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1、肿瘤病理学 Pathology of Neoplasia,基础医学研究所病理生物学研究室陆应麟,肿瘤是目前死亡常见原因之一。恶性肿瘤是男性第二位死因,女性第三位主要死因。我国最常见恶性肿瘤:城市:肺癌、胃癌、肝癌、肠癌 和乳癌 农村:胃癌、肝癌、肺癌、食管 癌、肠癌,基 本 概 念,肿瘤的慨念肿瘤是机体中正常细胞,在不同始动与促进因素长期作用下所产生的增生与异常分化所形成的新生物。肿瘤的特点新生物一旦形成,不因病因消除而停止增生。它不受机体生理调节,而是破坏正常组织与器官。,Introduction:,Inflammatory,Degenerative&NeoplasticGrowth Inc
2、rease in size due to synthesis of tissue components.Proliferatation-Cell division.Differentiation:functional and structural maturity of cells.Tumor Swelling/new growth/mass,Controls of Growth:,Cytokines:Cyclins,Cyclin dependent kinases(CDK).Growth factors PDGF,FGFGrowth Inhibitors.Cancer suppressor
3、genes p53Oncogenes c-onc,p-onc,v-onc etc.,Non-Neoplastic Proliferation:,*Controlled&ReversibleHypertrophy 肥大 SizeHyperplasia 增生 NumberMetaplasia 化生 ChangeDysplasia 异常增生 Disordered,Neoplasia:,Progressive,Purposeless,Pathologic,Proliferation of cells characterized by loss of control over cell division
4、.DNA damage at growth control genes is central to development of neoplasm.Carcinogens Chemical,physical&genetic DNA damage Neoplasm.,Pathogenesis of Neoplasia:,Normal Hyperplasia Metaplasia化生(DNA damage)Dysplasia 异常增生(DNA damage)(DNA damage)Anaplasia 间变(DNA damage)Infiltration 浸润(DNA damage)Metastas
5、is转移.Progressive DNA Damage features of neoplasia.,Pathogenesis of Neoplasia:,Non lethal DNA Damage leading to uncontrolled cell division.,病理,恶性肿瘤的发生发展过程一般致癌因素作用3040年,经10年左右的癌前阶段恶变为原位癌。原位癌历时35年,在促癌因素作用下发展成浸润癌。浸润癌的病程一般1年左右。,2.肿瘤细胞的分化分为高分化、中分化、低(未)分化。组织化学的变化:(1)核酸增多(2)酶的改变(3)糖原减少,3.生长方式:4.生长速度:良性肿瘤:外生
6、性生长 良性肿瘤生长慢恶性肿瘤:浸润性生长 恶性肿瘤生长快,Non-Neoplastic Neoplastic(Polyclonal)(Monoclonal),Normal Adaptation Benign Malignant,Mechanism of Neoplams,Structure of Neoplasm:,Neoplastic cells parenchyma.Non-neoplastic-stroma(Connective tissue&BV)Fast growth less stroma Less stroma more necrosis,Biology of Neoplasm
7、:,Cell of originRate of growthDifferentiationLocal InvasionMetastasis,Lung cancerGrade-low,highWell,Mod,P,Un.StagingStaging,Lung cancer:Squamus cell carcinoma.Poorly differentiated,high grade,stage 4,Liver+,Benign Malignant:,Slow growing,capsulated,Non-invasive do not metastasize,well differentiated
8、,suffix“oma”eg.Fibroma.,Fast growing,non capsulated,Invasive&Infiltrate Metastasize.poorly differentiated,Suffix“Carcinoma”or“Sarcoma”,Better Understanding of Cancer,1.Cancer Cancer cells,Cancer Research Cancer cell research,Cancer a tissue:Cancer cells Stromal cells Vascular cells(endothelia,pericy
