病理学课件：4-neoplasm(part II)肿 瘤

1、11Neoplasm/Tumor肿 瘤 (2)22Definition *Characteristics of neoplasm *Clinical features of neoplasm The molecular basis of cancerEtiology of cancerDiagnosis of tumor *Common tumors *Outlines33Essential alterations for malignant transformationcarcinogenNon lethal genetic damageGenetic alterations Prolife

2、ration Cell deathSustained angiogenesisEscape from immunity Additional mutations Clonal expansionSubclonesInvasion44Carcinogenesis is a multistep process at both the phenotypic and the genetic levels Nonlethal genetic damage: the heart of carcinogenesisMonoclonal (单克隆性)Four classes of normal regulat

3、ory genes are the principal targets of genetic damageThe growth-promoting proto-oncogenes (原癌基因)The growth-inhibiting tumor suppressor genes (肿瘤抑制基因) Genes that regulate programmed cell death (apoptosis)DNA repair genesOthers 55Carcinogenesis: The molecular basis of cancerGene mutation (genomic)Poin

4、t mutationAmplificationRearrangementDeletionInsertionMutations result in activation or inactivation of genes66OncogenesOncogenes: genes that promote autonomous cell growth in cancer cells Promote cell growth in the absence of normal mitogenic signals Oncoproteins: oncogenes products, resemble the no

5、rmal products of protooncogenes but are devoid of important regulatory elements. Proto-oncogenes: normal cellular counterparts of the oncogenesPhysiologic regulators of cell proliferation and differentiation77OncogenesGrowth factorsGrowth factor receptors: HER2 Signal-transducing proteins: ras, srcN

6、uclear transcription factors: myc, fos, junAdapted from Kumar: Robbins and Cotran: Pathologic Basis of Disease Mutations that affect cell cycle regulation88Gain of functionUsually somatic rather than germline alterationsMissense mutations: ras, src Gene amplifications: myc, Her2, c-metChromosomal tr

7、anslocationsBCR/ABL Philadelphia chromosome (费城染色体)Epigenetic modificationActivation of protooncogenesBRAF point mutation99Chronic myeloid leukemia Chromosomal translocations1010Gene amplificationsGreen: CEP17Red: HER2NormalAmplification1111Genes negatively regulate cell proliferation Can be inactiv

8、ated by genetic alterations (mutation/deletion) epigenetic modification Well known TSGsRb: cell cyclep53: guardian of the genome, DNA damage, cell cycle, apoptosis Others: APC, PTEN, p16, WT1, NF1, VHLTumor suppressor genes1212Cell cycle regulationCyclins (oncogene) : A, B, D, ECDKs: Cyclin-dependen

9、t kinasesCDKIs (CDK inhibitors, tumor suppressors) : p16, p21, p271313Adapted from Robbins Basic PathologyP53: the guardian of genome1414Mechanism of cell-cycle regulation by RB. In a resting cell, RB is a component of the E2F/DP1/RB complex, which represses gene transcription through the recruitmen

10、t of histone deacetylase, an enzyme that alters the conformation of chromatin, making it more compact. Phosphorylation of RB by cyclin D-CDK4 removes histone deacetylase from chromatin, allowing the activation of E2F transcriptional activity. E2F-mediated transcription of cyclins E and A, and of gen

11、es required for DNA replication, permit the passage through the G1 restriction point. 1515Both normal alleles of the RB locus must be inactivated (two hits) for the development of retinoblastomaIn familial casesBorn with one normal and one defective copysomatic mutation: just onceIn sporadic casesso

12、matic mutation on both RB alleles in one cell“two-hit” hypothesis of tumor suppressor gene二次打击学说 Knudson, in 19741616The role of APC in regulating the stability and function of -catenin1717Accumulation of neoplastic cells may result from mutations in the genes that regulate apoptosis BCL-2: activati

