8年制病理学英文课件：06肿瘤(133页PPT)

1、Neoplasia 第1页，共133页。Incidence and Mortality of CancerCancer is the first leading cause of death in China according to the public health statistic data in 2008.The common malignant tumors in China are from lung, liver, stomach, colon, esophagus, nasopharynx, breast, cervix, as well as leukemia and ly

2、mphoma. 第2页，共133页。Nomenclature Neoplasia means new growth, and a new growth is called a neoplasm.Tumor originally applied to the swelling caused by inflammation, but the non-neoplastic usage of tumor has almost vanished; thus, the term is now equated with neoplasm. Oncology is the study of tumors or

3、 neoplasms (Greek oncos = tumor). 第3页，共133页。The Concept of Tumor A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change. British oncolo

4、gist Willis 1952第4页，共133页。The Concept of TumorThe neoplasia results from genetic alterations that are passed down to the progeny of the tumor cells. These genetic changes allow excessive and unregulated proliferation that becomes autonomousThe entire population of neoplastic cells within an individu

5、al tumor arises from a single cell that has incurred genetic change, and hence tumors are said to be clonal 第5页，共133页。The Difference between Neoplastic and non-Neoplastic GrowthMonoclonality Abnormal morphology, metabolism and functionExcessive, unregulated and autonomous growthHeritable genetic cha

6、nges Harm to hostPolyclonalityNormal morphology, metabolism and functionLimited growthNo genetic alterationBenefit to host第6页，共133页。The Gross Features of TumorsSize and numberForm Color and consistenceHardnessInterface with surrounding tissue circumscribed or infiltrative (invasive)encapsulated or u

7、nencapsulated第7页，共133页。Multiple leiomyoma of the uterus (left) and lipoma (right)第8页，共133页。Menigioma (right)Villiform adenoma ofthe colon (right)第9页，共133页。Breast carcinoma第10页，共133页。Mucinous papillary cystadenoma of the ovary第11页，共133页。Neurofibroma in scalp第12页，共133页。Osteosarcoma in the humeral bone

8、Left is X-ray and right is gross photo第13页，共133页。Squamous cell carcinoma of the ankle (left)Malignant melanoma of the ankle (right)第14页，共133页。Fibrous adenoma of the breast第15页，共133页。Renal cell carcinoma 第16页，共133页。Osteosarcoma第17页，共133页。Parenchyma and Mesenchyma (stroma) Parenchyma: clonal neoplasti

9、c cells Mesenchyma: reactive stroma made up of connective tissue, blood vessels, and variable numbers of macrophages and lymphocytesParenchyma determines a tumors behavior and pathologic consequencesThe growth and evolution of tumors is dependent on stroma第18页，共133页。Papilloma of the skin. It is a be

10、nign tumor. Note the parenchyma and stroma of the tumor.第19页，共133页。Breast carcinoma. It is a malignant tumor.Note the parenchyma and stroma of the tumor. 第20页，共133页。Atypia and dysplasiaAtypia refers to the disimilated extent to which neoplastic parenchymal cells compare with the corresponding normal

11、 parenchymal cells, both morphologically and functionallyDysplasia is a term that literally means disordered growth. Dysplasia is encountered principally in epithelia, and it is characterized by a constellation of changes that include a loss in the uniformity of the individual cells as well as a los

12、s in their architectural orientation第21页，共133页。DifferentiationDifferentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionallyIn general, benign tumors are well differentiatedMalignant tumors are poo

13、rly differentiated 第22页，共133页。Anaplasia and Anaplastic NeoplasmLack of differentiation is called anaplasiaMalignant neoplasms that are composed of poorly differentiated cells are said to be anaplastic 第23页，共133页。Morphologic Changes of AtypiaPleomorphismcells and the nuclei Hyperchromatic nuclei Incr

14、eased nuclear-to-cytoplasm ratioMitoses (atypical, bizarre mitotic figures) Loss of polarityTumor giant cellsNecrosis 第24页，共133页。anaplasiahyperchromasia increased N:C ratio tumor giant cells 第25页，共133页。abnormal mitotic figures第26页，共133页。Tumor giant cells第27页，共133页。Growth and Spreading第28页，共133页。A tu

15、mor arises from a single cell i.e. monoclonal第29页，共133页。Rates of growthdoubling timegrowth fractioncell deathangiogenesis第30页，共133页。第31页，共133页。第32页，共133页。Rate of growthThe rate of growth of a tumor is determined by three main factors: the doubling time of tumor cellsthe fraction of tumor cells that

16、are in the replicative poolthe rate at which cells are shed and lost in the growing lesion第33页，共133页。Progression and HeterogeneityTumor progression and generation of heterogeneity. New subclones arise from the descendants of the original transformed cell by multiple mutations. With progression he tu

