病理学课件 病理绪论-14

ChapterOne

IntroductiontoPathologySectionA:DifinitionofPathologySectionB:DevelopmentofPathologySectionC:ObjectivesofResearchSectionD:LearningofPathologyWilliamOslerAsisourpathology,soisourmedicine.病理为医之本SectionA:DEFINITIONOFPATHOLOGYWithouttheconceptofsurgicaltreatment,oneisnotagoodphysician.Withouttheknowledgeofpathology,oneisnodoctor.Withouttheconceptofclinicaltreatment,oneisnotagoodpathologist.DefinitionofpathologyPathologyistostudydiseasesbyscientificmethods.Diseasemaybedefinedasanabnormalalterationofstructureorfunctioninanypartofthebody.Pathology:4aspectsofdiseaseETIOLOGY:Causeofdisease.PATHOGENESIS:Mechanismsofdevelopmentofdisease.MORPHOLOGY:Thestructuralalterationsinducedincellandtissues.FUNCTIONALCONSEQUENCES:Functionalconsequencesofthemorphologicchanges,asobservedclinically(clinico-pathologicalcorrelation,CPC).1.EtiologyKnowledgeofetiologyremainsthebackbone:DiseasediagnosesUnderstandingthenatureofdiseasesTreatmentofdiseases.1.EtiologyWhilemuchstillneedstobeuncoveredtolinkabnormalgenesandtheexpressionofdisease,gonearethetimewhenthemechanismsofmostdiseaseswereunknown?orobscure?ormysterious?Oneetiologicagent—onediseaseSeveraletiologicagents—onediseaseOneetiologicagent—severaldiseasesBASICRULESOFETIOLOGYCausesofcellinjuryanddiseaseOxygendeprivation(hypoxia,ischemia)NutritionalimbalancesPhysicalagentsChemicalagentsanddrugsInfectiousagentsImmunologicreactionsGeneticderangementsHYPOXIAIschemia(lossofbloodsupply)Inadequateoxygenation(cardiorespiratoryfailure)Decreaseofoxygen-carryingcapacityoftheblood(anemiaorCOpoisoning)HYPOXICINJURYLossofoxidativephosphorylationandATPgenerationbymitochondria.ResultinginaerobicglycolysisbydecreasedATP(withincreaseinAMP)Depletedglycogen.ReducedintracellularpH:Lacticacidandinorganicphosphate.MitochondrialdamageClumpingofnuclearchromatin.FourbiochemicalthemesOxygen-derivedfreeradicals.Lossofcalciumhomeostasisandincreasedintracellularcalcium.ATPdepletion.Defectsinmembranepermeability.PHYSICALAGENTSTraumaHeatColdRadiation(UV)ElectricshockCHEMICALAGENTSANDDRUGSEndogenousproducts:ureaExogenousagents:Therapeuticdrugs:hormonesNon-therapeuticagents:leadoralcoholMECHANISMSOFCHEMICALINJURYDirectly:MercuryofmercuricchloridebindstoSHgroupsofcellmembraneproteins,causingincreasedpermeabilityandinhibitionofATPase-dependenttransport.Indirectly:

Byconversiontoreactivetoxicmetaboliteswhichinturncausecellinjuryeitherbydirectcovalentbindingtomembraneproteinandlipid,ormorecommonlybytheformationoffreeradicals.MECHANISMSOFCHEMICALINJURY

MechanismofCCl4injuryCCl4inSERoflivercell(P-450)–CCl3.–lipidperoxidationandautocatalyticreactions–swellingandbreakdownofER,dissociationofribosome,anddecreasedhepaticproteinsynthesis(lossoflipidacceptorprotein–fattychangeoflivercell)–progressivecellularswelling,plasmamembranedamage,andcelldeath.FREERADICALINITIATIONAbsorptionofenergy(UVlightandx-rays)OxidativemetabolicreactionsEnzymaticconversionofexogenouschemicalsordrugs(CCl4>CCl3.)Oxygen-derivedradicalsSuperoxideCellinjurycausedbyfreeradicalsPeroxidationoflipids.Crosslinkingproteinsbytheformationofdisulfidebonds.InductionofDNAdamagethathasbeenimplicatedbothincellkillingandmalignanttransformation.INFECTIOUSAGENTSPrionVirusesRickettsiaeBacteriaFungiParasites肺---CMVGeneticdisorders:670per100050%ofspontaneousabortusesduringearlymonthsofgestation(chromosomalabnormalities)Chromosomalabnormalities:Trisomy21Single-genedisorders(APC)DisorderswithmultifactorialinheritanceGeneticderangementsAdenomatous