9、tes smooth muscle cells fibroblasts)Lymphatic vessel cells Immune cells,2.Do Cancer Stem Cells Exist in Caner?,cancer cell heterogeneity,1.genetic 2.phenotypic,differentin,MorphologyGrowth behaviorMetastasis potentialChemo/radio resistanceOther phenotypes,Do Cancer stem cells exist among cancer cell
10、 population?,Cancer cells,Cancer stem cells:(10-2 to 10-4)Persistent proliferation Renewal Metastatic potentialPartial differentiated cancer cells Limited number of proliferation Differential extent of differentiation Bulk of cancer cells,If the hypothesis is true Kill the cancer stem cells Abolish
11、the whole tumorDifficult Problems:How to identify?How to kill?(Cancer stem cells normal stem cells),?,Cancer stem cells reported:Breast cancer(human)Glioma(human)Lung cancer(animal)Gastric cancer(animal),Characteristics of reported“cancer stem cells”,May be early event quiescent,3.Metastasis:,Early
12、or late event?Dissemination Metastasis.Dissemination:Migration of cancer cells to distant places:,Micro-satellite Lymph node Blood:bone marrow,other organs,4.Metastasis:Disseminated cancers cells grow up to cancer tissues.,Dissemination:“stem cell like property”Mechanism of metastasis,Cancer cell pr
13、ogression:mutation,aneuploidyHost neural,endocrine,Immune,4.Cancer is a systems disease,Evidence:,A large Scale cDNA Transfection Screening of Genes Related to Cancer Development and Progression,PNAS November 2,2004 vol.101:15724-15729,分类,根据肿瘤的生物学行为主要分为:良性:称为“瘤”恶性:来源于上皮组织称为“癌”来源于间叶组织称为“肉瘤”胚胎性肿瘤称为“母细
14、胞瘤”某些恶性肿瘤沿用传统名称:恶性淋巴瘤,精原细胞瘤,白血病,霍奇金氏病,1.各种肿瘤根据其组织及器官来源而冠以不同名称。2.相同组织器官可发生不同细胞形态肿瘤。3.同一细胞类型,由于细胞分化程度不同,又分为高分化、中分化、低(未)分化。,Nomenclature:Cell of origin+Suffix,Suffix-omaFibroma OsteomaAdenomaPapilloma Chondroma,Carcinoma/SarcomaFibrosarcomaOsteosarcomaAdenocarcinomaSquamous cell carcinomaChondrosarcoma
15、,Exceptions:Leukemia,Lymphoma,Glioma,Bilateral Cystadenoma Ovary:,Lipoma Intestine:,meningioma,Lung carcinoma,Hepatic Adenoma:,Carcinoma Breast:,Carcinoma Lung:,Osteo-sarcoma:,Colon Polyp:,Hepatic Adenoma:,Normal Adenoma,Anaplasia in Sarcoma:,Anaplasia:,Hepatic Adenocarcinoma:,Hepatic Adenocarcinoma
16、:,Liver Metastasis:,分 级,Staging of Tumor,Grading Cellular Differentiation(Microscopic),Grading&Staging of Tumor,分 期,Staging of tumor,Staging Progression or Spread(clinical),TNM:Staging of tumor:,Pathways of Spread:,Direct SpreadBody cavitiesBlood vesselsLymphatic vesselsLungs Systemic Venous bloodLi
17、ver GIT venous return,nutrition.Brain End arteries.,5.转移直接蔓延:胰头癌侵及胆总管等淋巴道转移:多数情况为区域淋巴结转移种植性转移:最多见的为胃癌种植到盆腔血道转移:如肝、肺、骨转移,转移机制:CD44,整合素:改变细胞粘附性降解酶:形成瘤移动通道运动因子IGF-I,II:使肿瘤移动VEGF:促进转移灶形成,恶性肿瘤具有的表型,成瘤表型:与肿瘤生成有关的 基因所决定转移表型:与肿瘤转移有关的 基因所决定,体外研究成瘤性的生物学指标,倍增时间分裂指数生长曲线细胞周期PCNA表达,体外研究转移性的生物学指标,软琼脂集落形成数细胞爬片划痕实验T
