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1、Chapter IIntroduction to Pathology1Definition of pathologyDevelopment of pathologyObjective of researchResearch methodsLearning of pathologyDefinition of PathologyPathologyLiterally：pathos（suffering）logos（study）To study diseases by scientific methods.Disease may be defined as an abnormal alteration
2、of structure or function in any part of the body.Pathology: a bridge connecting basic science to clinicEtiology: Cause of disease. Knowledge of etiology remains the backbone:Pathogenesis: Mechanisms of development of disease. Understanding the nature of diseasesMorphology: The structural alterations
3、 induced in cell and tissues.Disease diagnosisFunctional consequences: symptoms, singes Functional consequences of the morphologic changes as observed clinically. Treatment of diseases.Pathology: still golden standard in diagnosis of diseasePathologyA bridge between:Evidence and practiceAdvances and
4、 applicabilityBenchside and bedside“Guiding the Surgeons Hand” (Juan Rosai)Doctors doctor患者患者临床医生临床医生胸外科医师胸外科医师内镜医师内镜医师收集组织标本收集组织标本病理科医生病理科医生疾病诊断疾病诊断实验操作及结果分析实验操作及结果分析实验室人员实验室人员报告结果给临床医生报告结果给临床医生-肿瘤科医生肿瘤科医生-放疗科医生放疗科医生-呼吸科医生呼吸科医生肺癌目前是全世界癌症死因的第一名肺癌目前是全世界癌症死因的第一名70%肺癌发现确诊时已属晚期肺癌发现确诊时已属晚期肺癌发生于支气管粘膜上皮亦称支
5、气管肺癌肺癌发生于支气管粘膜上皮亦称支气管肺癌基本类型基本类型 小细胞肺癌小细胞肺癌SCLC非小细胞肺癌（非小细胞肺癌（NSCLC)，约，约85%腺腺癌癌NOS腺腺鳞鳞癌癌鳞鳞癌癌大大细细胞胞癌癌肺癌Genetic alterations in lung cancerAdenocarcinomaSquamous-cellcarcinomaLargecellcarcinoma组织分型CurrentStandardofNSCLCCareNon-squamousNSCLC分型现状SquamousEGFRWTEGFRMuSquamousEGFRMuKRASMuALK+Othernon-squamous
6、WTSquamous2012NCCN2014NCCNEGFRMuALK+KRASMuOthernon-squamousWTSquamousROS1+2010NCCNNCCNGuidelines,NSCLC,Version4.2014HornL,etal.ClinOncol.2009驱动基因分型早期NSCLC肿瘤驱动基因-分子类型Organ pathologyHisto- or Cell- pathologyMolecular pathologyDevelopment of PathologyOrgan pathologyautopsy and macropathologic analysis
7、on organs 16th-18thcenturyPracticed by bedside cliniciansworkingpart-timeFor better understand the basisof the patients symptoms andsigns, and the cause of theirdeathsThemostfamousearlygrosspathologistwasGiovanniMorgagni(1682-1771).modernautopsyprocessderivesfromtheanatomistsoftheRenaissance.Giovann
8、iMorgagni(16821771),celebratedasthefatherofanatomicalpathologyHistopathology19thcentury:followingtheinventionofthecompoundmicroscopeRudolfVirchow（1821-1902,fatherofmodernpathology）&hismanyenlightenedpupils:Histopathology: a hallmark of modern pathologyAstudentofVirchows,JuliusCohnheim(1839-1884):inf
9、lammation,frozensectionThegreat19th-centurymedicalresearcherRudolfVirchow,inresponsetoalackofstandardizationofautopsyprocedures, established and publishedspecificautopsyprotocolsModern pathology20th centuryFormation of modern pathologySurgeons examining specimens for their patients, using microscope
10、 Academic researchModern pathologyModern pathologyOrgan pathology: Autopsy MacromorphologyHistopathology: light microscope: HE staining Histochemical pathology: chemical staining for lipid, protein, DNA, organelles Ultrastructural pathology: electron microscope Immunohistochemical pathology: antigen
11、-antibody reaction: protein staining Molecular pathology: DNA, RNA analysis: hybridization, PCR, microarray, flowcytometry, etcMolecular pathologyModern pathologyAcademic pathology: Department of pathology in medical school academic researchClinical pathology: Department of pathology in hospital Sur
12、gical pathologist in diagnosisAutopsy ResectionBiopsyCytology Molecules: proteins, DNA, RNA, etcExperimental studies: In vitro: tissue culture organ culture cell culture In vivo: Experimental animalsAnalytic objectivesMacroscopic observationMicroscopic observation (H&E)Electron Microscope (EM)Immuno
13、histochemistry (IHC)Molecular analysis: In Situ Hybridization PCR Flow Cytometry Microarray Sequencing: NGSPathology methods21Autopsy The Anatomy Lesson of Dr. Nicolaes Tulp Surgical resectionBiopsynOpenresection:nNeedlebiopsy:24LCNB: 14-gaugeVAB: 8-gaugeneedle 11-gauge needle vacuum assisted biopsy
14、 probeFrozen section25n n Benign or malignant n n Clear margin and metastasisn n Pitfallsn n Unsuitable conditions CervicalPapSmear26CytologyNormalLSILHSILcarcinoma27UltrapathologyElectron MicroscopyImmunohistochemistry28For Diagnosis+-For Treatment- HER-2/neu in breast carcinomaImmunohistochemistry
15、30In-situ HybridizationEBER in Nasopharyngeal carcinoma11111818MALT Lymphoma t(11;18): BCL-10 11q22 (Spectrum Green): YAC 906c5 & 921f3 18q22 (Spectrum Red): YAC 949b6FISH原理原理31Fluorescence in situ hybridization analysis for HER2/neu in breast carcinomaAnalysis of IgH PCR Products33polyclonalmonoclo