13、on by translocation or rearrangement, e.g. follicular lymphomaBAX: inactivation by mutationBCL-6: activation by translocation Evasion of apoptosis1818Figure: The extrinsic (death receptor-initiated) pathway of apoptosis, illustrated by the events following Fas engagement. Adapted from Kumar: Robbins

14、 and Cotran: Pathologic Basis of Disease 1919Defect in DNA repair systemMismatch repair (错配修复)Lynch Syndrome: germ line mutations in MMR the MSH2 (2p16) and MLH1 (3p21) genes each account for approximately 30% ofNucleotide excision repair (核苷酸剪切修复)Xeroderma Pigmentosum: defects in NER enzymes, enhan

15、ced sensitivity to UV lightDouble-stranded break repair (双链断裂修复)Breast and ovarian cancers: Brca1, Brca2 and ATM2020Function of ATM, Brca1 and Brca22121Telomerase activity and maintenance of telomere length are essential for the maintenance of replicative potential in cancer cellsNormal cells: lack

16、expression of telomerase (端粒酶) Shortened telomeres activate cell cycle checkpointsLeading to senescenceCells have disabled checkpointsDNA repair pathways inappropriately activated by shortened telomeres Leading to massive chromosomal instability and mitotic crisisStaving off mitotic catastrophe, ach

17、ieving immortalityLimitless replicative potential2222Telomere shortening and cell crisis, immortalization and transformation2323Epigenetic modificationChanges in gene expression that are independent of DNA base sequenceDNA methylation (甲基化)Hypermethylation in CpG islands: gene expression Hypomethyla

18、tion: destabilizes DNA structure Histone modifications (组蛋白修饰)Acetylation/Deacetylation transcriptional activation/silencingmiRNADouble-stranded, 22-base-pair-long RNA speciesBinding to mRNA degradation of the targeted transcript2424Most Cancers Involve Multiple Genetic ChangesMany cancers begin wit

19、h a benign mutation that, with time and more mutations leads to malignancyFurthermore, a malignancy can continue to accumulate genetic changes that make it even more difficult to treatIn 1990, Eric Fearon and Bert Vogelstein proposed a series of genetic changes that leads to colorectal cancer2525Ade

20、noma-carcinoma sequenceGerm-line or somatic mutationProoncogenes mutationLOH of additional cancer suppressor geneAdditional mutation Gross chromosomal alterations (aneuploid)2626Morphologic and molecular changes in carcinogenesis Note: It is the total number of genetic changes, not their exact order

21、, that is important.2727Tumors stimulate the growth of host blood vessels, a process called angiogenesis (血管生成)Essential for supplying nutrients to the tumor Tumor-associated angiogenic factorsProduced by tumor cells or derived from inflammatory cells that infiltrate tumors The two most important ar

22、e vascular endothelial growth factor (VEGF, 血管内皮生长因子)basic fibroblast growth factor (bFGF, 碱性纤维母细胞生长因子)Development of sustained angiogenesis2828Host Defense Against TumorsTumor ImmunityTumors are not entirely self and may be recognized by the immune system Immune recognition of autologous tumor cell

23、s may be a positive mechanism capable of eliminating tumors 2929Tumor antigensTumor specific antigenRepresent somatic mutations or alterations in protein (and other) processing unique to tumorsTend to be specific for individual patients tumors, making immunologic targeting for therapy complicated an

24、d highly personalizedTumor associated antigenReflect the production of normal proteins, either in excess or in a setting different from normal expressionDo not lead to effective immunologic responsesSome may serve as markers of cancer: CEA, AFP,CA19-9, CA125, etc.3030Host Defense Against TumorsCell-

25、mediated immunity is the dominant anti-tumor mechanism in vivo Cytotoxic T Lymphocytes play a protective role NK cells are capable of destroying tumor cells without prior sensitization Activated macrophages may kill tumors by mechanisms similar to those used to kill microbes Although antibodies can