polyposiscoliAPCloci,5q21Adenomatous

polyposisincolons(inteens).100%malignanttransformation(40ys).NormalAPCproteininthecytoplasm.Severalpartners,including-catenin.Causingdegradationof-cateninmaintaininglowlevelof-catenininthecytoplasm.AbnormalAPC:-catenin

enteringthenucleusactivatingtranscriptionofgrowth-promotinggenes.PolymeraseChainReaction

DetectionofAPCDNAinFeces家族性高胆固醇血症靶基因低密度脂蛋白受体基因技术方法单链构象多态性分析温度梯度凝胶电泳测序应用范围杂合子患者

(人群中1/500)

纯合子患者

(人群中1/1，000，000)

A606T(hmz)infamilyANormalcontrol2.PATHOGENESISThecoreofthescienceofpathology—thestudythepathogenesisofthedisease.PATHOGENESISPathogenesisThesequenceeventsintheresponseofthecellsortissuestotheetiologicagent,fromtheinitialstimulustotheultimateexpressionofthedisease.PathogenesisImmunologic,cytogeneticandmolecularanalysesoftissuesandcellsareincreasinglybecomingguidestorenderdiagnoses,toassessprognosis,andtosuggesttherapy.ABCD117CD34GIST：发病机制受体偶联的酪氨酸激酶基因功能获得性突变（gainoffunctionmutation）是主要的致癌事件1,2－KIT：80％-85%1－PDGFRA：7％2－野生型（无法检测到的突变）：10-15%1

突变导致激活的酪氨酸激酶受体持续的异常表达(KIT或PDGFRA)3伊马替尼（格列卫）治疗PDGFRA，血小板源性生长因子受体；PDGFRA，血小板源性生长因子受体基因1.CorlessCLetal.JClin

Oncol.2004;22:3813-3825.2.HeinrichMCetal.Science.2003;299:708-710.3.TrentJCetal.Curr

Opin

Oncol.2006;18:386-395.3.MORPHOLOGY大叶性肺炎Morphologicchange

CharacteristicforthediseaseDiagnosticfortheetiologicproceessFunctionalderangementsClinicalsignificanceMORPHOLOGYMorphologyremainsattheheartofdiagnosticpathology.

DevelopmentofPathologySectionBOrganpathologyCellpathologyMolecularpathologyCellPathologyRudolfWirchow(1821-1902),AGermanpathologistThefounderofmoderncellpathologySectionCOBJECTIVESANDMETHODSOFRESEARCH

AutopsyBiopsyCytologyExperimentalstudies

Invitro:

TissuecultureOrgancultureCellculture

Invivo:

ExperimentalanimalsNudemiceAutopsy(尸检)：(A5800)主述：F/46工人。患者因呼吸困难1天，神志不清12小时，急诊入院。现病史：患者自觉呼吸困难，全身不适，意识模糊，几小时后神志不清，入三院诊治。查体实验室检查：血压低，心率快，体温进行性升高。双肺中小水泡音。肛试子白血球15-20个/HPF，RBC2-3个/HPF，潜血（+）。末梢血WBC2-3万/mm3。诊断：考虑为痢疾、感染性休克。2002年7月11日下午心脏骤停，抢救无效死亡。检查肠系膜血管脾静脉血栓AVPancreas诊断肠系膜静脉、脾静脉、门静脉血栓性静脉炎伴阻塞性血栓形成，小肠出血性坏死，急性腹膜炎感染中毒性休克死亡Biopsy-活体组织检查1）Macroscopicobservation2）MicroscopicobservationFormalin-fixedparaffin-embedded

