ChapterOne

IntroductiontoPathologySectionA:DifinitionofPathologySectionB:DevelopmentofPathologySectionC:ObjectivesofResearchSectionD:LearningofPathologyWilliamOslerAsisourpathology,soisourmedicine.病理為醫之本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家族性高膽固醇血癥靶基因低密度脂蛋白受體基因技術方法單鏈構象多態性分析溫度梯度凝膠電泳測序應用范圍雜合子患者

(人群中1/500)

純合子患者

(人群中1/1，000，000)

A606T(hmz)infamilyANormalcontrol2.PATHOGENESISThecoreofthescienceofpathology—thestudythepathogenesisofthedisease.PATHOGENESISPathogenesisThesequenceeventsintheresponseofthecellsortissuestotheetiologicagent,fromtheinitialstimulustotheultimateexpressionofthedisease.PathogenesisImmunologic,cytogeneticandmolecularanalysesoftissuesandcellsareincreasinglybecomingguidestorenderdiagnoses,toassessprognosis,andtosuggesttherapy.ABCD117CD34GIST：發病機制受體偶聯的酪氨酸激酶基因功能獲得性突變（gainoffunctionmutation）是主要的致癌事件1,2－KIT：80％-85%1－PDGFRA：7％2－野生型（無法檢測到的突變）：10-15%1

突變導致激活的酪氨酸激酶受體持續的異常表達(KIT或PDGFRA)3伊馬替尼（格列衛）治療PDGFRA，血小板源性生長因子受體；PDGFRA，血小板源性生長因子受體基因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大葉性肺炎Morphologicchange

CharacteristicforthediseaseDiagnosticfortheetiologicproceessFunctionalderangementsClinicalsignificanceMORPHOLOGYMorphologyremainsattheheartofdiagnosticpathology.

DevelopmentofPathologySectionBOrganpathologyCellpathologyMolecularpathologyCellPathologyRudolfWirchow(1821-1902),AGermanpathologistThefounderofmoderncellpathologySectionCOBJECTIVESANDMETHODSOFRESEARCH

AutopsyBiopsyCytologyExperimentalstudies

Invitro:

TissuecultureOrgancultureCellculture

Invivo:

ExperimentalanimalsNudemiceAutopsy(尸檢)：(A5800)主述：F/46工人。患者因呼吸困難1天，神志不清12小時，急診入院。現病史：患者自覺呼吸困難，全身不適，意識模糊，幾小時后神志不清，入三院診治。查體實驗室檢查：血壓低，心率快，體溫進行性升高。雙肺中小水泡音。肛試子白血球15-20個/HPF，RBC2-3個/HPF，潛血（+）。末梢血WBC2-3萬/mm3。診斷：考慮為痢疾、感染性休克。2002年7月11日下午心臟驟停，搶救無效死亡。檢查腸系膜血管脾靜脈血栓AVPancreas診斷腸系膜靜脈、脾靜脈、門靜脈血栓性靜脈炎伴阻塞性血栓形成，小腸出血性壞死，急性腹膜炎感染中毒性休克死亡Biopsy-活體組織檢查1）Macroscopicobservation2）MicroscopicobservationFormalin-fixedparaffin-embedded

Freshtissue:FrozensectionFrozensectionBreastmass:Benignlesion:localresectionInfiltratingductalcarcinoma:mastectomy+removalofregionalLN病理學檢查申請單臨床醫師向病理醫師發出的會診邀請單疾病診治過程中的有效醫學文書各項信息必須真實，應由主管臨床醫師親自逐項認真填寫并簽名臨床醫師向病理醫師傳遞關于患者的主要臨床信息:癥狀、體征、各種輔助檢查結果和手術所見、診斷意向和對病理學檢查提出的某些特殊要求TheimportanceofclinicaldataAge：SLLrareinpatientslessthan20ysMFHmainlyinagedpeopleLocation：LiposarcomaindeepertissueplainAngioblastoma同一戰壕的戰友診斷意向：腹部腫快？發燒待查？結腸腫物？重要化驗結果：

PSA、AFPCytology-細胞學ExperimentalstudyRESEARCHMETHODSMacroscopicobservationMicroscopicobservation(HE)EMImmunohistochemistryHybridizationPCRFlowcytometryMicroarray1.ElectronicmicroscopyCelljunctionCytoskeletonNeuroendocrinegranulesMelanosomesMitochondria

HER2（紅色）/CEP17（綠色）無擴增有擴增2.Hybridization:FISH,CISHALKBREAKAPARTPROBES,FISH彌漫性間變性大細胞性淋巴瘤,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基因持續表達2021Predictivemarkers

(Targetchemotherapy)

Breastcarcinoma：HerceptinGIST(gastrointestinalstromaltumor)：

Gleevec(格列衛)Bcelllymphomas:CD20amtibodies（美羅華）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)

