1、 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. Nomenclat
2、ure 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 neoplasms (Greek oncos =
3、tumor). 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 Willis 1952The Concept of Tumor
4、 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 tumor arises from a single cell that has
5、incurred genetic change, and hence tumors are said to be clonal The Difference between Neoplastic and non-Neoplastic Growth Monoclonality Abnormal morphology, metabolism and function Excessive, unregulated and autonomous growth Heritable genetic changes Harm to host Polyclonality Normal morphology,
6、metabolism and function Limited growth No genetic alteration Benefit to hostThe Gross Features of Tumors Size and number Form Color and consistence Hardness Interface with surrounding tissue circumscribed or infiltrative (invasive) encapsulated or unencapsulatedMultiple leiomyoma of the uterus (left
7、) and lipoma (right)Menigioma (right)Villiform adenoma ofthe colon (right)Breast carcinomaMucinous papillary cystadenoma of the ovaryNeurofibroma in scalpOsteosarcoma in the humeral boneLeft is X-ray and right is gross photoSquamous cell carcinoma of the ankle (left)Malignant melanoma of the ankle (
8、right)Fibrous adenoma of the breastRenal cell carcinoma OsteosarcomaParenchyma and Mesenchyma (stroma) Parenchyma: clonal neoplastic cells Mesenchyma: reactive stroma made up of connective tissue, blood vessels, and variable numbers of macrophages and lymphocytes Parenchyma determines a tumors behav
9、ior and pathologic consequences The growth and evolution of tumors is dependent on stromaPapilloma of the skin. It is a benign tumor. Note the parenchyma and stroma of the tumor.Breast carcinoma. It is a malignant tumor.Note the parenchyma and stroma of the tumor. Atypia and dysplasia Atypia refers
10、to the disimilated extent to which neoplastic parenchymal cells compare with the corresponding 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 c
11、onstellation of changes that include a loss in the uniformity of the individual cells as well as a loss in their architectural orientationDifferentiation Differentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphological
12、ly and functionally In general, benign tumors are well differentiated Malignant tumors are poorly differentiated Anaplasia and Anaplastic Neoplasm Lack of differentiation is called anaplasia Malignant neoplasms that are composed of poorly differentiated cells are said to be anaplastic Morphologic Ch
13、anges of Atypia Pleomorphism cells and the nuclei Hyperchromatic nuclei Increased nuclear-to-cytoplasm ratio Mitoses (atypical, bizarre mitotic figures) Loss of polarity Tumor giant cells Necrosis anaplasiahyperchromasia increased N:C ratio tumor giant cells abnormal mitotic figuresTumor giant cells
14、Growth and SpreadingA tumor arises from a single cell i.e. monoclonalRates of growthdoubling timegrowth fractioncell deathangiogenesisRate of growth The rate of growth of a tumor is determined by three main factors: the doubling time of tumor cells the fraction of tumor cells that are in the replica
15、tive pool the rate at which cells are shed and lost in the growing lesionProgression and HeterogeneityTumor progression and generation of heterogeneity. New subclones arise from the descendants of the original transformed cell by multiple mutations. With progression he tumor mass becomes enriched fo
16、r variants that are more adept at evading host defenses and are likely to be more aggressive. Angiogenesis v.s. Vasculogenesis angiogenesis factors angiogenesis inhibitorsTUMOR NEWVASCULARIZATIONsustained angio-genesis VEGF inducerCANCER STEM CELLS AND CANCER CELL LINEAGES Stem cell asymmetric repli
17、cation Cancer stem cell or tumor-initiating cell Resistance to conventional therapies New strategy of tumor treatmentLocal Invasion Nearly all benign tumors grow as cohesive expansile masses The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surroundin
