北京大学医学院《病理学》肿瘤

1、肿 瘤NEOPLASM/TUMORPancreatic cancer 胰腺癌 Neuroendocrine tumor 神经内分泌肿瘤1-2%65% Ductal adenocarcinoma 导管腺癌Incidence most 5 years survival 3-5%肿瘤病理诊断Global Cancer Statistics 56%64%in developing countries Cancer statistics in US, 2014CA CANCER J CLIN 2014Cancer statistics in US, 2014CA CANCER J CLIN 2014Ca

2、ncer statistics in China, 2013新发肿瘤人数死亡人数312万人270万人No.1 cause of human death in ChinaMorbidity (发病率) Mortality (死亡率) Six person are Dx of Cancer in one minuteCommon Cancers in China源自2012中国肿瘤登记年报Please rememberPathologic evaluation is still the golden standard in tumor diagnosisTumor pathology is the

3、 starting point for understanding of tumorThe great significance of tumor research OverviewDefinition *Characteristics of neoplasm ( benign and malignant) *The molecular basis of cancerEtiology of cancerDiagnosis of tumor *Clinical features of neoplasmCommon tumors *Nature of neoplasm solitary massI

4、nflammation-like massWhere is tumor? diffusiveDefinition A neoplasm is abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persist the same excessive manner after cessation of the stimuli which evoke the change. Willis Neoplasia (new growth i

5、n Greek,肿瘤形成): the process of abnormal and uncontrolled growth of cells in a tissue or organ, usually forming a distinct mass. GlossaryNeoplasm (a tumor, 肿瘤): neoplastic mass of cellsTumor (swelling in Latin) is a synonym forneoplasm.Cancer: malignant neoplasm (carcinosor crab in Greek) Oncology (肿瘤

6、学): the study of neoplasms Carcinogenesis:(癌发生）: mechanism of neoplasia (Tumorigenesis)Transformation（转化）: cancers induced in experimental Immortalization（永生化）: unlimited cell growth, induced in experimental, incomplete transformationThe characteristics of tumorAutonomous growth: loss of normal grow

7、th controls, independence of stimuliPhenotypes maintaining through cell divisionMonoclonal cell derivationHarmful to host: loss of function, deathGenetic basis: genetic mutationNeoplasiaReactive hyperplasiaGrowthAutonomy, unlimitedResponse, limitedCellsmonoclonalpolyclonalGeneticmutationNoFunctionNo

8、nRepair, protectionHost Damage or deathNo or little damagedifference between tumor and reactive hyperplasiaCategories of tumorsBenign tumor: localized and relatively limited growth. Malignant tumor: unlimited growth, invade (浸润), destroy and spread to distant sites (metastasize转移). Cancer: carcinoma

9、癌deriving from epithelia sarcoma肉瘤deriving from mesenchyma leukemia白血病cancer of hematopoietic tissueSolid tumor: forming a massLeukemia: diffusing infiltration without a massTumor pathologythe biological basis of tumorsGross Morphology: size, shape, color, growth pattern etc HistopathologyArchitectu

10、re Differentiation: Atypia: anaplasia; Dysplasiathe biological behaviors of tumorsGrowth (or death)Invasion or spreadProgression: tumor heterogeneityTumor pathology the biological basis of tumorsGross Morphology: size, shape, color, growth pattern etc HistopathologyArchitecture Differentiation: Atyp

11、ia: anaplasia; DysplasiaShapeNumberSingle, multiple (数个-上千个）Familial adenomatous polyposis (FAP) 大肠家族性腺瘤性息肉病 SizeInfluencing factorsstage location nature (benign or malignant) Diagnostic markerPrognostic marker lung carcinoma lipomahemangiomamelanomachloromarenal cell carcinomaColorConsistencyInflue

12、ncing factors types Consistencysecondary changes cystic change, necrosis, calcification, ossification etc. Crab Cancer Benign tumor All of benign tumors remain localized. Nearly all benign tumors do not invade surrounding tissues, develop a rim of compressed connective tissue called capsule(包膜), Som

13、e are well demarcated without capsule. Some are exceptions. Growth Pattern: Expansive growthGrowth Pattern: Invasive growth Malignant tumors Invade and destroy surrounding tissuesDo not develop capsule Pseudo-capsule may developed in some slowly growing cancersRadical surgery must be performed to re

14、move all cancer tissues. Surgical margin must be carefully examined.Breast carcinoma Infiltrative massSquamous cell carcinoma of the penisSquamous cell carcinoma of the cervix Ulcerative growth Exophytic growthulcerativePolypoidCombinedInvade through tissue space、interspace outside lymph vessel, blo

