医科大学病理学英文课件医科大学病理学英文课件Chapter5.NeoplasiaChapter 5. Neoplasia 病 例，女，女，2121岁岁主诉：近半年左下肢膝关节附近疼痛，活动后主诉：近半年左下肢膝关节附近疼痛，活动后 加重，一个月前发现左股骨下端局部隆加重，一个月前发现左股骨下端局部隆 起，逐渐长大，疼痛难忍，来诊。起，逐渐长大，疼痛难忍，来诊。查体：左股骨下端局部肿物，压痛（）查体：左股骨下端局部肿物，压痛（）处置：处置：1. 1. 左股骨下端左股骨下端X X线正侧位像线正侧位像2. 2. 胸部胸部X X线正侧位像线正侧位像3. 3. 左股骨下端肿物穿刺活检左股骨下端肿物穿刺活检检查结果 1.1.左股骨下端左股骨下端X X线正位像：线正位像： 左股骨下端占位病变，左股骨下端占位病变， 骨皮质破坏骨皮质破坏, ,骨膜反应。骨膜反应。2.2.胸部胸部X X线正侧位像：线正侧位像： 未见明显异常未见明显异常临床诊断：恶性骨肿瘤？ 活检病理诊断：骨肉瘤 治疗原则 1.1.手术切除手术切除 2.2.化化 疗疗 3.3.放放 疗疗 4.4.支持疗法支持疗法1.1.什么是肿瘤？具有哪些特性？什么是肿瘤？具有哪些特性？2.2.肿瘤有哪些种类、各自特点？肿瘤有哪些种类、各自特点？3.3.肿瘤生物学行为如何？对机体有何影响肿瘤生物学行为如何？对机体有何影响？4.4.肿瘤的结局如何？肿瘤的结局如何？5.5.肿瘤是如何发生发展的？如何防治？肿瘤是如何发生发展的？如何防治？思 考 题 Chapter 5. NeoplasiauTumors is common diseases. uBad news: Malignant tumor (cancer) is the second leading cause of death in some countries. (The first leading cause is cardiovascular diseases.)uAccording to American Cancer Society estimates, in 2003, about 23% of all deaths in the United States (1500 cancer deaths per day).uGood news: u The rapid progress has been made in understanding the molecular basis and biological behavior of cancer and cancer therapy. Many cancers can be cure or arrested. u For exle: breast cancer, cervical canceruBut many problems still need to be solved!Section 1. Definition and morphologyTwo question:lWhat is tumor? DefinitionlWhat are tumors look like? MorphologyDefinitionlNeoplasia literally means the process of “new growth” and a new growth is called a neoplasm.ltumor was originally applied to the swelling caused by inflammation. lOncology is the study of tumors or neoplasms. lCancer is the common term for all malignant tumors. NeoplasialIn 1953, The eminent British oncologist Willis had given neoplasia a famous definition: “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.” lA more scientific difinition: “Neoplasia is genetic disease, in which the growth of tumors is loss of responsiveness to normal growth control, and shows an excessive hyperplasia with abnormal differentiation.”Tumor (neoplasm): under the stimulation of tumorgenic agents a single cell of local tissue loss the controlling to its growth at the gene level excessive proliferation to form neoplasmDistinguish between neoplastic and non-neoplastic hyperplasia Neoplastic Non-neoplastic Monoclonality Polyclonality Abnormal morphology Normal morphology and function and function Abnormal differentiation Matured differentiationPersistent, autonomous LimitedHarmful BeneficialMorphology and structure uNumber and Size: variousuShape: sessile, papillary, nodular, lobular, cystic, fungating, ulcerated, and infiltratinguColor: dependent on histogenesis and secondary changes (hemorrhage, necrosis)uConsistency: Parenchyma-stroma ratio, Secondary changesuCapsule: benign with intact capsuleuSecondary changes: hemorrhage, necrosisMacropathology: The gross appearance of tumors is varied, reflecting the nature of the tumor to some extent.Number and size:variousFibroadenomaPolypous adenoma papillarypolypousShape: relate to histogenesis, site and biologic behaviorPapillomaPolypous adenomaBenignNodular or lobularcysticLipoma FibroadenomaMucinous cystadenoma BenignFungating Ulcerated InfiltrativeMalignantColor: lThe color of a benign tumor resembles that of the normal tissue from which it derived. lThe color of the cut surface of a malignant tumor may be gray-white, and often varied due to secondary changes (hemorrhage, degeneration and necrosis).CapsuleThe benign tumor is usually circumscribed by a clearly defined border and often encapsulated by thin fibrous capsule.The malignant tumor is invasive and poorly circumscribed.FibromaCarcinoma of stomach Consistency uResembles the normal tissue it derived fromuTumors are usually firmer than surrounding tissuesuProportion of parenchyma and stromauSecondary changesAdipose tissue Lipoma: softCartilage Chondroma: hardScirrhous Scirrhous carcinomacarcinomaConsistencyParenchyma-stroma