17、mor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive.第34页，共133页。 Angiogenesis v.s. Vasculogenesis angiogenesis factors angiogenesis inhibitorsTUMOR NEWVASCULARIZATION第35页，共133页。sustained angio-genesis VEGF inducer第36页，共133页。CANCER S

18、TEM CELLS AND CANCER CELL LINEAGES Stem cell asymmetric replicationCancer stem cell or tumor-initiating cellResistance to conventional therapiesNew strategy of tumor treatment第37页，共133页。Local InvasionNearly all benign tumors grow as cohesive expansile masses The growth of cancers is accompanied by p

19、rogressive infiltration, invasion, and destruction of the surrounding tissue. 第38页，共133页。Local InvasionGrowth patternsexpansive growth exophytic growth invasive growth 第39页，共133页。expansive growth: renal cell carcinoma第40页，共133页。follicular thyroid adenomaexpansive growth第41页，共133页。exophytic growth: l

20、eiomyoma第42页，共133页。Invasive growth: breast carcinoma第43页，共133页。Spreading of Tumor Direct spread Metastasis lymphatic metastasis hematogeneous metastasis transcoelomic metastasis 第44页，共133页。第45页，共133页。第46页，共133页。第47页，共133页。第48页，共133页。lymph node metastasis第49页，共133页。第50页，共133页。第51页，共133页。第52页，共133页。第5

21、3页，共133页。transcoelomic metastasis (seeding)第54页，共133页。Kreukenberg tumors第55页，共133页。The Clinical Aspects of Neoplasia Local and Hormonal EffectsBenign v.s. malignantCancer Cachexia Paraneoplastic SyndromesIn affected patients they may represent significant clinical problems and may even be lethalThey

22、 may mimic metastatic disease and therefore confound treatment They may represent the earliest manifestation of an occult neoplasm第56页，共133页。cachexiacac bad + hexis habit +iaweight losswasting of muscleloss of appetitegeneral debility 第57页，共133页。Cushings Syndrome (Glucocorticoid excess, ACTHoma)第58页

23、，共133页。GRADINGGrading of a cancer is based on the degree of differentiation of the tumor cellsLow grade v.s. high gradeWell differentiatedIntermediate differentiatedPoorly differentiated第59页，共133页。Grading well moderately poorlydifferentiated differentiated differentiatedlow grade intermediate high g

24、rade gradegrade I grade II grade III第60页，共133页。STAGINGThe staging of cancer is based on the size of the primary lesion, its extent of spread to regional lymph node, and the presence or absence of blood-borne metastasesTNM systemI to IV stages第61页，共133页。StagingThe TNM systemT TumorN NodeM Metastasis第

25、62页，共133页。TNM staging system：T：Primary tumorT0：in situ lesionT1-T4: Increase of tumor sizeN：regional lymph nodeN0：no metastases in lymph nodeN1-N3：number of involved lymph nodesM：distant metastasesM0: no distant metastasesM1：distant metastases第63页，共133页。CharacteristicsBenignMalignantDifferentiation/

26、anaplasiaWell differentiated; structure may be typical of tissue of originSome lack of differentiation with anaplasia; structure is often atypicalRate of growthUsually progressive and slow; may come to a standstill or regress; mitotic figures are rare and normalErratic and may be slow to rapid; mito

27、tic figures may be numerous and abnormalLocal invasionUsually cohesive and expansile well-demarcated masses that do not invade or infiltrate surrounding normal tissuesLocally invasive, infiltrating the surrounding normal tissues; sometimes may be seemingly cohesive and expansileMetastasisAbsentFrequ

28、ently present; the larger and more undifferentiated the primary, the more likely are metastasesComparisons Between Benign and Malignant Tumors 第64页，共133页。Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of the same origin (leiomyosarcoma).第65页，共133页。malignantbeni

29、gnborderline第66页，共133页。Nomenclature & ClassificationIn general, benign tumors are designated by attaching the suffix -oma to the cell of origin. Tumors of mesenchymal cells generally follow this rule Malignant tumors arising in mesenchymal tissue are usually called sarcomas (Greek sar = fleshy)Malig

30、nant neoplasms of epithelial cell origin, derived from any of the three germ layers, are called carcinomas 第67页，共133页。benign tumors -oma fibroma lipoma adenoma squamous cell papilloma papillary cystadenoma第68页，共133页。malignant tumors (cancers)epithelial： carcinomasquamous cell carcinoma adenocarcinom

31、a papillary cystadenocarcinomamesenchymal： sarcomafibrosarcoma liposarcoma 第69页，共133页。Exceptions: -blastomaNeuro-blastomaMedullo-blastomaNephro-blastomaOsteo-blastomaChondro-blastomaLipo-blastoma第70页，共133页。SchwannomaEwings sarcomaHodgkins lymphoma Wilms tumor第71页，共133页。malignant melanomamalignant sc

