1、 第1页，共133页。Incidence and Mortality of Cancer Cancer 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 lymphoma.
2、 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 neopl
3、asms (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 oncologist W
4、illis 1952第4页，共133页。The Concept of Tumor The 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 autonomous The entire population of neoplastic cells within an individual t
5、umor 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 changes
6、 Harm to host Polyclonality Normal morphology, metabolism and function Limited growth No genetic alteration Benefit to host第6页，共133页。The Gross Features of Tumors Size and number Form Color and consistence Hardness Interface with surrounding tissue circumscribed or infiltrative (invasive) encapsulate
7、d or unencapsulated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 humera
8、l boneLeft 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 neo
9、plastic cells Mesenchyma: reactive stroma made up of connective tissue, blood vessels, and variable numbers of macrophages and lymphocytes Parenchyma determines a tumors behavior and pathologic consequences The growth and evolution of tumors is dependent on stroma第18页，共133页。Papilloma of the skin. It
10、 is a benign 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 dysplasia Atypia refers to the disimilated extent to which neoplastic parenchymal cells compare with the correspondi
11、ng normal parenchymal cells, both morphologically and functionally Dysplasia 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 wel
12、l as a loss in their architectural orientation第21页，共133页。Differentiation Differentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally In general, benign tumors are well differentiated Malignant t
13、umors are poorly differentiated 第22页，共133页。Anaplasia and Anaplastic Neoplasm Lack of differentiation is called anaplasia Malignant neoplasms that are composed of poorly differentiated cells are said to be anaplastic 第23页，共133页。Morphologic Changes of Atypia Pleomorphism cells and the nuclei Hyperchro
14、matic nuclei Increased nuclear-to-cytoplasm ratio Mitoses (atypical, bizarre mitotic figures) Loss of polarity Tumor giant cells Necrosis 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 Spre
15、ading第28页，共133页。A tumor 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 growth The rate of growth of a tumor is determined by three main factors: the doubling time of tumor cells the fractio
16、n of tumor cells that are in the replicative pool the 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.
17、 With progression he tumor 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 ind
18、ucer第36页，共133页。CANCER STEM CELLS AND CANCER CELL LINEAGES Stem cell asymmetric replication Cancer stem cell or tumor-initiating cell Resistance to conventional therapies New strategy of tumor treatment第37页，共133页。Local Invasion Nearly all benign tumors grow as cohesive expansile masses The growth of
19、cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. 第38页，共133页。Local Invasion Growth 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4
20、1页，共133页。exophytic growth: leiomyoma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1
21、33页。第51页，共133页。第52页，共133页。第53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 Effects Benign v.s. malignant Cancer Cachexia Paraneoplastic Syndromes In affected patients they may represent significant clinical prob
22、lems and may even be lethal They 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 (Glu
23、cocorticoid excess, ACTHoma)第58页，共133页。GRADING Grading of a cancer is based on the degree of differentiation of the tumor cells Low grade v.s. high grade Well differentiated Intermediate differentiated Poorly differentiated第59页，共133页。Grading well moderately poorlydifferentiated differentiated differ
24、entiatedlow grade intermediate high grade gradegrade I grade II grade III第60页，共133页。STAGING The 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 metastases TNM system I to IV stages第61页，共133页。Staging
25、The TNM systemT TumorN NodeM Metastasis第62页，共133页。TNM staging system： T：Primary tumorT0：in situ lesionT1-T4: Increase of tumor size N：regional lymph nodeN0：no metastases in lymph nodeN1-N3：number of involved lymph nodes M：distant metastasesM0: no distant metastasesM1：distant metastases第63页，共133页。Cha
26、racteristicsBenignMalignantDifferentiation/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 n
27、ormalErratic and may be slow to rapid; mitotic 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
28、cohesive and expansileMetastasisAbsentFrequently 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 origi
29、n (leiomyosarcoma).第65页，共133页。malignantbenignborderline第66页，共133页。Nomenclature & Classification In 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 usual
