ifsevere,thelossoftheepitheliallining(erosionorulceration)andepithelialrepair(reparativeatypiaordysplasiaofrepair).MicroscopyNabothianCyst(纳博特囊肿，粘液潴留性囊肿）

Overgrowthoftheregeneratingsquamousepitheliumblockstheorificesofendocervicalglandsleadingtocysticdilationoftheseglands增生的鳞状上皮覆盖或阻塞子宫颈管腺体开口，使粘液潴留，腺体扩大呈囊，形成子宫颈囊肿Cervicalpolyp(宫颈息肉）

usuallyoccurinendocervicalcanalwithproliferationofmucosaepitheliumtoformfingerlikeinflammatorypolyp宫颈粘膜、腺体和间质结缔组织局限性增生形成PolypusInsquamousmetaplasia,thenucleimaybelargerandmoreimmatureappearingandthecytoplasmmoredense.Squamousmetaplasia鳞状上皮化生宫颈管内膜的柱状上皮为成熟的复层鳞状上皮替代Squamousmetaplasiaatthetransitionzone.Mature

squamousepitheliumSquamousmetaplasiaCurablePersistedchronicinflammationColumnarSquamousmetaplasia

Dysplasia

CervicalCarcinomaconsequence?CervicalCarcinoma

(宫颈癌)TumorsoftheCervicalthe2ndcommonestfemalemalignancyCIN——cervicalintraepithelialneoplasiaInvasivecarcinomaEpidemiologyPeakageCIN--30yInvasivecarcinoma--45yTransformationzoneSquamousCa.（75%）adenocarcinoma(20%)NeuroendocrineCa.(lessthan5%)RiskFactors:MajorEarlyageatfirstintercourseMultiplesexualpartnersAmalepartnerwithmultipleprevious sexualpartnerspersistentinfectionby“high-risk”papillomavirusesMinorSmokingLowersocialclassImmunosuppressione.g.HIV,post-transplantSlightincreaseinriskwithuseofcombinedoralcontraceptiveNon-attendanceatcervicalscreeningprogram(Papsmear).HPVinfectionEtiologyandPathogenesisCondyloma(尖锐湿疣)CINLowriskHPV-6

HPV-11

HPV-42HPV-44HPVinfectionsHighriskHPV-16

HPV-18HPV-31

HPV-33

HPV-35EtiologyandPathogenesisEncode

E6E7proteinHPVinfectionsTP53Growthinhibitors

TP53RB

hyperphosphorylatedRB

hypophosphorylatedRBPathogenesis：Predilectionsite:TransformationZoneHPVsinfectimmaturebasalcellsofthesquamousepitheliuminareasofepithelialbreaks,orimmaturemetaplasticsquamouscellspresentatthesquamocolumnarjunction.Sequenceofevents:HPVinfection--precancerouslesion(CIN)invasivecarcinoma

Cervicalintraepithelialneoplasia

(宫颈上皮内肿瘤，CIN)定义：宫颈上皮部分被不同程度的异形性细胞取代。Precancerouslesionofcervicalcarcinoma

GradingCINI:MilddysplasiaCINII:ModeratedysplasiaCINIII:SeveredysplasiaandcarcinomainsituLatentperiod：Aslongas20yrsPapsmearscreening:CytologicexaminationCervicalintraepithelialneoplasia

(宫颈上皮内肿瘤，CIN)MicroscopyCINI:limitedinthelower1/3layersoftheepithelium

CINII:limitedinthelower2/3layersoftheepithelium

CINIII:alllayersoftheepithelium,noinvasionNormalCINICINIICINIIILowgrade,LSILSquamousintraepitheliallesionHighgrade,HSILCervicalintraepithelialneoplasiaKoilocyte(凹空细胞):