16、nal 1 2 3 4 5 100bp10% polyacrylamide gelGene ScanFr3-JHFr3-JHPCRFlow cytometry34n DNA Ploidyn Growth Fragmentn Surface Receptorsn Immunophenotyping of Lymphohematopoitic Cellsn Sorting of Viable CellsMicroarrays35cDNA Microarray - Diffuse large B cell lymphoma NEJM 2002;346:1937-47高通量测序类型NudemiceKn
17、ock-outmice，Transgenemice37Experimental studiesThe flowchart of computerized image analysis for prognosis based on H&E histopathology images The system (a) acquires a digitized image via microscope-mounted digital camera or whole slide image scanner, (b1) preprocesses the image via color normalized
18、and automatically detects the region of interest (ROI), (b2) automatically detects and segments the objects, (b3) extracts pixel-level, object-level, and spatial-arrangement-level features based on the segmentation results, and (c) builds the computer-aided prognosis (CAP) system on top of these fea
19、tures. DR: dimensionality reduction.Tumor diagnosisOrigin:Biologic behavior: benign or malignantSubtypes:Prognosis:Treatment: molecular targetingA 12-year-old boy presented with a short history of pain in his thighSolitary Bone Cyst (SBC)The x-ray picture of GCT usually shows a large, eccentric, ova
20、l, radioluscent destructive lesion centered in the epiphysis, producing cortical erosion and thinning, and expanding the bone contours without a border of periosteal reactive new-bone formation and sclerosis.Giant cell tumor (GCT)composed of plump, spindly, and oval stromal cells and multinucleated
21、tumor giant cellsOsteosarcomaOsteosarcomaNeuroendocrine tumorNeuroendocrine granules in cytoplasm of tumor cellBreast carcinomaMorphology in carcinogenesisBronchial: from normal to squamous carcinoma正常上皮轻度异型Adenoepithelial cell preneoplasia and genetic alterationsK-rasp53LOH: 3p, 9p, 17phTERTLung no
22、dule Histologic progression of atypical adenomatous hyperplasia (AAH)Low-grade AAHhigh-grade AAHhigh-grade AAH and anearly bronchioloalveolar carcinomawell-differentiated adenocarcinomaBreast lesionsDCISADHLCISLCISColumnar cell change Columnar cell change Columnar cell change with atypiaE-cadherin乳腺
23、癌分子类型与治疗乳腺癌分子类型与治疗Estrogen receptorC-erbB-2 (Her2) expressionLearning of pathologyAs a basic medical scienceGeneral pathology: concerned with the basic reactions of cells and concerned with the basic reactions of cells and tissues to abnormal stimuli that underlie all tissues to abnormal stimuli tha
24、t underlie all diseases.diseases.Systemic pathology: examines the specific responses of examines the specific responses of specialized organs and tissues to more or less specialized organs and tissues to more or less well defined stimuli.well defined stimuli.Major pointsDefinitionCausesPathogenesisP
25、athologic lesions: macro- or micro- changesmacro- or micro- changesEffects: Morphology Morphologic changeMorphologic change Characteristic of the diseaseCharacteristic of the disease Diagnostic of the etiologic processes Diagnostic of the etiologic processes Functional derangementsFunctional derange
26、ments Clinical significanceClinical significanceMorphology remains at the heart of diagnostic pathology.Pathology focuses on 4 aspects of disease Etiology:Etiology: Cause of disease. Cause of disease. Knowledge of etiology remains the backbone:Knowledge of etiology remains the backbone: Pathogenesis
27、:Pathogenesis: Mechanisms of development of disease. Mechanisms of development of disease. Understanding the nature of diseases Understanding the nature of diseases Morphology:Morphology: The structural alterations induced in cell and tissues. The structural alterations induced in cell and tissues.
28、Disease diagnosisDisease diagnosis Functional consequences: symptoms, singesFunctional consequences: symptoms, singes Functional consequences of the morphologic changes as observed Functional consequences of the morphologic changes as observed clinically.clinically. Treatment of diseases. Treatment
29、of diseases.Major pointsDefinitionCausesPathogenesisLesionsEffectsChinese ProverbI hear, I forgetI see, I rememberI do, I understandThe core of the science of pathology the study the pathogenesis of the diseaseOne etiologic agentone disease.Several etiologic agentsone disease.One etiologic agentseve
30、ral diseases.Genetic background of diseasePathogenesisThe sequencial events in the response of the cells or tissues to the etiologic agent, from the initial stimulus to the ultimate expression of the diseaseInflammatory:Tumorious:Metabolic:Developmental:Genetic:Aged:PathogenesisImmunologic, cytogenetic and molecular analyses of tissues and cells are increasingly becoming guides to render diagnoses, to assess prognosis, and to suggest therapy.