Freshtissue:FrozensectionFrozensectionBreastmass:Benignlesion:localresectionInfiltratingductalcarcinoma:mastectomy+removalofregionalLN病理学检查申请单临床医师向病理医师发出的会诊邀请单疾病诊治过程中的有效医学文书各项信息必须真实，应由主管临床医师亲自逐项认真填写并签名临床医师向病理医师传递关于患者的主要临床信息:症状、体征、各种辅助检查结果和手术所见、诊断意向和对病理学检查提出的某些特殊要求TheimportanceofclinicaldataAge：SLLrareinpatientslessthan20ysMFHmainlyinagedpeopleLocation：LiposarcomaindeepertissueplainAngioblastoma同一战壕的战友诊断意向：腹部肿快？发烧待查？结肠肿物？重要化验结果：

PSA、AFPCytology-细胞学ExperimentalstudyRESEARCHMETHODSMacroscopicobservationMicroscopicobservation(HE)EMImmunohistochemistryHybridizationPCRFlowcytometryMicroarray1.ElectronicmicroscopyCelljunctionCytoskeletonNeuroendocrinegranulesMelanosomesMitochondria

HER2（红色）/CEP17（绿色）无扩增有扩增2.Hybridization:FISH,CISHALKBREAKAPARTPROBES,FISH弥漫性间变性大细胞性淋巴瘤,t（2;5）(NPM－ALK)In-situHybridizationEBERinNasopharyngealcarcinoma3.ImmunohistochemistryDiagnsticMarkersPrognosticmarkersPredictivemarkers(Targetchemotherapy)Follicularlymphoma

T(14;18)(q32;q21)t(14,18)(q32,q21)抗凋亡的bcl2基因持续表达2021Predictivemarkers

(Targetchemotherapy)

Breastcarcinoma：HerceptinGIST(gastrointestinalstromaltumor)：

Gleevec(格列卫)Bcelllymphomas:CD20amtibodies（美罗华）1+2+3+Immunohistochemistry

Treatment:HER-2/neuinbreastcarcinomaO+4.PCRPolymeraseChainReaction

ChromosomalTranslocation靶基因：

SYT-SSX1，t(x;18)(p11.23;q11)

SYT-SSX2，t(x;18)(p11.21;q11)

技术方法:RT-PCR

应用范围：

90%以上的滑膜肉瘤，特别是不常见部位的、发生于老年的滑膜肉瘤滑膜肉瘤病历1病历2M75bp100bp107bp通

III通

III5.MicroarrayscDNAMicroarrayDiffuselargecelllymphomaNEJM2002;346:1937-476.FLOWCYTOMETRYGeneticHallmarkofCompleteMoleDiploidDNAcompositionPaternal/androgenicgenome46XpXp23XSpermEmptyEggCOMPLETEMOLEPaternalChromosomeOnly(Androgenetic)PARTIALMOLE23XSperm23XSperm23XEgg69XpXpXmPaternalandMaternalChromosome(Triploid)FLOWCYTOMETRYFORPLOIDYLEARNINGOFPATHOLOGYSectionDGeneralpathologyisconcernedwiththebasicreactionsofcellsandtissuestoabnormalstimulithatunderliealldiseases.Systemicpathologyexaminesthespecificresponsesofspecializedorgansandtissuestomoreorlesswelldefinedstimuli.MajorpointsDefinitionCausesPathogenesisLesionsEffectsChineseproverbIhear,Iforget;Isee,Iremember;Ido,Iunderstand.ChapterTwo

CellandTissueInjury

CELLINJURYANDNECROSISGeneralmechanisms:Maintenanceoftheintegrityofcellmembranes.AerobicrespirationandproductionofATP.Synthesisofenzymesandstructureproteins.Preservationoftheintegrityofthegeneticapparatus.CELLSREACTTOADVERSEINFLUENCESADAPTINGSUSTAININGREVERSIBLEINJURYSUFFERINGIRREVERSIBLEINJURYANDDYINGSectionA:CellularAdaptation

SectionB:Degeneration

(reversibleinjury)

SectionC:CellDeath

SectionD:CellularAging

SectionA

Cellularadaptation:AtrophyHypertrophyHyperplasia

MetaplasiaCELLULARADAPTATIONExcessivephysiologicstresses.Somepathologicstimuli.Anew,butalteredstatepreservingtheviabilityofthecell.ATROPHYDecreaseinmassofthecellHYPERTROPHY