AsquamouscellwithHPVvirus.Thenucleiarehyperchromatic(dark)andraisinoid,crinkly;(seearrows),withasurroundingclearhalointhecytoplasm.细胞核深染，皱缩，核周胞质有空晕Low-gradesquamousintraepitheliallesion,LSIL低级别上皮内肿瘤KoilocytesCINI，扁平湿疣Thenucleiarehyperchromaticandmayhaveslightlyirregularnuclearoutlines,butthemoststrikingfeatureatlowpoweristhehighnuclear/cytoplasmicratiospresentfromtoptobottom.High-gradesquamousintraepitheliallesion,HSILCINII&IIICervicalintraepithelialneoplasiaGrossmorphology1.Carcinomainsituisverydifficulttobedistinguishedfromchroniccervicitis2.Schiller’sTest碘溶液涂抹实验：癌细胞内缺乏糖原，不显红棕色。Cytologicexamination:Papsmear巴氏涂片-用于宫颈癌的筛查与预防。取宫颈外口鳞柱上皮交界处的细胞标本涂在玻片上，经巴氏染色后在显微镜下观察。

50%-60%regression逆转30%persistence

20%CINIII1%-5%invasivecarcinoma(20years)33%regression6%-74%progressionCondylomahundredsofthousands/yrCINmillion/yrHigher-gradeCIN300,000/yrInvasivecancer15,000/yrMetastasis5000/yr

CINI

CINIIIPrevalenceIncidenceNormalCINbasilarmembraneCervicalintraepithelialneoplasiaInvasivecarcinomaofthecervix

(浸润性宫颈癌)Grossmorphology3types:

cauliflower-like(菜花型) ulcer(溃疡型) diffuselyinvasive(弥漫浸润型)spreadtothepelvisStage0carcinomainsituStageIThelesionislimitedinthecervixIainvasivelesion<5mmIbinvasivelesion>5mm，nospreadtothecervicalaroundtissueStageIItumorspreadtothecervicalaroundtissue,buthasnottothepelvis.Spreadtothevagina,buthasnottothelower1/3.StageIIItumorspreadtothelower1/3vaginatissueortothepelvis.StageIVtumorspreadstothetissueoutsidethepelvis,orinfiltratesbladderorrectum.5Stages分期Invasivecarcinomaofthecervixlimitedtothecervix(stageI)0stage：carcinomainsituIa：invasivelesion<5mmIb：invasivelesion>5mmBroadfrontsofcellspushintothestromaofthecervix,andattheleadingedgethereisaraggedborderwithindividualinfiltratingcells(arrowhead).Occasionalhugeandpleomorphiccellsarevisible(arrow).AdenocarcinomaAdenocarcinomainsitu.Thisfieldshowssomeresidualnormalendocervicalglands(arrowhead)adjacenttoaveryabnormalpopulationwithdark,elongated,crowded,andstratifiednucleirepresentingadenocarcinomainsitu.InvasiveadenocarcinomaClinicalPathologicconference(CPC,临床与病理联系)CIN:NoclinicalmanifestationorthemanifestationofchroniccervicitisInvasivecarcinoma:bleedingaftertouch.Inadvancedcases:unscheduledvaginalbleeding,leukorrhea（白带）,painfulcoitus,dysuria（排尿困难）,secondaryinfection,fistulabetweenrectumandvagina,orbladderandvagina,remotemetastasis.

Sign:Inearly-stage,examinationcanberelativelynormal.whiteorredpatchesonthecervix.Rectalexamination:amassorbleedingduetoerosion.Bimanualpalpation:pelvicbulkiness/massesduetopelvicspread.Legedemamaydevelopduetolymphaticorvascularobstruction.Hepatomegalymaydevelopinthecaseoflivermetastases.Prognosis(预后)

5-yearsurvivalsStage0:100% Stage1:90%Stage2:82%Stage3:35%Stage4:10%

PrecancerouslesionscanbediagnosedandtreatedwithPapsmearscreening.Invasivecancersareremovedbysurgicalexcision,withadjunctiveradiationtherapyandchemotherapy.AnewaspectisanHPVvaccinationprogram,approvedbytheUSFoodandDrugAdministration(FDA)forpreventingHPVinfection.HPVvaccinesarealsobeingevaluatedforeffectivenessasatherapeutictoolincervicalprecancers.Treatment&