ratio stromaParenchyma hardMedullary carcinomaConsistencyParenchymaStroma softSecondary changesNecrosisHemorrhageHistological structureAll tumors have basic two components:1. Parenchyma lMajor component of tumor: neoplastic celllDetermine the biologic nature and specificity2. StromalComposed of CT and BV support the tumorlGrowth speed depend on the stroma blood supplylLC infiltration immune reaction to tumorParenchyma StromaStromal BVFibrosarcomaNO stromal BV Take home question:What is neoplasia? (The definition)(The definition)How to describe the gross appearance of a tumor? ( (Number, size, shape, color, consistency, capsule,secondary changes)lWhat is neoplastic atypia?lThe atypia of tissue architecturelThe atypia of neoplasic cellsSection 2. Neoplastic atypiaWhat is atypia? Atypia: Neoplastic tissue has various extent of differences with its originated normal tissue, both cell morphologically and tissue architecturally. Differentiation: The degree to which a neoplasic cells resembles its originated normal mature cells, both morphologically and functionally.lAnaplasia: Lack of differentiation of malignant neoplastic cell, with obviously atypia.lAnaplastic tumor: composed of undifferentiated cell.lPleomorphism: obvious variation in size, shape obviously atypiaAtypia of tissue architectureRefers to difference between neoplastictissue and its originated normal tissueuThe arrangement of neoplastic tissue uThe polarization of neoplastic tissue uthe relationship with stromaIntestinal adenomaAdenocarcinomaSquamous cell carcinomaAtypia of neoplastic cellsPleomorphism of neoplastic cells1. Variation in size and shape2. Generally larger than normal cells tumor giant cells Pleomorphism of nucleus1. Increased nucleus: The nuclear- to - cytoplasmic ratio may approach 1:1 instead of the normal 1:4 - 6. 2. Variation in size, color and shape of nucleus: Size: Huge, two or more nuclei, bizarre nuclei, large nucleoli are usually present. Color: The nuclei contain an abundance of DNA and are extremely dark staining Shape :i) The shape is usually extremely variable, the chromatin is coarsely clumped ii) Increased mitotic figures : Atypical, bizarre mitotic figures producing tripolar, quadripolar, or multipolar spindles. Normal structureAdenocarcinoma Changes of cytoplasm1. Cytoplasm: Basophilic nucleoprotein increased2. Abnormal products or secretion: Mucus, glycogen, lipid helpful to determine histogenesis of tumorMucoid carcinomaSquamous cell carcinomaMelanoma of the skin Ultrastructural changes ( (electron microscopeelectron microscope) )Organelles : signs of histogenesis Neuroendocrine granules neuroendocrine tumorTonofilament and desmosomes squamous cell carcinomaMyofilament and dense body SMC Take home questions:What is atypia? (The definition)What is atypia include? The atypia of tissue architectureThe atypia of neoplasic cellsCell nucleusCytoplasmUltrastructureSection 3. Growth and spread of tumorlGrowth pattern of tumorlBiology of tumor growthlSpread of neoplasms (Invasion and metastasis)lMechanisms of invasion and metastasislGrading and staging of tumor1. The growth of tumorI. Growth pattern of tumor1.Expansive growth2.Exophytic growth3.Infiltrating growth Growth pattern of tumor 1. Expansive growth:The mode of most benign tumornodularintact capsuleLeiomyoma (1) Sites: surface of body, body cavities or tract organs.