IncreaseinmassofthecellAtrophyPhysiologicalPathological

Fig2-5PATHOLICALATROPHY

Decreasedworkload(废用性).Lossofinnervation(神经性).Diminishedbloodsupply(贫血性).Pressure(压迫性).Inadequatenutrition(营养不良性).Lossofendocrinestimulation(内分泌性).Aging(老年性).MorphologyofatrophyBrownatrophyReductioninthenumberofcellorganelles.Increaseinthenumberofautophagicvacuoles.Lipofuscingranules(Brownatrophy)AtrophyEffects:ReversibleDecreaseinfunctionalcapacityHYPERTROPHYPhysiologicalPathological

Fig2-6HYPERTROPHYIncreasedfunctionaldemand.Specifichormonalstimulation.HYPERTROPHYPathologic:工作性代偿性替代性内分泌性HYPERPLASIAThemythofPrometheus.

Fig2-1HYPERPLASIA

Physiologichyperplasia:HormonalhyperplasiaCompensatoryhyperplasiaPathologichyperplasia:Excessivehormonalstimulation.EffectsoflocallyproducedGFsontargetcells.PARTIALHEPATECTOMYPrimingProliferationGroeth

lnhibitionGROWTHFACTORSANDCYTOKINESHGFTGF-EGFTNF-IL-6OthersADJUVANTSNorepinephrineInsulinGlucagonThyroidhormoneGROWTHINHIBITORSTGF-

OthersGrowthfactorsAdjuvanisMatrixdegradationProliferated

endometriumComplexhyperplasiaMetaplasiaOneadultcelltypeisreplacedbyanother.Geneticreprogrammingofstemcells.Epithelialandmesenchymal

metaplasia.Squamous

metaplasia

BronchialepitheliaEpitheliainbileductCervicalepitheliaIntestinalmetaplasiaofgastricepitheliaBonemetaplasia.慢性萎缩性胃炎，AB/PAS

染色：胃腺上皮--肠上皮化生chronicgastritis胃粘膜肠化Degeneration：Definition1.ACUTECELLULARSWELLINGSectionBEtiologyIschemicInfectiousToxic

心肌空泡变CELLULARSWELLINGEM:线粒体肿胀内质网扩张核糖体脱失糖原颗粒减少CELLULARSWELLINGEffects:Reversible,mildDecreaseinfunctionalcapacity

IntracellularaccumulationAnormalcellularconstituentaccumulatedinexcess,(e.g.Water,lipid,protein,carbohydrates,pigment)Anabnormalsubstance:exogenousendogenousIntracellularaccumulationAnormalendogenoussubstance,buttherateofmetabolismisinadequatetoremoveGeneticoracquireddefectsinmetabolism,packaging,transportorsecretion--storagedisease.Anabnormalexogenoussubstanceisdepositedduetothecellunabletodegradeortransportittoothersites2.FATTYCHANGEEtiologyIschemicInfectiousToxic

Starvation,corticosteroidtherapyHepatitistypeCAlcoholExcessiveentryoffreefattyacidsintotheliver(starvation,corticosteroidtherapy).Enhancedfattyacidsynthesis.Decreasedfattyacidoxidation.

Dncreased

esterificationoffattyacid---triglycerides(alcohol).Decreasedapoproteinsynthesis(CCl4).Impairedlipoproteinsecretionfromtheliver(alcohol).FATTYCHANGEMorphologyoffattychangeSudanIII,OilredO,OsmicacidLiverHeartKidney脂肪肝严重的肝细胞脂肪变性，并出现一系列临床异常——肝区胀满、痛、厌油食转氨酶高等心肌脂肪变LipidsSteatosis(fattychanges)

clearvacuolesinliver,heartCholesterolandcholesterolestersAtherosclerosis

XanthomasInflammationandnecrosis

CholesterolosisIntracellularhyalinechangesHyalinedegenerationofarteriolesHyalinedegenerationofconnectivetissue3.Hyalinechanges(degeneration)

Absorptionofproteincausinghyalinedropletsinproximalepithelialcellsinthekidney.