Prevention(治疗&预防)二、Gestationaltrophoblastictumors(绒毛膜滋养细胞肿瘤)

HydatidiformMole(水泡状胎块) InvasiveMole（恶性水泡状胎块）

Choriocarcinoma(绒毛膜上皮细胞癌)LevelofHCG（绒毛膜促性腺激素）inurineandblood：

choriocarcinoma>invasivemole>hydatidiformmole51绒毛：胎盘的组成单位

表面主要由两种细胞覆盖：细胞滋养层细胞

合体滋养层细胞功能：吸收营养和生成激素（如HCG),间质的血管：连接母体和胎儿血液循环的桥梁异常：胎儿

母体

正常绒毛

Pathogenesis：

Uncertain

Abnormalfertilization胚胎发育不正常胎儿死亡滋养层细胞继续增生绒毛间质血管关闭水泡状胎块吸收水分Hydatidiformmole

(水泡状胎块,俗称葡萄胎)Incidence:1-1.5/2000pregnanciesCompletehydatiformmolePartialhydatiformmoleFeaturesofCompleteversusPartialHydatidiformMoleFeature CompleteMole PartialMoleKaryotype Diploid(46,xx/46,xy) Triploid(69,xxy)Villousedema Allvilli SomeVilliTrophoblast Diffuse;Focal;slightproliferationcircumferentialAtypia Oftenpresent AbsentSerumhCG Elevated LesselevatedhCGintussue ++++ +Behavior 2%choriocarcinoma rareMorphology(病理变化)Gross:theuterinecavityisfillwithadelicate,friablemassofthinwalled,translucentcysticstructures.Fetalpartsarenotseenincompletemolesbutarerareinpartialmoles.Completehydatidiformmole子宫腔充满大小不一的水泡，状如葡萄PartialhydatidiformmoleMicroscopyThreecharacters:1.hydropicswellingofchorionicvilli,withmyxomatousedematousstroma.2.mostofbloodvesselsintheinterstitial liferationofchorionicepitheliumbothcytotrophoblastandsyncytiotrophoblast绒毛间质疏松，呈粘液性性水肿绒毛间质血管消失绒毛滋养细胞显著增生NormalvillihydatidiformmoleClinico-pathologicrelations

(临床与病理联系)Occurduring12-14weeksofgestationUterusgrowfasterthanthatinthenormalpregnancy（超过正常妊娠子宫）UnpainfulvaginalbleedingIncreasedhCGinurineandbloodNofetalheartbeatinginultrasounddetectionUltrasound;elevatedHCGlevels;absenceoffetalpartsandfetalheartsoundsprognosisCompletemoles:80%-90%benign10%completeinvasive<2.5-3%choriocarcinomaPartialmoles：rarelygiverisetochoriocarcinomasmalignant/InvasiveMole

(侵袭性水泡状胎块/恶性水泡状胎块）Character:penetratetheuterinewall.水泡状绒毛侵入子宫肌层，肌层出血坏死Microscope:retainshydropicvilli（水肿绒毛）.ClinicalPathologicconference1.Hydropicvilllimayembolizetodistant organs,butitcanregressspontaneously.2.Truemetastasisdonotoccur.3.althoughitisnoteasytoberemovedcompletelybycurettage（刮宫）,itcanbecuredbychemotherapyinmostcases.MorphologyGross:水泡状绒毛侵入子宫肌层，肌层出血坏死Choriocarcinoma

（绒毛膜上皮癌）

Incidence:

1/30,000inWestern 1/2,000inAsianandAfrican.50%fromcompletehydatidiformmole25%fromabortion25%fromnormalpregnancyMorphologyGross:hemorrhagic,necroticmassesMicroscope:

(1)Thetumorispurelyepithelial,composedof anaplasticcuboidalcytotrophoblastand syncytiotrophoblast.异常增生的滋养细胞

(2)Severehemorrhageandnecrosis.出血坏死明显

(3)Withoutbloodvesselandstroma.无间质和血管(4)Novilliareformed.无绒毛形成肿瘤靠侵袭宿主血管获得营养cytotrophoblastsyncytiotrophoblastClinico-pathologicrelations