18、g tissue. Local Invasion Growth patternsexpansive growth exophytic growth invasive growth expansive growth: renal cell carcinomafollicular thyroid adenomaexpansive growthexophytic growth: leiomyomaInvasive growth: breast carcinomaSpreading of Tumor Direct spread Metastasis lymphatic metastasis hemat
19、ogeneous metastasis transcoelomic metastasis lymph node metastasistranscoelomic metastasis (seeding)Kreukenberg tumorsThe Clinical Aspects of Neoplasia Local and Hormonal Effects Benign v.s. malignant Cancer Cachexia Paraneoplastic Syndromes In affected patients they may represent significant clinic
20、al problems and may even be lethal They may mimic metastatic disease and therefore confound treatment They may represent the earliest manifestation of an occult neoplasmcachexiacac bad + hexis habit +iaweight losswasting of muscleloss of appetitegeneral debility Cushings Syndrome (Glucocorticoid exc
21、ess, ACTHoma)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 differentiatedGrading well moderately poorlydifferentiated differentiated differentiatedlow grade intermediate high g
22、rade gradegrade I grade II grade IIISTAGING 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 stagesStagingThe TNM systemT TumorN NodeM Metastasis TNM staging system：
23、 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 metastasesCharacteristicsBenignMalignantDifferentiation/anaplasiaWell differentiated; structu
24、re 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; mitotic figures may be numerous and abnor
25、malLocal 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 expansileMetastasisAbsentFrequently present; the larger and more un
26、differentiated the primary, the more likely are metastasesComparisons Between Benign and Malignant Tumors Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of the same origin (leiomyosarcoma).malignantbenignborderlineNomenclature & Classification In general, benig
27、n 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) Malignant neoplasms of epithelial cell origin, derived from any of the th
28、ree germ layers, are called carcinomas benign tumors -oma fibroma lipoma adenoma squamous cell papilloma papillary cystadenomamalignant tumors (cancers)epithelial： carcinomasquamous cell carcinoma adenocarcinoma papillary cystadenocarcinomamesenchymal： sarcomafibrosarcoma liposarcoma Exceptions: -bl
29、astomaNeuro-blastomaMedullo-blastomaNephro-blastomaOsteo-blastomaChondro-blastomaLipo-blastomaSchwannomaEwings sarcomaHodgkins lymphoma Wilms tumormalignant melanomamalignant schwannoma malignant meningiomamalignant lymphomaoat cell carcinomaclear cell sarcomaseminomaleukemiaThe WHO Classification o
30、f TumorsPrecancerous Conditions Certain non-neoplastic disorders mostly related with chronic inflammatory states, have a well-defined association with cancer that they have been termed precancerous conditions Certain forms of benign neoplasia also constitute precancerous conditionsPathologic Conditi
31、onAssociated Neoplasm(s)Etiologic AgentAsbestosis, silicosisMesothelioma, lung carcinomaAsbestos fibers, silica particlesBronchitisLung carcinomaSilica, asbestos, smokingCystitis, bladder inflammationBladder carcinomaChronic indwelling urinary cathetersGingivitis, lichen planusOral squamous cell car
32、cinoma Inflammatory bowel diseaseColorectal carcinoma Lichen sclerosisVulvar squamous cell carcinoma Chronic pancreatitisPancreatic carcinomaAlcoholism Hereditary pancreatitisPancreatic carcinomaMutation in trypsinogen geneReflux esophagitis, Barrett esophagusEsophageal carcinomaGastric acidsSialade
33、nitisSalivary gland carcinoma Sjgren syndrome, Hashimoto thyroiditisMALT lymphoma cancers associated with infectious agentsOpisthorchis, cholangitisCholangiosarcoma, colon carcinomaLiver flukes Bile acidsChronic cholecystitisGallbladder cancerBacteria, gallbladder stonesGastritis/ulcersGastric adeno
34、carcinoma, MALTHelicobacter pyloriHepatitisHepatocellular carcinomaHepatitis B and/or C virusMononucleosisB-cell non-Hodgkin lymphoma and Hodgkin lymphomaEpstein-Barr virusAIDSNHL, squamous cell carcinoma, Kaposi sarcomaHIV, human herpesvirus type 8OsteomyelitisCarcinoma in draining sinusesBacterial