(2) Shape: papillary, polypoid, cauliflower(3) Growth pattern of both benign (has a pedicle) and malignant tumor (also grow by infiltrating)2. Exophytic growth:E Exophytic growth The mode of most malignant tumorabsence of capsule, infiltrate and destroy surrounding tissue 3. Infiltrating growthII. Biology of tumor growth1. Monoclonality: Tumor is formed by a transformed cell proliferation 2. The natural history of most malignant tumors can be divided into four phases:(1) Malignant transformation in the target cell(2) Clonal growth of the transformed cells(3) Local invasion(4) Distant metastasis3. The multiple factors that influence tumor growth are considered under three headings:(1) kinetics of tumor cell growth(2) Tumor angiogenesis(3) Tumor progression and heterogeneity Kinetics of tumor cell growthlDoubling time of tumor cellslGrowth fractionlTumor cell production and losslDoubling time of tumor cells: In reality, cell cycle time for many tumors equal to or longer than that of corresponding normal cells growth of tumor is not associated with a shortening of cell doubling timelGrowth fraction: the proportion of cells within the tumor population that are in the proliferative pool ( S + G2 phase ). Early stage vast majority of transformed cell are in the proliferative pool high growth fraction As tumors continue to grow cell leave the replicative pool by differentiating and by reversion to Go in rapidly growing tumors approximately 20%lTumor cell production and loss: Growth of tumors are determined by the excess of cell production over cell loss. The rate of tumor growth depends on: Growth fraction Degree of imbalance between cell production and cell lossHigh grow fraction: Clinical course is rapid (lymphoma) susceptibility to chemotherapyLow grow fraction (cell production exceeds cell loss by only about 10%): Grow at a much slower pace (car. of colon) no susceptibility to chemotherapy Tumor angiogenesislAngiogenesis is a necessary biologic correlate of malignancy: tumors cannot enlarge beyond 1 to 2 mm in diameter or thickness unless they are vascularized.lAngiogenesis is requisite not only for continued tumor growth, but also for metastasis. l Neovascularization has dual effect: Perfusion supplies nutrients and oxygen Newly formed endothelial cell secreting polypeptides such as insulin-like GF, PDGF stimulate the growth of tumor cell l How do growing tumors develop a blood supply? Tumor associated angiogenesis factors produced by tumor cells infiltrated inflammatory cells VEGF, FGF, PDGF Tumor induce antiangiogenesis molecules: WP53 induce thrombospondin 1 inhibit formation of BV P53 gene mutation thrombospondin 1BVPlasminogen, collagen, transthyretin Plasminogen, collagen, transthyretin proteolytic cleavage proteolytic cleavage angiostatin, endostatin, vasculostatin, angiostatin, endostatin, vasculostatin, potent angiogenesis inhibitors potent angiogenesis inhibitors Tumor progression and heterogeneity 1. Tumor progression Malignant tumor become more aggressive in the process of growth laccelerated growthllocal invasionldistant metastasis 2. Tumor heterogeneity In the process of growth, monoclonal tumor cells generate subclones with different characteristics 3. Mechanism: Mutant additional genes damagelInvasiveness, rate of growthlhormonal responsivenesslsusceptibility to antineoplastic drugs2. Spread of neoplasmslLocal invasion (direct spread)lMetastasisLymphatic metastasisHematogeneous metastasisTranscoelomic metastasis (Metastasis in body cavities) (seeding) Spread of neoplasms1. Direct spread Malignant tumor C infiltrate tissue, lymphatic, BV, nervous tissue 2. Metastasis Malignant cells from primary site invade into lymphatics, BVs and body cavities and reach distant site continues growth to form the same type tumor with primary tumor The most common pathway for the initial dissemination of carcinoma Sarcoma may also use this route The most common site: Lung Gastrointestinal tract Arm pit, groin, cervical glands(1) Lymphatic metastasis:Left supraclavicular LNAfferent lymphaticsTumor emboliSubcapsular sinusEfferent lymphaticsRetrograde metastasisPrimary tumorLymphatic nodule Lymphatic metastasisLymphatic metastasis(2) Hematogeneous metastasis The favored pathway of sarcoma. Metastatic pathway: Caval blood lung Portal blood liver Pulmonary v(cap) brain, bone, kidney Vertebral vein paravertebral plexus brain ( Prostate, thyroid) Common sites: lung (most), liver, bone Features of hematogeneous metastatic tumor: multiple, rounded nodules with clear border, scattered in distribution, close to surface of organ.Choriocarcinoma Carcinoma umbilicus Hematogeneous metastatic tumor located surface of the organ forms umbilication because of central hemorrhage and necrosis(3) Transcoelomic metastasis (Metastasis in body cavities or Seeding) Definition: Malignant tumor cell of an organ in body cavity penetrate into the surface of the organ and break off to seed in the surface of the organs of body cavity and form metastatic tumor.Transcoelomic metastasisColloid carcinoma of stomachseed in the surface of intestine krukenberg tumor: Gastric carcinoma destroy gastric wall and tumor cell seed in the ovaries to form metastatic tumor Sites peritoneal cavity (most common) pleural, pericardial, subarachnoid, joint space Surgical instruments: rare an artificial mode of dissemination The mechanisms of invasion and metastasislThe mechanism of local invasionlVascular dissemination and homing of tumor cellslMolecular genetics of metastasis The mechanism of local invasion(1) Detachment of the tumor cells from each other : Down-regulation of E-cadherin (CAM) expression(2) Attachment to matrix components: Integrin (epithelium) binding to laminin (BM)(3) Degradation of extracellular matrix: Tumor cell secrete proteolytic enzymes induce host cell to elaborate proteases(4) Migration of tumor cells: Mediated by Tumor cell derived motility factors Cleavage products of matrix components Vascular dissemination and homing of tumor cellsSingle tumor cell is destroyed by nature killer cell (NKC)Formation of platelet-tumor aggregateEnhance the survival and implantabilityTumor emboli involve adhesion to endothelium cells (EC) Egress through the basement membrane (BM) prostate to boneprostate to bone lung to adrenal, brain lung to adrenal, brain breast to lung, liver, bone breast to lung, liver, bone(1) Tumor cell express the adhesion molecules whose ligands are expressed on the EC of the target organs.(2) Some target organs may liberate chemoattractants to recruit tumor cell to the site.(3) Some organs may be an unfavorable soil for the growth of tumor seeding: such as spleen, heart, skeletal muscleOrgan tropism Molecular genetics of metastasis 1.No single metastasis gene has been found.2.The gene that encode E-cadherin, inhibitors of metalloproteinases, nm23, etc. is considered metastasis suppressor genes.III. Grading and staging of tumor Grading of tumor: According to degree of differentiation and the number of mitoses: Grade : well-differentiated Grade : moderately-differentiated Grade : poorly-differentiated Grade : undifferentiated Well-differentiatedModerately-differentiatedPoorly-differentiatedUndifferentiated Staging of tumor: Based on size of the primary lesion, its extent of spread to LN distant metastasis: UICC (international union against cancer) TNM classification of malignant tumours T: primary tumor, T1T4 increasing size N: Regional LN involved, N0no involved; N1-N3 M: distant metastasis, M0no; M1-M2Take home question:lHow tumor growth? (growth pattern)lHow neoplasms Spread? (Invasion and metastasis)lThe concepts of metastasis, carcinoma umbilicus and transcoelomic metastasis, tumor progression and heterogeneity?lTry to explain The process of tumor cells local invasionSection 4. Effects of tumor on hostBenign tumor: less effects Local oppression and obstruction: Relate to site and secondary changelImportant organs: intestinal, brainhernialTumor of endocrine glands: systemic symptomsAcidophilic adenoma of hypophysis cerebri: gigantism or acromegalyAdenoma of pancreatic islets: fatal hypoglycemia Malignant tumor1. Local compression + obstruction + pain 2. Constitutional symptoms: Fever, infection, night sweat3. Cachexia: Refer to the state of progressive loss of weight, anemia, weakness and systemic