(临床与病理联系)1.vaginalbleeding.2.uterusgrowfasterthanthatinthenormalpregnancy.3.increasedhCGinurine.4.Rapidlydisseminatetootherorgansviablood.5.Sensitivetochemotherapy.三、Breast1.Mammaryadenosis2.Fibroadenoma3.CarcinomaStructure:Ducts+Lobule+StromaEstrogen&ProgestinNormalbreastNormalbreast正常的乳腺导管结构，上皮呈柱状，有顶浆分泌Breast“lumps”Fibrocysticchanges(乳腺增生症

)

Estrogen

21-40y/oFemaleClinicalmanifestation:

painfulbeforemenses,poorlydemarcated,mobileMammaryadenosis

(乳腺病)3Types：Simplefibrocysticchange(单纯性纤维囊肿型)Proliferativefibrocysticchange(增生性纤维囊肿型)Sclerosingadenosis(硬化性腺病)BiopsyspecimensFibrocysticchangeofthebreast

FibrocysticchangeofthebreastClassifications:NonproliferativechangefibrousstromadilationofductsandformationofcystsProliferativechangetypicalhyperplasias

1.SimplefibrocysticchangeFibrocysticchangeofthebreast单纯性纤维囊肿：间质纤维增生，伴有导管扩张，大小不等的囊肿形成1.Simplefibrocysticchangeapocrinemetaplasia(arrow)大汗腺化生，有顶浆分泌小突起1.SimplefibrocysticchangeCalcificationsandfoamymacrophages2.ProliferativefibrocysticchangeEpithelialhyperplasiaNormalEpithelialhyperplasiaEpithelialhyperplasia,withatypiaSclerosinglesion,S-MA+(肌细胞上皮标志物）3.Sclerosingadenosis（较少）大体：坚实与癌类似，但界限清，无黄白色坏死区镜下：小导管和末梢导管增生及小叶内纤维化BenigntumorFibroadenoma纤维腺瘤（themostcommonbenigntumorofthefemalebreast）Intraductalpapilloma导管内乳头状瘤Fibroadenoma结节状，包膜完整、界限清楚，质韧FibroadenomaIntraductalpapilloma无痛性乳头溢液导管内乳头状瘤CarcinomaoftheBreastEtiologyandPathogenesis

Riskfactors:1.Geographicvariations:NorthAmericaandnorthernEurope>AsiaandAfrica2.Age:uncommon<30years3.Geneticsandfamilyhistory:5-10%relatedtospecificinheritedmutation1stmalignantneoplasm

inwomenCarcinomaoftheBreastEtiologyandPathogenesisPathogenesis:(1)GeneticChanges:mutationsofBRCA1,BRCA2;mutationsofRBandTP53genes;OverexpressionofHER2/neu(2)HormonalInfluences:prolongedexposuretoestrogens(3)Others:radiotherapy,

obesity,

fatdiet,excessivedrinking,fibrocysticchangesCompositionLocationoftheTumorswithintheBreastUpperouterquadrant 50%Centralportion20%Lowerouterquadrant 10%Upperinnerquadrant 10%Lowerinnerquadrant 10%NormalAllthecarcinomaofthebreastderivefromtheTDLU(terminalduct-lobularunit)

终末导管小叶单位Classifications:Breastcarcinomasaredividedintotwogroups:

Noninvasive1.Ductalcarcinomainsitu(DCIS) Themostcommonsubtypeiscomedo,andcribriform.2.Lobularcarninomainsitu(LCIS)Invasive1.invasiveductalcarcinoma(70-80%)2.invasivelobularcarcinoma3.medullarcarcinoma4.colloidcarcinoma5.tubularcarcinoma