26、be made against tumors, there is no evidence that they play a protective role under physiologic conditions 3131Immunosurveillance 免疫监视Several escape mechanisms have been proposedSelective outgrowth of antigen-negative variantsLoss or reduced expression of MHC antigensLack of co-stimulationImmunosupp

27、ressionAntigen masking (抗原化妆）Apoptosis of CTL 3232Oncogenes activationTSGs inactivationTelomarase activationEvasion of apoptosisAngiogenesisHost defensesparenchymastromaMutationAmplificationDeletionTranslocationEpigenetic modification3333Definition *Characteristics of neoplasm *Clinical features of

28、neoplasm The molecular basis of cancerEtiology of cancerDiagnosis of tumor *Common tumors *Outlines3434Carcinogenic agentsAgents that cause genetic damage and induce neoplastic transformation of cellsChemical carcinogens: carcinogensPhysical factors: radiant energyBiologic factors: viruses and other

29、 microbes3535Adapted from Kumar: Robbins and Cotran: Pathologic Basis of Disease Initiation and promotion of a neoplasm(多环烃)(巴豆油)Chemical carcinogens3636Chemical carcinogensInitiation (激发) : causer - initiator Causes permanent DNA damage (mutations)Rapid and irreversible and has memory Initiation al

30、one is not sufficient for tumor formation Promotion (促进): agent - promoter Do not affect DNA directlyInduce tumors in initiated cells and are reversible Nontumorigenic by themselvesProgressionGrowth becomes autonomous, i.e., independent of the carcinogen or the promoterprevention3737Table: Major Che

31、mical Carcinogens in Humans 3838Mesothelioma (间皮瘤)Exceedingly rare in the general populationHas been reported to occur in 2% to 3% of heavily asbestos exposed workersThe latent period is usually about 20 years but can be twiceThe pathogenesis of asbestos-associated mesotheliomas is obscure3939Radiat

32、ion carcinogenesisUV rays of sunlightX-raysNuclear fission (原子核裂变)Radionuclides (放射性核素)DNA damage: Chromosome abnormality4040VirusRNA oncogenic viruses DNA oncogenic viruses BacteriaHelicobacter pylori (幽门螺杆菌)Viral and microbial oncogenesis4141Viral infections are responsible for some 15% of all hum

33、an cancersRNA oncogenic viruses HTLV-1: T-cell leukemia/ lymphomaHCV: HCCDNA oncogenic viruses HPV: cervical carcinomaEBV: lymphoma, nasopharyngeal carcinoma, etc.HBV: HCCHHV8: Kaposi sarcomaViral and microbial oncogenesis4242HPV virus E6 and E7 proteins cause inactivation of p53 and RB genes, resul

34、ting in increased cell proliferation and suppression of apoptosis 4343Small seagull-shaped organismPresent in the surface mucous layer which covers the surface epithelium and the glandular lumenHelicobacter pylori (幽门螺杆菌)4444Other risk factor for carcinogenesisHormoneEstrogen: breast cancer, endomet

35、rial carcinomaAndrogen: prostate cancerDiets and lifestyleHigh fat diet: CRC, BC, PCSedentary lifestyleAlcohol consumption: HCCGeographic/environmental factors Hereditary factorsHereditary cancer syndromeInherited predisposition to cancer 4545Inherited Cancer Syndromes (Autosomal Dominant)GeneInheri

36、ted PredispositionRBRetinoblastomap53Li-Fraumeni syndrome (various tumors)p16INK4AMelanomaAPCFamilial adenomatous polyposis/colon cancerNF1, NF2Neurofibromatosis 1 and 2BRCA1, BRCA2Breast and ovarian tumorsMEN1, RETMultiple endocrine neoplasia 1 and 2MSH2, MLH1, MSH6, PMS2Hereditary nonpolyposis col