15、od vessel and lamellar sheath to adjacent organInvasion 浸润 (direct spread)Squamous cell carcinomaCharacteristics of Benign NeoplasmsGross Well defined Slow growth Expanding growthCharacteristics of Malignant NeoplasmsGross Poorly definedFast growth: necrosis, ulcerativeInvasive growthTumor pathology

16、 the biological basis of tumorsGross Morphology: size, shape, color, growth pattern etc HistopathologyArchitecture Differentiation: Atypia: anaplasia; DysplasiaParenchyma (实质) : tumor cells which determine the nature of the tumorStroma (间质): supportive tissues Architecture of tumorconnective tissues

17、 blood vessels nervous tissuesDifferentiation (分化)- the maturation of parenchymaPathology: the extent to which tumor cells resemble comparable normal cells, both morphologically and functionallyBenign tumors: well-differentiated Malignant tumors: loss of differentiation with varying degree.Degree of

18、 differentiation generally relates to its biological behavior Atypia (非典型性、异型性)1. Cytology of tumor cells:nuclear atypia (or pleomorphic)2. Disorganized architecture: disordered, growth pattern Atypia is prominent in malignant tumors Atypia is minimal in benign tumors Atypia accompanies failure of d

19、ifferentiationAtypia refers to the differences between the tumor and tissue from which it originated both cytologically and structurallyRelationship of Differentiation and AtypiaWell-dif.Moderately-dif.Poorly-dif.De- or Un-dif.No- or low atypiaAtypiaProminent atypiaAnaplasia(间变）, (pleomorphic or pri

20、mitive) Pleomorphism (多形性) Nuclear atypia Abnormal nuclear morphology (异常核形态) Abnormal mitoses (异常核分裂象) Loss of polarity (极性丢失) Cytoplasmic changesAtypia of tumor cellCellular atypia Size: larger than normal cells: the ratio of nuclear vs cytoplasmShape: varying in shape and size: irregularityTumor

21、giant cells: giant nucleus or multinucleateBizarre tumor cells: giant and irregularPleomorphismUndifferentiated status: small primitive tumor cells, similar to lymphocytesNuclear atypiaLarge nuclei and variation in shape and sizeHyperchromatic nuclei 染色质深染Chromatin aggregated under nuclear membraneP

22、rominent nucleoli 大核仁Increased N/C ratio (nucleus/cytoplasm 核浆比值) (normal:1:41:6; cancer: 1:1)Bizarre and multiple nuclei Aneuploid or polyploid highly proliferation activitySquamous cell carcinomaPleomorphic sarcomabenignmalignantmalignantPNETUndifferentiated or primitive tumorMitoses 核分裂像: increas

23、e or abnormalThe increasing number of mitoses: reflecting the higher proliferative activity of the tumor cells.Pathologic mitoses: malignant neoplasm have atypical, bizarre mitotic figures: tripolar, quadripolar, or multipolar, abortive, unequal mitoses. Figure: Normal mitosis. Images obtained with

24、a confocal laser scanning microscope from cultured cells. An interphase nucleus and several nuclei are in several phases of mitosis. DNA appears red, and microtubules in the cytoplasm are blue. Medium magnification. Abnormal mitosesAsymmetricTripolarQuardripolarAbortiveStructure and function of cent

25、rosomesAbnormal mitoses caused by amplified centrosomes, and the consequential destabilization of chromosomes.Disordered organization of tumor cellsLoss in normal orientationLoss in normal polarity (极向) in epitheliaLoss in secreted products or too much abnormal productsLoss in intercellular junction

26、 complexDisordered covering epitheliaSquamous；Transitional；Columnar:Increased cellular layers:Loss of polarity:Loss of differentiation: basal cell to differentiatedFigure: Diagrams of stratified and pseudostratified epithelial tissue. A: Stratified squamous epithelium. B: Transitional epithelium. C:

27、 Ciliated pseudostratified epithelium. The goblet cells secrete mucus, which forms a continuous mucous layer over the ciliary layer. SkinSquamous cell papillomaSquamous cell carcinomaThe disordered glandular epitheliaVarying in shape or sizeIrregularIncreased cellular layersDysfunction of secretion:

28、 loss or excess secretion Glandular epithelia Adenoma Adenocarcinoma Disordered mesenchymal tumorsIncreased cellularity: hypercellularityIncreased mitosesLoss of normal architectureDysfunctionAdipose tissue Lipoma Liposarcoma Smooth muscle Leiomyoma Leiomyosarcoma Characteristics of Benign Neoplasms

29、Gross: Well definedSlow growth: seldom necrosis or hemorrhageExpanding growthHistology: Low atypia: differentiated tumor cell, rare mitoses, without abnormal mitoses Characteristics of Malignant NeoplasmsGross:Poorly definedFast growth: necrosis, hemorrhage, ulcerationInvasive growth:Histology:Atypi