Russelbodiesinplasmacells.Viralinclusionsinthecytoplasmorthenucleus.Massesofalteredintermediatefilaments(Mallorybodies).IntracellularhyalinechangesProteinreabsorptiondropletsintherenaltubularepithelium.胶元纤维玻璃样变Aheterogeneousgroupofpathogenicfibrillarproteinsaccumulatingintissuesandorgans.ExcesssynthesisResistancetocatabolism4.AMYLOIDOSISChemicalnatureofamyloidfibrilsTwomajorforms:AL(amyloidlightchainprotein)AA(amyloid-associatedprotein):

DerivedfromserumAA(12kd)synthesizedinliverandelevatedininflammatorystates.Minorformsofamyloidfibrils:Transthyretin(TTR):Amutantformofaserumproteininfamilialamyloid

polyneuropathy.AvariantofTTRinaging.Beta-2-microglobulin(thecomponentofclassIMHCmolecules)inlong-term

hemidialysis.

primary(B-celldyscrasia,AL)Secondaryorreactive(AA):Collagendiseases,bronchiectasis,chronic

osteomyelitis.

Hemodialysis-related:Beta-2-microglobulindeposition.Hereditary(AA)ClinicalformsofamyloidosisSystemicamyloidosis:

Nodular(tumor-formingdeposits,B-celldyscrasia,AL)Endocrineamyloidosis(procalcitonin)

Amyloidosisofaging:Heart,lung,pancreas,spleen,brain.LocalizedamyloidosisAmyloidosisoftheliverischaracterizedbyhomogeneouseosinophilicmaterialinthesinusoids5.GlycogenExcessiveintracellulardepositsofglycogenareseeninpatientswithanabnormalityineitherglucoseorglycogenmetabolismClearvacuolesinthecytoplasmDMGlycogenstoragedisease肝糖元，卡红

Exogenous:

CarbonTattooingEndogenous:

LipofuscinMelanin

Hemosiderin

Bilirubin6.Pigmentation文身之皮肤痣，黑色素肺GPC，含铁血黄素，Fe肝血色病Idiopathichemochromatosis

胆汁与胆色素DystrophiccalcificationMetastaticcalcification7.Pathologiccalcification

Necrotictissues

AtheromaDamagedheartvalves

DystrophiccalcificationFig2-13冠状动脉钙化

IncreasedsecretionofparathyroidhormoneDestructionofbonetissueVitaminD-relateddisorders:

SarcoidosisRenalfailureMetastaticcalcificationHypercalcimiaMetastaticcalcificationAffectingInterstitialtissueofgastricmucosaKidneysLungsPulmonaryveinsSystemicarteries肺转移性钙化肺转移性钙化SectionCCELLDEATH一、NECROSISDefinitionCausesLesionTypesFatesNECROSISThesumofthemorphologicchangesthatfollowcelldeathinlivingtissueandorgan:Denaturationofproteins.Enzymaticdigestionoforganellesandcytosol.Swelling,denaturationandcoagulationofproteinsBreakdownofcellularorganellesCellrupture

Commontypeofnecrosisafterexogenousstimuli.Enzymaticdigestionbylysosomalenzymesofthedeadcellsthemselves.AUTOLYSISHETEROLYSISDigestionbylysosomalenzymesofimmigrantleukocytes.ThreepatternofnuclearchangesKaryolysis(DNaseactivity)Pyknosis(DNAcondensation)Karyorrhexis(fragmentationofpyknoticnucleus)MorphologicappearanceofnecrosisIncreasedeosinophilia:LossofRNAinthecytoplasmIncreasedbindingofeosintodenatured

cytoplasmic

proteinMoreglassyhomogeneousappearanceLossofglycogenparticlesVacuolatedandmoth-eatencytoplasmCalcificationofnecroticcellsTYPESOFCELLDEATH

necrosis

Coagulationnecrosis

Caseousnecrosis

Gangrene

Liquefactionnecrosis(fatnecrosis)