35、 infectionChronic cervicitischronic pelvic inflammationsCervical/anal carcinomaHuman papillomavirus,gonorrhea, chlamydiaChronic cystitisBladder, liver, rectal carcinomaSchistosomiasisprecancerous lesionsdysplasiacarcinoma in situ (CIS)invasive carcinomadysplasia (atypical hyperplasia)dysplasia (atyp
36、ical hyperplasia)slightmoderate severe CISintraepithelial neoplasia I IIIIIdysplasiaCIN IIcervical intraepithelial neoplasiaCIN IIInormal CISMolecular basis of cancerMolecular basis of cancer Fundamental principles Nonlethal genetic damage lies at the heart of carcinogenesis A tumor is formed by the
37、 clonal expansion of a single precursor cell that has incurred genetic damage (i.e., tumors are monoclonal)Molecular basis of cancer Four classes of normal regulatory genes are the principal targets of genetic damage. growth-promoting proto-oncogenes growth-inhibiting tumor suppressor genes genes th
38、at regulate programmed cell death (apoptosis) genes involved in DNA repairMolecular basis of cancer Carcinogenesis is a multistep process at both the phenotypic and the genetic levels, resulting from the accumulation of multiple mutationsFlowchart depicting a simplified scheme of the molecular basis
39、 of cancerESSENTIAL 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 p53 Limitless replicative potential Telomerase activatio
40、n ESSENTIAL ALTERATIONS FOR MALIGNANT TRANSFORMATION Sustained angiogenesis Ability to invade and metastasize Defects in DNA repair Immune surveillance and escapeSELF-SUFFICIENCY IN GROWTH SIGNALS: ONCOGENES Genes that promote autonomous cell growth in cancer cells are called oncogenes Their unmutat
41、ed 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 products are called oncoproteins DNA related to the transforming gene(s) of av
42、ian 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 unregulatedOncogenes Mutations convert proto-oncogenes into constitutively active cellular oncogenes that are involv
43、ed 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 the normally civilized proto-oncogenes turn into enemies within? Oncogenes Growth factors Growth fac
44、tor receptors Signal transduction proteins (RAS) Nuclear-regulatory proteins (MYC) Cell cycle regulatorsThe chromosomal translocation and associated oncogenes in Burkitt lymphoma and chronic myelogenous leukemiaTUMOR SUPPRESSOR GENES The products of tumor suppressor genes apply brakes to cell prolif
45、eration The protein products of tumor suppressor genes may function as transcription factors cell cycle inhibitors signal transduction molecules cell surface receptors regulators of cellular responses to DNA damage TUMOR SUPPRESSOR GENES RB gene The first discovered tumor suppressor gene Mutant in t
46、he patients with retinoblastoma Knudsons two-hit hypothesis of oncogenesis TUMOR SUPPRESSOR GENES p53: 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)
47、Triggering of programmed cell death (apoptosis) LIMITLESS REPLICATIVE POTENTIAL: TELOMERASE Most normal human cells have a capacity of 60 to 70 doublings This phenomenon has been ascribed to progressive shortening of telomeres at the ends of chromosomes Re-expression of telomerase allows the cells t
48、o escape the bridge-fusion-breakage cycle, thus promoting their survival and tumorigenesisSequence of events in the development of limitless replicative potentialANGIOGENESIS Angiogenesis is thus a necessary biologic correlate of malignancy The molecular basis of the angiogenic switch involves incre
49、ased production of angiogenic factors and/or loss of angiogenic inhibitors An anti-VEGF monoclonal antibody, bevacizumab, has recently been approved for use in the treatment of multiple cancers INVASION AND METASTASIS Invasion and metastasis are biologic hallmarks of malignant tumors Invasion of the
50、 extracellular matrix (ECM) Vascular dissemination, homing of tumor cells, and colonization A-D, Sequence of events in 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 bas