30、a: poorly-differentiated or undifferentiated, pleomorphic, abnormal mitosesDysplasia（异型性增生） (Atypical hyperplasia，非典型性增生)Disordered growth of epithelial cellsLoss in the uniformity of epithelial cells Loss in normal architectural orientationVariation in shape and size of cellsHyperchromatic nuclei M

31、ore mitotic figures May be reversible to a certain point with stimulus removed癌变过程形态与分子改变 Intraepithelial neoplasia上皮内瘤变Mild dysplasia: lower 1/3Moderate dysplasia: more than lower 1/3, but less than lower 2/3Severe dysplasia: More than 2/3, not whole layerCervical intraepithelial neoplasia (CIN) Dy

32、splastic columnar epitheliumCarcinoma-in-situ 原位癌Definition: The whole layer of epithelium is involved, but without invasion (with intact basement membrane)Represents a very early stage of malignancyImportant to diagnose at this stage since if left alone will become invasive whereas if treated now i

33、s often completely curativeExamples breast ductal or lobular carcinoma in situ skin squamous cell carcinoma in situ Figure: Carcinoma in situ. This low-power view shows that the entire thickness of the epithelium is replaced by atypical dysplastic cells. There is no orderly differentiation of squamo

34、us cells. The basement membrane is intact and there is no tumor in the subepithelial stroma. B, A high-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface. Carcinoma in situInvasive

35、carcinomaPrecancerous Lesions 癌前病变(Preneoplastic disorders)Some epithelial lesions with predispositions to development of malignant neoplasmChronic atrophic gastritisChronic ulcerative colitisAdenoma of colon: Familial AdenomatosisDysplasia of epithelia: cervix, esophagus, endometriumMalignant chang

36、e: 恶变 Cancers from precancerous lesions or benign tumor Cancer Epidemiology流行病学Geographic and environmental factorsGenderAgeHeredityAcquired preneoplastic disordersGeographic and environmental factors Geographic variations Gastric and Esophagus Ca Nasopharygeal Ca Cervic Ca Hepatocarcinoma Adult T c

37、ell lymphoma/leukemia Nasal NK/T lymphoma源自2012中国肿瘤登记年报PREVALENCE OF HTLV-1 INFECTIONLife styleColon rectal:Breast:Gastric:Lung:Biological agentsDNA Virus: EBV: lymphoma, nasopharygeal carcinoma HPV: cervic carcinoma HBV: hepatocellular carcinoma KSV (HHV8): Kaposi sarcoma Polyoma virus: Merkel Cell

38、 tumor RNA virus: HCV: hepatocellular carcinoma HTLV-1: T cell lymphoma/leukemia HIV-1: Kaposi sarcoma, lymphoma Bacteria: Helicobacter pylori: stomach carcinoma, MALTomaThe frequency of occurrence of most types of cancer varies greatly at different ages.Children: leukemia, -blastomas, sarcomas.Adul

39、ts: carcinomas, the frequency of carcinoma increases with age. Most cancer mortality occurs between ages 55 and 75 years. AgeGender Men: Lung: Liver: Prostate:Women:Breast:Ovary:Cervic:Evidence now indicates that for a large number of cancer types, including the most common forms, there exist not on

40、ly environmental influences but also hereditary predispositions. Heredity 遗传性Inherited Cancer Syndromes (Autosomal Dominant)GeneInherited PredispositionRBRetinoblastomap53Li-Fraumeni syndrome (various tumors)p16INK4AMelanomaAPCFamilial adenomatous polyposis/colon cancerNF1, NF2Neurofibromatosis 1 an

41、d 2BRCA1, BRCA2Breast and ovarian tumorsMEN1, RETMultiple endocrine neoplasia 1 and 2MSH2, MLH1, MSH6Hereditary nonpolyposis colon cancerPATCHNevoid basal cell carcinoma syndromeInherited Predisposition to CancerRetinoblastoma 视网膜母细胞瘤Familial adenomatous polyposis of the colon 结肠家族性腺瘤性息肉病Neurofibrom

42、atosis 神经纤维瘤病 Inherited Predisposition to CancerFamilial CancersFamilial clustering of cases, but role of inherited predisposition not clear for each individualBreast cancer: BRCA1Ovarian cancer: BRCA1Pancreatic cancerInherited Autosomal Recessive Syndromes of Defective DNA RepairXeroderma pigmentos

43、um (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 syndrome: WRNXeroderma pigmentosumCarcinogenesis: The molecular basis of cancerGene mutation (genomic): Point mutation Amplification Rearrangement Deletion InsertionChromosome a