技術方法:RT-PCR

應用范圍：

90%以上的滑膜肉瘤，特別是不常見部位的、發生于老年的滑膜肉瘤滑膜肉瘤病歷1病歷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(廢用性).Lossofinnervation(神經性).Diminishedbloodsupply(貧血性).Pressure(壓迫性).Inadequatenutrition(營養不良性).Lossofendocrinestimulation(內分泌性).Aging(老年性).MorphologyofatrophyBrownatrophyReductioninthenumberofcellorganelles.Increaseinthenumberofautophagicvacuoles.Lipofuscingranules(Brownatrophy)AtrophyEffects:ReversibleDecreaseinfunctionalcapacityHYPERTROPHYPhysiologicalPathological

Fig2-6HYPERTROPHYIncreasedfunctionaldemand.Specifichormonalstimulation.HYPERTROPHYPathologic:工作性代償性替代性內分泌性HYPERPLASIAThemythofPrometheus.

Fig2-1HYPERPLASIA

Physiologichyperplasia:HormonalhyperplasiaCompensatoryhyperplasiaPathologichyperplasia:Excessivehormonalstimulation.EffectsoflocallyproducedGFsontargetcells.PARTIALHEPATECTOMYPrimingProliferationGroeth

lnhibitionGROWTHFACTORSANDCYTOKINESHGFTGF-EGFTNF-IL-6OthersADJUVANTSNorepinephrineInsulinGlucagonThyroidhormoneGROWTHINHIBITORSTGF-

OthersGrowthfactorsAdjuvanisMatrixdegradationProliferated

endometriumComplexhyperplasiaMetaplasiaOneadultcelltypeisreplacedbyanother.Geneticreprogrammingofstemcells.Epithelialandmesenchymal

metaplasia.Squamous

metaplasia

BronchialepitheliaEpitheliainbileductCervicalepitheliaIntestinalmetaplasiaofgastricepitheliaBonemetaplasia.慢性萎縮性胃炎，AB/PAS

染色：胃腺上皮--腸上皮化生chronicgastritis胃粘膜腸化Degeneration：Definition1.ACUTECELLULARSWELLINGSectionBEtiologyIschemicInfectiousToxic

心肌空泡變CELLULARSWELLINGEM:線粒體腫脹內質網擴張核糖體脫失糖原顆粒減少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脂肪肝嚴重的肝細胞脂肪變性，并出現一系列臨床異常——肝區脹滿、痛、厭油食轉氨酶高等心肌脂肪變LipidsSteatosis(fattychanges)

clearvacuolesinliver,heartCholesterolandcholesterolestersAtherosclerosis

XanthomasInflammationandnecrosis

CholesterolosisIntracellularhyalinechangesHyalinedegenerationofarteriolesHyalinedegenerationofconnectivetissue3.Hyalinechanges(degeneration)

Absorptionofproteincausinghyalinedropletsinproximalepithelialcellsinthekidney.

Russelbodiesinplasmacells.Viralinclusionsinthecytoplasmorthenucleus.Massesofalteredintermediatefilaments(Mallorybodies).IntracellularhyalinechangesProteinreabsorptiondropletsintherenaltubularepithelium.膠元纖維玻璃樣變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，卡紅

Exogenous:

CarbonTattooingEndogenous:

LipofuscinMelanin

Hemosiderin

Bilirubin6.Pigmentation文身之皮膚痣，黑色素肺GPC，含鐵血黃素，Fe肝血色病Idiopathichemochromatosis

膽汁與膽色素DystrophiccalcificationMetastaticcalcification7.Pathologiccalcification

Necrotictissues

AtheromaDamagedheartvalves

DystrophiccalcificationFig2-13冠狀動脈鈣化

IncreasedsecretionofparathyroidhormoneDestructionofbonetissueVitaminD-relateddisorders:

SarcoidosisRenalfailureMetastaticcalcificationHypercalcimiaMetastaticcalcificationAffectingInterstitialtissueofgastricmucosaKidneysLungsPulmonaryveinsSystemicarteries肺轉移性鈣化肺轉移性鈣化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，干酪樣壞死GangreneAsubtypeofcoagulationnecrosisDrygangreneWetgangreneGasgangrene2.LiquefactivenecrosisBacterialorfungalinfectionsCentralnervoussystemAmebiasis肺膿腫腸阿米巴，液化性壞死腸阿米巴，液化性壞死腦軟化FatnecrosisTraumaticActivatedpancreaticlipasesAcutepancreatitis:fatnecrosisandinflammatorycellsindamagedpancreaticparenchyma3.FibrinoidnecrosisThecombinationofcelldeathanddepositionoffibrin-likematerialFibrinImmunoglobulinOtherplasmaproteinsFibrinoidnecrosis

DeeplyeosinophilicCollagendiseasesNecroticvasculitisMalignanthypertension纖維素樣壞死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