18、ranwell(类似Boyden chember)细胞游走实验细胞穿膜(Metrigel膜)浸润实验,体内肿瘤转移实验,自发性肿瘤转移实验实验性肿瘤转移实验,少数肿瘤形态上属于良性,但常浸润性生长,切除后易复发,多次复发有的出现转移,生物行为上显示良性与恶性之间的类型,故称交界性或临界性肿瘤。,Clinical Features.,Tumor Impingement on nearby structuresPancreatic ca on bile duct Obst.Jaund.Ulceration/bleedingColon,Gastric,and Renal cell carcinoma
19、sInfection(often due to obstruction)Pneumonia,Urinary inf.Rupture or InfarctionOvarian,Bladder,colon,病因(1)外界因素(2)内在因素临床表现(1)局部表现(2)全身症状诊断(1)病史(2)体格检查(3)实验室检查(4)影 像学检查(5)内镜检查(6)病理形态学检查预防治疗(1)手术治疗(2)化学疗法(3)放射疗法(4)生物治疗(5)中医中药治疗,Tumor Diagnosis:,History and Clinical examinationImaging-X-Ray,US,CT,MRITum
20、or markers Laboratory analysis Cytology Pap smear,FNABBiopsy-Histopathology,markers.Molecular Tech Gene detection.,CT:metastatic adenocarcinoma,Biopsy Slide preparation,staining,病因,(一)外界因素:化学因素:(1)烷化剂:如有机农药、硫芥等(2)多环芳香烃化合物:3,4-苯并芘(3)氨基偶氮类:染料类(4)亚硝胺类(5)真菌毒素和植物毒素:黄曲霉菌、苏铁素等(6)其他:重金属,2.物理因素(1)电离辐射(2)紫外线(
21、3)其他:慢性病变,石棉纤维,滑石粉3.生物因素 主要是病毒感染:如EB病毒,单纯疱疹 病毒,(二)内在因素遗传因素内分泌因素免疫因素,临床表现,(一)局部表现肿块疼痛溃疡出血梗阻转移症状,(二)全身症状(1)多无明显全身症状,或仅有非特异性全身症状:贫血,低热,消瘦,乏力。(2)恶病质常是恶性肿瘤晚期全身衰竭表现。(3)某些部位的肿瘤可引起相应的功能亢进或低下,继发全身改变:如嗜铬细胞瘤,甲状旁腺瘤。,诊断,目的:确定有无肿瘤,明确其性质,了解其范围和程度,以便拟订治疗方案。目前仍缺乏理想的特异性强的早期诊断方法。,(一)病史年龄:儿童肿瘤多为胚胎性肿瘤或白血病;青少年肿瘤多为肉瘤;癌多发于
22、中年以上。病程:良性者病程较长,恶性者较短。过去史:(1)有无家族史或遗传史(2)有无癌前病变或相关疾病病史(3)注意个人史中,行为与环境相关情况,(二)体格检查全身体检:注意浅表淋巴结是否肿大;是否有肿块。局部检查:1.肿块的部位:有助于分析肿块的组织来源与性 质2.肿瘤的性状:有助于分析诊断。3.区域淋巴结或转移灶的检查,(三)实验室检查常规化验:并非特异性检查,但可提供诊断线索。血清学检查:特异性较差,但可用作辅助诊断。酶学检查:碱性磷酸酶:肝癌,骨肉瘤时酸性磷酸酶:前列腺癌乳酸脱氢酶:肝癌及恶性淋巴瘤糖蛋白:消化系统肿瘤激素类:绒毛膜上皮癌绒毛膜促性腺激素 垂体肿瘤抗利尿激素 胰岛细胞
23、瘤胰岛素,3.免疫学检查:常用放射免疫测定法。常用的有:癌胚抗原(CEA),结肠癌、胃癌、肺癌、乳癌-胚胎抗原(AFP),肝癌、恶性畸胎瘤肿瘤相关抗原:抗EB病毒抗原的IgA抗体(VCA-IgA)鼻咽癌时间分辨荧光分析技术(TRF)以稀土离子极其螯合物进行标记。灵敏度高,特异性强,无污染。,4.流式细胞分析术:用以判断肿瘤恶性程度及推测其预后。5.基因诊断:肿瘤的发生是由于细胞中基因改变积累的结果,包括(1)癌基因的激活、过度表达。(2)抑癌基因的突变、丢失。(3)微卫星不稳定,出现核苷酸异常的串联重复分布于基因组(4)错配修复基因突变,导致细胞遗传不稳定或致肿瘤易感性。,(四)影像学检查X线
24、检查(1)透视与平片,Skull in Myeloma:,(2)造影钡餐,钡灌肠,器官造影IVP口服胆囊造影逆行肾盂造影胆道与胰管逆行造影,血管造影,(3)特殊X线显影术干板摄影钼靶X线球管摄影主要用于软组织和乳腺组织,2.电子计算机断扫描(CT),螺旋CT与三维成像,3.超声显像:对判断囊性与实质性肿块很有价值,4.放射性核素成像,5.MRI,(五)内镜检查,(六)病理形态学检查1.临床细胞学检查自然脱落细胞粘膜细胞细针穿刺涂片,2.病理组织学检查 对色素性结节或痣,应完整切除检查,肿瘤分期,I期:T1N0M0II期:T0-1N1M0III期:T1-2N2M0或T3N0-2M0IV期:T1-
25、3N0-2M1或T0N0-2M1,预防,一级预防:消除或减少可能致癌的因素,防止癌症的发生。二级预防:早期发现,及时治疗。对高危区及高危人群定期检查,从中发现癌前期病变及时治疗。三级预防:改善生存质量,对症治疗。(1)最初用非吗啡类药(2)小剂量开始(3)口服为主(4)定期给药。,治疗,良性肿瘤或临界性肿瘤以手术切除为主。恶性肿瘤I期:手术治疗为主II期:切除或放疗原发肿瘤,辅以有效的全身化疗III期:手术前、后及术中放疗或化疗。IV期:全身治疗为主,辅以局部对症治疗,(一)手术治疗根治手术:包括原发癌所在器官的部分或全部,连同周围正常组织和区域淋巴结整块切除。扩大根治术:在原根治范围基础上适