30、ly called sarcomas (Greek sar = fleshy) Malignant 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： c
31、arcinomasquamous cell carcinoma adenocarcinoma 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 t
32、umor第71页，共133页。malignant melanomamalignant schwannoma 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 stat
33、es, have a well-defined association with cancer that they have been termed precancerous conditions Certain forms of benign neoplasia also constitute precancerous conditions第74页，共133页。Pathologic ConditionAssociated Neoplasm(s)Etiologic AgentAsbestosis, silicosisMesothelioma, lung carcinomaAsbestos fi
34、bers, silica particlesBronchitisLung carcinomaSilica, asbestos, smokingCystitis, bladder inflammationBladder carcinomaChronic indwelling urinary cathetersGingivitis, lichen planusOral squamous cell carcinoma Inflammatory bowel diseaseColorectal carcinoma Lichen sclerosisVulvar squamous cell carcinom
35、a Chronic pancreatitisPancreatic carcinomaAlcoholism Hereditary pancreatitisPancreatic carcinomaMutation in trypsinogen geneReflux esophagitis, Barrett esophagusEsophageal carcinomaGastric acidsSialadenitisSalivary gland carcinoma Sjgren syndrome, Hashimoto thyroiditisMALT lymphoma 第75页，共133页。cancer
36、s associated with infectious agentsOpisthorchis, cholangitisCholangiosarcoma, colon carcinomaLiver flukes Bile acidsChronic cholecystitisGallbladder cancerBacteria, gallbladder stonesGastritis/ulcersGastric adenocarcinoma, MALTHelicobacter pyloriHepatitisHepatocellular carcinomaHepatitis B and/or C
37、virusMononucleosisB-cell non-Hodgkin lymphoma and Hodgkin lymphomaEpstein-Barr virusAIDSNHL, squamous cell carcinoma, Kaposi sarcomaHIV, human herpesvirus type 8OsteomyelitisCarcinoma in draining sinusesBacterial infectionChronic cervicitischronic pelvic inflammationsCervical/anal carcinomaHuman pap
38、illomavirus,gonorrhea, chlamydiaChronic cystitisBladder, 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 CISin
39、traepithelial neoplasia I IIIIIdysplasia第80页，共133页。CIN 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 cancer Fundamental principles Nonlethal genetic damage lies at the heart of carcinogenesis A tumor is fo
40、rmed by the clonal expansion of a single precursor cell that has incurred genetic damage (i.e., tumors are monoclonal)第85页，共133页。Molecular basis of cancer Four classes of normal regulatory genes are the principal targets of genetic damage. growth-promoting proto-oncogenes growth-inhibiting tumor sup
41、pressor genes genes that regulate programmed cell death (apoptosis) genes involved in DNA repair第86页，共133页。Molecular basis of cancer Carcinogenesis 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 depictin
42、g a simplified scheme of the molecular basis of cancer第88页，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 apoptosis as a consequence of inactivation of p
43、53 Limitless replicative potential Telomerase activation 第89页，共133页。ESSENTIAL ALTERATIONS FOR MALIGNANT TRANSFORMATION Sustained angiogenesis Ability to invade and metastasize Defects in DNA repair Immune surveillance and escape第90页，共133页。SELF-SUFFICIENCY IN GROWTH SIGNALS: ONCOGENES Genes that prom
44、ote autonomous cell growth in cancer cells are called oncogenes Their unmutated cellular counterparts are called proto-oncogenes Oncogenes are created by mutations in proto-oncogenes and are characterized by the ability to promote cell growth in the absence of normal growth-promoting signals Their p
45、roducts are called oncoproteins 第91页，共133页。DNA related to the transforming 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。Oncoge
46、nes Mutations convert proto-oncogenes into constitutively active cellular oncogenes that are involved in tumor development because the oncoproteins they encode endow the cell with self-sufficiency in growth Two questions follow: What are the functions of oncogene products, the oncoproteins? How do t
47、he normally civilized proto-oncogenes turn into enemies within? 第93页，共133页。Oncogenes Growth factors Growth 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 oncogene
48、s in Burkitt lymphoma and chronic myelogenous leukemia第97页，共133页。TUMOR SUPPRESSOR GENES The products of tumor suppressor genes apply brakes to cell proliferation The protein products of tumor suppressor genes may function as transcription factors cell cycle inhibitors signal transduction molecules c
49、ell surface receptors regulators of cellular responses to DNA damage 第98页，共133页。TUMOR SUPPRESSOR GENES RB gene The first discovered tumor suppressor gene Mutant in the patients with retinoblastoma Knudsons 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 GENES p5
50、3: Guardian of the Genome A little over 50% of human tumors contain mutations in this 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 POTENT