FibrinoidnecrosisApoptosis1.CoagulationnecrosisDenaturesofbothstructuralandenzymaticproteinsbyinjuryorthesubsequentincreasingintracellularacidosis.HerpessimplexhepatitiswithscatteredfociofcoagulativenecrosisCaseousnecrosisAsubtypeofcoagulationnecrosisWhiteandcheesyTuberculosisCompletelyobliteratedtissuearchitectureTB，干酪样坏死GangreneAsubtypeofcoagulationnecrosisDrygangreneWetgangreneGasgangrene2.LiquefactivenecrosisBacterialorfungalinfectionsCentralnervoussystemAmebiasis肺膿肿肠阿米巴，液化性坏死肠阿米巴，液化性坏死脑软化FatnecrosisTraumaticActivatedpancreaticlipasesAcutepancreatitis:fatnecrosisandinflammatorycellsindamagedpancreaticparenchyma3.FibrinoidnecrosisThecombinationofcelldeathanddepositionoffibrin-likematerialFibrinImmunoglobulinOtherplasmaproteinsFibrinoidnecrosis

DeeplyeosinophilicCollagendiseasesNecroticvasculitisMalignanthypertension纤维素样坏死AbsorptionDischarge:ErosionUlcerSinusFistulaCavitationOrganizationEncapsulationCalcificationFatesofnecrosis二、APOPTOSIS(Programmedcelldeath)

Programmeddestructionofcellsduringembryogenesis.Hormonedependentinvolutionoftissuesintheadult.Celldeletioninproliferatingcellpopula-

tions(intestinalcryptepithelium),tumors,andlymphoidorgans.

Pathologicatrophyinparenchymal

organsafterductobstruction.CelldeathbycytotoxicTcells.Cellinjuryincertainviraldiseases.Celldeathproducedbyavarietyofinjuriousstimuligiveninlowdoses(dthermalinjury).MORPHOLOGICALFEATURESOFAPOPTOSISCellshrinkageChromatincondensationandfragmentation.Formationofcytoplasmicblebsandapoptoticbodies.Phagocytosisofapoptoticbodiesbyadjacenthealthycellsormacrophages.Lackofinflammation.

Necrosis

ApoptosisStimuliHypoxiaPhysicalToxinsPathologicalHistology

CellswellingSinglecellCoagulationNChromatinDisruptionofcondensationorganellesApoptoticbodiesDNA

RandomInternucleosomalbreakdown

Diffuse

Necrosis

ApoptosisMechanismATPdepletionGeneactivationMembraneEndonucleaseinjuryFreeradicalsTissue

InflammationNoinflammation

reaction

PhagocytosisofapoptoticbodiesFig1-18Biochemicalfeaturesofapoptosis1.PROTEINCLEAVAGE:

Caspases(cysteineprotease)Nuclearscaffold

Cytoskeletalprotein2.PROTEINCROSS-LINKING:

Transglutaminase

Cytoplasmicproteinshrunkenshalls

apoptoticbodiesBiochemicalfeaturesofapoptosis3.DNAbreakdown:50-300kbpiecesCa2+,Mg2+dependentendonucleasesDNAoligonucleosomesDNAladders(alsoseeninnecrosis)4.PHAGOCYTICRECOGNITION

Receptorsonmacrophagesforthesurfacecomponents(phosphatidylserine,thrombospondin)onapoptoticbodies.Fig1-19Apoptosis-associatedgenesbcl-2,c-myc,p53Fig1-20SectionD:CellularAging

AnumberofcellfunctiondeclineOxidativephosphorylationisreducedAdecreasedcapacityforuptakeofnutrientsandforrepairofDNAdamageAccumulationoflipofuscinAgeneticallydeterminedclockEffectsofcontinuousexposuretoexogeneousinfluenceSectionA:RegenerationSectionB:FibrousRepairSectionC:WoundhealingSectionD:FractureRepairChapterThree:RepairLabilecellsStablecellsPermanentcellsRegenerationcapacitySectionA:

Regeneration1.Completelyregeneration2.FibrousrepairLabilecells

Normallydividedactivelytoreplacecellsthatarebeingcontinuouslostfromthebody.

Thechancesofrestorationbyregenerationareexcellent.

Includingepithelialstemcellsinbasallayer,hematopoieticstemcellinbonemarrow.TheregenerativecapacitytypesofcellsStablecells

Alonglifespanandarecharacterizedbyalowrateofdivision,retainthecapacitytoenterthemitoticcellcycleiftheneedarises.Chancesofregenerationremain.Includingparenchymalcellofsolidglandularorgan(liver,pancreas)andmesenchymalcells.TheregenerativecapacitytypesofcellsPermanentcells

Nocapacityformitoticdivisioninpostnatallife.

Neurons,striatedandcar