32、hwannoma malignant meningiomamalignant lymphomaoat cell carcinomaclear cell sarcomaseminomaleukemia第72页，共133页。The WHO Classification of Tumors第73页，共133页。Precancerous Conditions Certain non-neoplastic disorders mostly related with chronic inflammatory states, have a well-defined association with canc

33、er that they have been termed precancerous conditionsCertain forms of benign neoplasia also constitute precancerous conditions第74页，共133页。Pathologic ConditionAssociated Neoplasm(s)Etiologic AgentAsbestosis, silicosisMesothelioma, lung carcinomaAsbestos fibers, silica particlesBronchitisLung carcinoma

34、Silica, asbestos, smokingCystitis, bladder inflammationBladder carcinomaChronic indwelling urinary cathetersGingivitis, lichen planusOral squamous cell carcinomaInflammatory bowel diseaseColorectal carcinomaLichen sclerosisVulvar squamous cell carcinomaChronic pancreatitisPancreatic carcinomaAlcohol

35、ismHereditary pancreatitisPancreatic carcinomaMutation in trypsinogen geneReflux esophagitis, Barrett esophagusEsophageal carcinomaGastric acidsSialadenitisSalivary gland carcinomaSjgren syndrome, Hashimoto thyroiditisMALT lymphoma第75页，共133页。cancers associated with infectious agentsOpisthorchis, cho

36、langitisCholangiosarcoma, colon carcinomaLiver flukes Bile acidsChronic cholecystitisGallbladder cancerBacteria, gallbladder stonesGastritis/ulcersGastric adenocarcinoma, MALTHelicobacter pyloriHepatitisHepatocellular carcinomaHepatitis B and/or C virusMononucleosisB-cell non-Hodgkin lymphoma and Ho

37、dgkin lymphomaEpstein-Barr virusAIDSNHL, squamous cell carcinoma, Kaposi sarcomaHIV, human herpesvirus type 8OsteomyelitisCarcinoma in draining sinusesBacterial infectionChronic cervicitischronic pelvic inflammationsCervical/anal carcinomaHuman papillomavirus,gonorrhea, chlamydiaChronic cystitisBlad

38、der, liver, rectal carcinomaSchistosomiasis第76页，共133页。precancerous lesionsdysplasiacarcinoma in situ (CIS)invasive carcinoma第77页，共133页。dysplasia (atypical hyperplasia)第78页，共133页。dysplasia (atypical hyperplasia)第79页，共133页。slightmoderate severe CISintraepithelial neoplasia I IIIIIdysplasia第80页，共133页。C

39、IN IIcervical intraepithelial neoplasia第81页，共133页。CIN III第82页，共133页。normal CIS第83页，共133页。Molecular basis of cancer第84页，共133页。Molecular basis of cancerFundamental principles Nonlethal genetic damage lies at the heart of carcinogenesis A tumor is formed by the clonal expansion of a single precursor ce

40、ll that has incurred genetic damage (i.e., tumors are monoclonal)第85页，共133页。Molecular basis of cancerFour classes of normal regulatory genes are the principal targets of genetic damage. growth-promoting proto-oncogenesgrowth-inhibiting tumor suppressor genesgenes that regulate programmed cell death

41、(apoptosis)genes involved in DNA repair第86页，共133页。Molecular basis of cancerCarcinogenesis is a multistep process at both the phenotypic and the genetic levels, resulting from the accumulation of multiple mutations第87页，共133页。Flowchart depicting a simplified scheme of the molecular basis of cancer第88页

42、，共133页。ESSENTIAL ALTERATIONS FOR MALIGNANT TRANSFORMATION Self-sufficiency in growth signals usually as a consequence of oncogene activation Insensitivity to growth-inhibitory signals Evasion of apoptosisas a consequence of inactivation of p53 Limitless replicative potentialTelomerase activation 第89

43、页，共133页。ESSENTIAL ALTERATIONS FOR MALIGNANT TRANSFORMATION Sustained angiogenesis Ability to invade and metastasizeDefects in DNA repairImmune surveillance and escape第90页，共133页。SELF-SUFFICIENCY IN GROWTH SIGNALS: ONCOGENES Genes that promote autonomous cell growth in cancer cells are called oncogene

44、sTheir unmutated cellular counterparts are called proto-oncogenesOncogenes are created by mutations in proto-oncogenes and are characterized by the ability to promote cell growth in the absence of normal growth-promoting signalsTheir products are called oncoproteins 第91页，共133页。DNA related to the tra

45、nsforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260: 176-173 (1976)v-src oncogene derives from c-src proto-oncogene and contains mutation(s) that renders it hyperactive and unregulated第92页，共133页。OncogenesMutations convert proto-oncogenes into constitutively active c