37、on cancerPATCHNevoid basal cell carcinoma syndromeInherited predisposition to cancer4646Inherited Autosomal Recessive Syndromes of Defective DNA RepairXeroderma pigmentosum (着色性干皮病): XPsAtaxia-telangiectasia (毛细血管扩张性共济失调症): ATMBloom syndrome (Bloom 综合症): BLMFanconi anemia (Fanconi 贫血) Werner syndrom

38、e: WRN4747Familial CancersFamilial clustering of cases, but role of inherited predisposition not clear for each individualBreast cancer (BC): BRCA1/2Ovarian cancer: BRCA1/2Pancreatic cancerSporadic BC: 90-95% familial BC: 510% People having mutations in BRCA1/247-55% probability of developing BC 17-

39、39% risk of ovarian cancer by the age 70 years4848Definition *Characteristics of neoplasm *Clinical features of neoplasm The molecular basis of cancerEtiology of cancerDiagnosis of tumor *Common tumors *Outlines4949Diagnosis of cancerPathologic methods HistopathologyImmunohistochemistry Flow cytomet

40、ryElectron microscopyCytologic DiagnosisMolecular diagnosisBiochem assays5050Pathological diagnosis of tumorBenign or malignantOrigination: primary or metastaticHistogenesis (direction of differentiation)Degree of differentiationSubtype, classificationPrognosisSpreadMolecular features 5151Histologic

41、al diagnosisHistologic diagnosis: the definitive method of establishing the diagnosis of a neoplasmResection: the entire neoplasm removed at surgery Biopsy: a sample of the neoplasm obtained either by incisional biopsy or with a large-bore cutting needle5252Techniques of histological diagnosisFrozen

42、 Section: sections are prepared from quickly frozen tissue at the time of surgical operationTakes about 15 minParaffin Section: tissues are formalin-fixed, embedded in paraffin and then cuttedPermanent sectionsTakes about 24 hrsProvide the best material for microscopic diagnosis. Hematoxylin and eos

43、in (H&E) stain is the standard staining5353Cell type or subpopulationSpecific molecules: hormone, receptorProliferation potentialOncoproteinsDifferential diagnosisClassificationPredictive or prognostic markersImmunohistochemistry5454Immunohistochemical staining of ER (A) and Her-2 (B) and Her-2 FISH

44、 (C) 5555Flow cytometryCell-surface antigensWidely used in the classification of leukemias and lymphomas Advantage: multiple moleculesDNA contentAneuploidyPolyploid5656Cytologic diagnosisExfoliated cellsSputum, urine, cerebrospinal fluid and body fluidsBrushing or scraping of a lesion that has been

45、visualized by endoscopy Fine-needle aspiration (FNA)Cells obtained are smeared on slides for cytologic examinationCT scan and ultrasonography may help guide the needle into the mass5757squamous cell carcinoma5858Molecular diagnosisDiagnosis of malignant neoplasmsPrognosis of malignant neoplasms Guid

46、ance of targeted therapyDetection of minimal residual diseaseDiagnosis of hereditary predisposition to cancer -Germ line mutations5959Big science: The cancer genome challenge 6060Cancer genome6161Molecular profile of tumors- high through put analysisGenomicsGenomic chip: genomeExpression chip: trans

47、criptomeProteomicsDetermines the protein profiles of tumorsCancer genomeHigh through-put sequencing of whole genome (or exome) of a tumorPersonal genome6262RTK signaling and resulting cellular responses can be modulated by using monoclonal antibodies and small molecule inhibitors6363PSA (prostate sp

48、ecific antigen)Prostate cancerCEA (carcinoembryonic antigen)Cancers of colon, lung, pancreas, breast and stomachAFP (alpha-fetoprotein)Hepatocellular carcinoma CA-125Ovarian cancerCA-199Cancers of colon, pancreas, breastBiochemical assays6464Definition *Characteristics of neoplasm *The molecular bas