26、当切除附近器官及区域淋巴结。对症手术或姑息手术:以手术解除或减轻症状,延长生命,争取综合治疗机会,改进生存质量。激光手术或冷冻手术,(二)化学治疗药物分类(1)细胞毒素类药物:烷化剂,作用于DNA和RNA、酶、蛋白质导致细胞死亡。如环磷酰胺、氮芥。(2)抗代谢类:对核酸代谢物与酶结合反应有相互竞争作用,影响与阻断了核酸的合成。如5-FU,甲氨蝶呤。(3)抗生素类:如放线菌素D,丝裂霉素。(4)生物碱类:干扰细胞内纺锤体的形成,使细胞停留在有丝分裂中期。如长春新碱,羟基喜树碱。,(5)激素类:能改变内环境进而影响肿瘤生长。如乙烯雌酚黄体酮等。(6)其他:如顺铂,卡铂等根据药物对细胞周期作用分类:
27、细胞周期非特异性药物细胞周期特异性药物细胞周期时相特异药物,2.给药方式:静脉点滴或注射,口服,肌肉注射。静脉给药:大剂量冲击治疗中剂量间断治疗小剂量维持治疗,3.化疗副作用白细胞血小板减少消化道反应毛发脱落血尿免疫功能降低,易并发感染,(三)放射治疗器械:光子类:深度X线、射线,各种同位素粒子类:粒子加速器,感应加速器,中子加速器方法外照射,内照射副作用骨髓抑制,皮肤粘膜改变,胃肠反应,(四)生物治疗免疫治疗(1)生物反应调节因子(BRM)BRM是一些在自然和特异性免疫的效应阶段起调节作用的激素蛋白质。(2)过继性免疫治疗2.基因治疗,BRM的临床疗效(以肾细胞癌为例),BRM治疗的毒副作用
28、,高热,寒战,呕吐,腹泻,伴有心、肺、肝及肾功能不全。,过继性免疫治疗的几种方法,肿瘤浸润淋巴细胞(TIL)激活的T淋巴细胞(ALT)活化的肿瘤特异性CTLs,过继性免疫治疗的疗效,基因治疗方法,转基因肿瘤细胞(肿瘤疫苗)基因导入的常用方法:逆转录病毒,脂质体,基因枪病灶内注射基因治疗常用方法:腺病毒,脂质体,基因枪,Bottle Necks of Cancer Gene Therapy,Vectors targeting to cancer cellsGene expression controlEffective Therapeutic Genes,Key Issue:Better und
29、erstanding of Cancer,Therapeutic Genes Currently Used In Cancer Gene Thesapy(59/652),I.Genes related to cell cycle,apoptosis and proliferation(20/110),II.Immune Related(27/361),III.Oncolytic Viruses(4/50),IV.Miscellaneous(8/29),VSV,(五)中医中药治疗 对肿瘤患者应定期随诊。常用3年,5年,10年生存率表示治疗效果生存者的百分率包括带瘤生存者;无瘤生存的百分率是治愈率
30、。影响转归和预后的主要因素是肿瘤的性质和治疗的彻底性。肿瘤的治疗以综合治疗为主。,summary,neoplasia-uncontrolled cell division non responsive to growth controls.Benign and MalignantNaming Cell of origin+Suffix Oma,Carcinoma,Sarcomabenign slow-growing,well-differentiated,localized,do not metastasize,amenable to surgery.,summary,malignant ne
31、oplasms tend to be fast-growing lesions which invade normal structuresmalignant neoplasms vary in the degree of differentiation and some show anaplasia.malignant neoplasms are capable of infiltration,invasion&metastasis.,summary,The prognosis of a patient with any type of neoplasm depends on a numbe
32、r of factors including:the rate of growth of the tumor,the size of the tumor,the tumor site,the cell type and degree of differentiation,the presence of metastasis,responsiveness to therapy,and the general health of the patient.,NEOPLASM Uncontrolled cell Division(DNA abnormality),Self Assessment Que
33、stions:,What is a neoplasm?Write two special characters?What is a papilloma,adenomaWhat is dysplasia,Metaplasia,Anaplasia Hyperplasia?Mention examples?Mention major classes of neoplasms with five differentiating features?Mention three features of malignant tumor?,Self Assessment Questions:,What is carcinoma-in-situ?What is grading?And staging?How are neoplasms named?What is CIN?ClassifyWhat are the common routes of cancer spread?How do we diagnose cancer?Brief note of tumor markers?,