46、ellular oncogenes that are involved in tumor development because the oncoproteins they encode endow the cell with self-sufficiency in growthTwo questions follow: What are the functions of oncogene products, the oncoproteins? How do the normally civilized proto-oncogenes turn into enemies within? 第93

47、页，共133页。OncogenesGrowth factorsGrowth factor receptors Signal transduction proteins (RAS)Nuclear-regulatory proteins (MYC)Cell cycle regulators第94页，共133页。第95页，共133页。第96页，共133页。The chromosomal translocation and associated oncogenes in Burkitt lymphoma and chronic myelogenous leukemia第97页，共133页。TUMOR

48、SUPPRESSOR GENESThe products of tumor suppressor genes apply brakes to cell proliferationThe protein products of tumor suppressor genes may function astranscription factorscell cycle inhibitorssignal transduction moleculescell surface receptorsregulators of cellular responses to DNA damage 第98页，共133

49、页。TUMOR SUPPRESSOR GENESRB geneThe first discovered tumor suppressor geneMutant in the patients with retinoblastomaKnudsons two-hit hypothesis of oncogenesis 第99页，共133页。第100页，共133页。第101页，共133页。TUMOR SUPPRESSOR GENESp53: Guardian of the GenomeA little over 50% of human tumors contain mutations in thi

50、s gene Activation of temporary cell cycle arrest (quiescence)Induction of permanent cell cycle arrest (senescence)Triggering of programmed cell death (apoptosis) 第102页，共133页。第103页，共133页。LIMITLESS REPLICATIVE POTENTIAL: TELOMERASE Most normal human cells have a capacity of 60 to 70 doublingsThis phen

51、omenon has been ascribed to progressive shortening of telomeres at the ends of chromosomes Re-expression of telomerase allows the cells to escape the bridge-fusion-breakage cycle, thus promoting their survival and tumorigenesis第104页，共133页。Sequence of events in the development of limitless replicativ

52、e potential第105页，共133页。ANGIOGENESIS Angiogenesis is thus a necessary biologic correlate of malignancy The molecular basis of the angiogenic switch involves increased production of angiogenic factors and/or loss of angiogenic inhibitorsAn anti-VEGF monoclonal antibody, bevacizumab, has recently been

53、approved for use in the treatment of multiple cancers 第106页，共133页。INVASION AND METASTASIS Invasion and metastasis are biologic hallmarks of malignant tumorsInvasion of the extracellular matrix (ECM)Vascular dissemination, homing of tumor cells, and colonization 第107页，共133页。A-D, Sequence of events in

54、 the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced adhesiveness, then secrete proteolytic enzymes, degrading the basement membrane. Binding to proteolytically generated binding sites and tumor cell migration follow.第108页，共133页。The met

55、astatic cascade. Sequential steps involved in the hematogenous spread of a tumor第109页，共133页。DEFECT OF DNA REPAIRHereditary Nonpolyposis Colon Cancer SyndromeXeroderma Pigmentosum DNA-repair genes themselves are not oncogenic, but their abnormalities allow mutations in other genes during the process

56、of normal cell division第110页，共133页。STROMAL MICROENVIRONMENT AND CARCINOGENESIS Tumors are comprised of a complex mixture of cells of numerous lineages, including the tumor cells themselves, innate and adaptive immune cells, fibroblasts, endothelial cells, and othersCross-talk between the ECM and tum

57、or cells play an important role in carcinogenesis 第111页，共133页。DYSREGULATION OF CANCER-ASSOCIATED GENES Point mutationChromosomal ChangeDeletionAmplificationEpigenetic changesmiRNAs and Cancer 第112页，共133页。c-abl proto-oncogene can beactivated by chromosome translocation 第113页，共133页。Molecular Basis of

58、Multistep Carcinogenesis Each cancer must result from the accumulation of multiple mutationsAdenoma-carcinoma sequence of the colonretical carcinomaInactivation of the APC tumor suppressor geneActivation of RAS Loss of a tumor suppressor gene on 18q Loss of p53第114页，共133页。Molecular model for the evo

59、lution of colorectal cancers through the adenoma-carcinoma sequence第115页，共133页。CHEMICAL CARCINOGENESISIndirect-acting agentsRequire metabolic conversion to an ultimate carcinogen before they become active Polycyclic and heterocyclic aromatic hydrocarbons in fossil fuelsBenzoapyrene is formed in the

60、high-temperature combustion of tobacco in cigarette smokingAromatic amines and azo dyesNitrosamine and amides Toxins of fungi (Aflatoxin B1 )第116页，共133页。CHEMICAL CARCINOGENESISDirect-acting agentsCancer chemotherapeutic drugs (alkylating and acylating agents) No metabolic conversion to become carcin