failure.4. Paraneoplastic syndrome ( PNS ) l Neoplastic product (ectopic hormones) l Abnormal immune reaction (cross immune, autoimmune, immune complex ) l Other unclear causes Lead to lesions of endocrine, nervous, digestive system and so on (1) Ectopic endocrine syndrome: Some non-endocrine tumors elaborate hormones or hormone-like substance cause endocrine disorder. Hypercalcemia: parathormone -like substance elaborated by carcinoma of lung, kidney Hypoglycemia: elaboration of insulin-like substance by fibrosarcoma, mesothelioma(2) Hypertrophic osteoarthropathy: Formation of bone, arthritis of the adjacent joint and clubbing of the digits.(3) Vascular and hematologic syndrome: Migratory thrombophlebitis, endocarditisSection 6. Differences between Benign and malignant tumor Degree of well poorlydifferentiation structure is typical obvious atypiaMitotic figure rare and normal increased no pathologic mitotic pathologic mitoticRate of growth slow rapidGrowth pattern expansive infiltrative exophytic exophytic well demarcated poorly demarcated Benign malignant Difference between benign and malignant tumor(Part I)Secondary rare commonSecondary rare common changes ( hemorrhage, necrosis) changes ( hemorrhage, necrosis) Local invasive noninvasive locally invasive Local invasive noninvasive locally invasive Metastasis absent common Metastasis absent common Recurrence rare commonRecurrence rare commonEffects compression cachexia Effects compression cachexia on host obstruction metastasison host obstruction metastasisBenign malignant Difference between benign and malignant tumorDifference between benign and malignant tumor (Part II)Section 3. Nomenclature and classification Nomenclature Benign tumor:(1) Cells of origin + “oma” Fibroma, adenoma, fibroadenoma(2) Cells of origin + morphologic feature Adenoma + cystic cystadenoma + papillary papillary cystadenoma Malignant tumor(1) Carcinoma: Arising in epithelial cell Squamous cell carcimnoma Adenocarcinoma Transitional cell carcinoma(2) Sarcoma: Arising in mesenchymal tissue Cells of origin + “sarcoma” Fibrosarcoma, liposarcoma, Leiomyosarcoma, rhabdomyosarcoma(3) Carcinosarcoma: Carcinoma + sarcoma(1) Arising in totipotential cells: Teratoma (benign, malignant): Made up of a variety parenchymal cell type of more than one germ layer (2) -blastoma: Neuroblastoma, medulloblastoma, (3) Malignant-: Malignant melanoma, meningioma(4) Custom: Leukemia, seminoma(5) Name: Ewings sarcoma, Hodgkins lymphoma(6) Tumor cell morphology: Clear (oat ) cell sarcoma(7) -omatosis: Neurofibromatosis, lipomatosis Others Classification Tissue of origin Benign MalignantEpithelial tumorsStratified squamous squamous cell squamous cell or palilloma epidermoid carcinoma Basal cells of skin or adnexa basal cell carcinomaEpithelial lining Glands or ducts adenoma adenocarcinoma papilloma papillary carcinoma cystadenoma cystadenocarcinoma pleomorphic adenoma malignant mixed tumor (mixed tumor of salivary origin) of salivary gland originUrinary tract epithelium Transitional cell Transitional cell (transitional) papilloma carcinomaMesenchymal tumorsConnective tissue fibroma fibrosarcoma lipoma liposarcomaSmooth muscle leiomyoma leiomyosarcomaStriated muscle rhabdomyoma rhabdomyosarcomaBlood vessels hemangioma angiosarcomaLymph vessels lymphangioma lymphangiosarcoma osteoma osteogenic sarcoma chondroma chondrosarcomaSynovium synovil sarcomaMesothelium mesothelioma malignant mesotheliomaTissue of origin Benign MalignantLymphoid tissue malignant lymphomasHematopoietic cells leukemiasBrain coverings meningioma invasive meningiomaMelanin cell nevus malignant melanomaPlacental epithelium Hydatidiform mole choriocarcinoma(trophoblast) Testicular epithelium seminoma(germ cells) embryonalcarcinomaTotipotential cells in gonads mature teratoma immature teratoma or in embryonic rests dermoid cystteratocarcinomaTissue of origin Benign Malignant