6.Othertypes:inflammatory

NoninvasivelobularcarcinomainsituNoninvasiveductalcarcinomainsitu粉刺癌导管内癌管腔内灰黄色软膏样坏死物质，挤压时由导管溢出，如皮肤粉刺Noninvasiveductalcarcinomainsitu实性筛孔状Pagetdisease佩吉特病，导管内癌沿导管生长累及乳头皮肤。出现渗出和浅表溃疡，又称湿疹样癌。肿瘤细胞体积大，胞质透明呈空泡状浸润性导管癌(70-80%)浸润性小叶癌髓样癌胶样癌管状癌其他类型:炎性乳癌乳房浸润癌94InvasiveCarcinomaoftheBreastGrossmorphology肿瘤内纤维组织增生收缩使乳头下陷局部淋巴转移，淋巴回流障碍，局部皮肤增厚，呈橘皮状。Carcinomaofthebreast1.Invasiveductalcarcinoma2.Invasivelobularcarcinoma

（几乎都表达ER和PR，无HER2过表达）3.Medullarycarcinoma(约2%，不表达ER和PR，无HER2过表达)髓样癌，癌细胞大，间质少，排列呈片状，间质淋巴细胞浸润4.Colloid(mucinous)carcinoma

（绝大多数表达ER和PR，少数HER2过表达）胶样癌，粘液癌。细胞外大量粘液。5.Tubularcarcinoma管状癌，少见，排列良好的腺管状结构，细胞无明显异形，无基膜。ClinicalPathologicconference无痛性肿块2-3cm可被推动，约半数淋巴转移晚期累积肌肉和胸壁深筋膜，不易推动乳头下陷、皮肤橘皮样改变炎性乳癌（inflammatorycarcinoma)：肿瘤生长迅速，引起急性炎症样反应，出现红、肿、触痛。见于妊娠妇女。Grading,StagingandMetastasis

1.Gradingisnotverycommonlyusedinthebreastcarcinoma.Noninvasivecarcinomaisacurablelesion;Medullar,colloid,tubularcarcinomahaverelativelybetterprognosis;Invasiveductalandlobularcarcinomaarehighgrademalignanttumors.

2.Staging: ThemostcommonlyusedisAJCsystem. Includingstage0~stageⅣ.3.Metastasis:Theouterquadrantandcentrallylocatedlesionstypicallyspreadtotheauxillarynodes.（外上象限和中央区肿瘤转移至腋窝淋巴结）Theinnerquadrantsofteninvolvethelymphnodealongtheinternalmammaryarteries.(内测象限肿瘤转移至内乳淋巴结).Distantdisseminationeventuallyinvolvesalmostanyorganortissueinthebody.Favoredlocationsarethelungs,skeleton,liver,andadrenals.MajorfactorsMinorfactors1.Tumorsize2.Lymphnodemetastases4.Distantmetastases5.Locallyadvanceddisease6.InflammatorycarcinomaHistologicsubtypes

LymphovascularinvasionTumorgradeEstrogenandprogesteronereceptorsHER2/neuProliferativerateDNAcontentPrognosis(预后)Withnoaxillarylymphnodeinvolvement,5yearssurvivalrateiscloseto90%.LymphaticMetastasisisimportantfactforpoorprognosis.

1.Lymphnodeinvolvementandmetastases2.ThegradeofthecarcinomaGradingisnotverycommonlyusedinthebreastcarcinoma.Usually,thenoninvasivecarcinomaisacurablelesion;medullary,colloid,tubularcarcinomahaverelativelybetterprognosis.Invasiveductalandlobularcarcinomasarehighgrademalignanttumorswithpoorprognosis.

3.Thepresenceofestrogenreceptororprogesteronereceptor

Thepresenceofhormonereceptorsconfersaslightlybetterprognosis.Thehighestrateofresponse(～80%）toanti-estrogentherapyisseeninwomenwhosetumorswithpositiveof

estrogenreceptororprogesteronereceptor.ERorPRoftumorcanbedetectedbyimmunohisto-chemistrymethod.Overexpressionofthismembrane-boundproteinisassociatedwithapoorerprognosis.However,thesignificanceofevaluatingHER2/neuistopredictresponsetoamonoclonalantibody(Hereceptin)tothegeneproduct,andimprovetheprognosisofpatients.4.OverexpressionofHER2/neu乳腺癌分子分型(基底细胞标志