44、bnormality (cytogenetic): Numeric: Aneuploid, polyploid: chromosome copy Structure: Gain or loss, amplification Chromosome translocation: gene fusion Mutations result in activation or inactivation of genesGenetic abnormality in carcinogenesisThe molecular basis of cancerNonlethal genetic damage lies

45、 at the heart of carcinogenesis. Tumor is monoclonal (单克隆性)Four classes of normal regulatory 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 repa

46、ir genesOthers: Carcinogenesis is a multistep process at both the phenotypic and the genetic levels. Figure: Diagram depicting the use of X-linked isoenzyme cell markers as evidence of the monoclonality of neoplasms. Because of random X inactivation, all females are mosaics with two cell populations

47、 (with G6PD isoenzyme A or B in this case). When neoplasms that arise in women who are heterozygous for X-linked markers are analyzed, they are made up of cells that contain the active maternal (XA ) or the paternal (XB ) X chromosome but not both.Adapted from Robbins Basic PathologyThe clonal analy

48、sis of tumorsThe clonal analysis of tumorsT cell receptor (TCR) genes: T cells: lymphoma or reactive hyperplasiaB cell IgH gene: B cells: lymphoma or reactive hyperplasiaIg Light chain expression: kappa or lambdaSelf-sufficiency in growth signalsInsensitivity to growth-inhibitory signalsDefects in D

49、NA repairEvasion of apoptosis Limitless replicative potentialSustained angiogenesisAbility to invade and metastasizeEssential alterations for malignant transformation Genes that promote autonomous cell growth in cancer cells are called oncogenes, and their normal cellular counterparts are called pro

50、tooncogenes. Protooncogenes are physiologic regulators of cell proliferation and differentiation; oncogenes are characterized by the ability to promote cell growth in the absence of normal mitogenic signals. Oncogenes products, called oncoproteins, resemble the normal products of protooncogenes with

51、 the exception that oncoproteins are devoid of important regulatory elements.Self-sufficiency in growth signals: oncogenes (癌基因)C-oncogene of cellsProto-oncogenes activated into Oncogenes through genetic mutationA proto-oncogene is a normal cellular gene that can incur a mutation to become an oncoge

52、ne1. Missense mutations: ras, src 2. Gene amplifications: myc, fos, erb3. Chromosomal translocations: myc, met4. Viral integration: mycActivation of protooncogeneOncogenes:Growth factorsGrowth factor receptors: Her2 Signal-transducing proteins: ras, src,Nuclear transcription factors: myc, fos, junAd

53、apted from Kumar: Robbins and Cotran: Pathologic Basis of Disease The products of oncogenesCell cycle regulation Cyclin D (oncogene) Cyclins: A, B, D, E CDKs: Cyclin-dependent kinases CDKIs (tumor suppressors): Cyclin-dependent kinase inhibitors: p16, p21, p27The proteins that apply brakes to cell p

54、roliferation are the products of tumor suppressor genes, which can be inactivated by genetic alterations (mutation/deletion) and epigenetic modification: hypermethylation (甲基化 ), by oncoproteins (HPV E6, HBV X, EBV LMP-1). P53: guardian of the genome: DNA damage, cell cycle, apoptosis Rb: cell cycle

55、 PTEN: inhibitor of growth receptors APC-b-catenin pathway: growth, adhesion p16: cell cycle, senescenceLoss of growth-inhibitory signals: TSGTumor suppressor genesTumor Suppressor Gene Both normal alleles of the RB locus must be inactivated (two hits) for the development of retinoblastoma.In famili

56、al cases, children are born with one normal and one defective copy of the RB gene. They lose the intact copy in the retinoblasts through some form of somatic mutation (point mutation, interstitial deletion of 13q14, or even complete loss of the normal chromosome 13). In sporadic cases, both normal R

57、B alleles are lost by somatic mutation in one of the retinoblasts. Knudson, in 1974 “two-hit” hypothesis of tumor suppressor gene二次打击学说Pathogenesis of retinoblastoma. Two mutations of the RB locus on chromosome 13q14 lead to retinoblastoma. In the familial form, all somatic cells inherit one mutant

58、RB gene from a carrier parent. The second mutation affects the Rb locus in one of the retinal cells after birth. In the sporadic form, both mutations at the RB locus are acquired by the retinal cells after birth.Mechanism of cell-cycle regulation by RB. In a resting cell, RB is a component of the E2

59、F/DP1/RB complex, which represses gene transcription through the recruitment 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 transcri

60、ptional activity. E2F-mediated transcription of cyclins E and A, and of genes required for DNA replication, permit the passage through the G1 restriction point. Adapted from Kumar: Robbins and Cotran: Pathologic Basis of Disease Role of RB as a cell-cycle regulator. Various growth factors promote th