49、is of cancerEtiology of cancerDiagnosis of tumor *Clinical features of neoplasmCommon tumors *Outlines6565Common tumorsEpithelial tumorsBenign: papilloma (Squamous, urothelial), adenomaMalignant: SCC, BCC, urothelial carcinoma, adenocarcinomaMesenchymal tumorsBenign: fiborma, lipoma, leiomyoma, hema

50、ngiomaMaignant: liposracoma, leiomyosarcoma, rhbdomyosarcoma, osteosarcomaTeratoma (mature/immature), melanoma6666Benign epithelial neoplasmsPapilloma (乳头状瘤)A benign neoplasm arising from lining epithelium, with a papillary growth patternSites of involvement: skin and mucosaGrossFinger shaped, exoph

51、ytic papillae protrude to the surface, usually solitaryMicroscopyCentral fibrovascular core Covered by well differentiated squamous, glandular epithelium or urothelium noninvasive676768686969A benign epithelial neoplasms producing gland patterns or derived from glandsSites of involvementThyroid, ova

52、ry, salivary gland, gastrointestinal tract, etc.Gross Polypoid, nodular, cysticUsually well demarcated w/o capsulAdenoma (腺瘤)7070MicrospyEpithelial cells with mild atypia forming glandular structureGlands are varied in size and shape7171Follicular adenoma of the thyroid7272serous cystadenoma 7373浆液性

53、上皮粘液性上皮7474Papillary mucinous cystadenoma of the ovary75757676Pleomorphic adenoma777778787979Malignant epithelial neoplasma Squamous cell carcinoma (鳞状细胞癌)A malignant tumor derived from squamous epitheliumSites of involvementOrgans that normally lined by squamous epithelium: skin, esophagus, cervix,

54、 penisOrgans where squamous metaplasia is frequent occur: bronchus, gallbladder, renal pelvis Gross Nodular, ulcerative or infiltrativeFirm, grey-white in color, ill defined8080SCC of the esophagusSCC of the lung8181MicroscopyAtypical squamous cells arranged in lobules showing various degree of kera

55、tinizationKeratin “pearls” (角化珠): eosinophilic aggregates of keratin surrounded by concentric (“onion skin”) layers of squamous cellsIntercellular bridges (细胞间桥): slender gaps between adjacent cells, which are traversed by fine strands of cytoplasmDyskeratosis (角化不良): single-cell keratinization Grad

56、ing：on basis of the extent of keratinization82828383Normal skinSCC8484Squamous cell carcinoma 鳞状细胞癌858586868787Basal cell carcinoma (基底细胞癌) Tumor cells resemble the normal epidermal basal cell layerTends to occur at sites subject to chronic sun exposure slow-growing, rarely metastasizes 8888Adenocar

57、cinoma (腺癌) Malignant neoplasm derived from glandular epitheliumSites of involvement: commonly seen in GI tract, breast, prostate, lung, endometrium, thyroid, etc.Gross Polypoid, nodular, ulcerative, Firm, grey-white in color, ill defined89899090MicroscopyAtypical epithelial cells forming glandsGlan

58、ds are varied in shape and sizeGrading: on the basis of the extent of glandular appearancesVariants: medullary , mucinous , signet ring cell 9191Infiltrating duct carcinoma9292Papillary carcinoma of the thyroid939394949595969697979898 Urothelial Carcinoma (尿路上皮癌) Malignant neoplasm derived from urot

59、heliumSites of involvement: bladder, urethra, ureter, renal pelvicGross: papillary, polypoid, flatMicroscopy: atypical urothelial cells forming papillary structure or solid nestsGradingLow grade: mild dysplasiaHigh grade: severe dysplasia9999low gradehigh gradeUrothelial Carcinoma100100Fibroma (纤维瘤)

60、 A benign tumor composed of proliferative fibroblasts Sites of involvement: subcutis, fasciaGross: firm, grey white well demarcated or encapsulated noduleMicroscopy: well differentiated fibroblasts intermingled with collagenous fibers forming fasciclesMesenchymal neoplasms101101102102Lipoma (脂肪瘤)A b