腫瘤病理學(xué)課課件

1、腫瘤病理學(xué) Pathology of Neoplasia,基礎(chǔ)醫(yī)學(xué)研究所病理生物學(xué)研究室陸應(yīng)麟,腫瘤是目前死亡常見原因之一。惡性腫瘤是男性第二位死因，女性第三位主要死因。我國最常見惡性腫瘤： 城市：肺癌、胃癌、肝癌、腸癌 和乳癌 農(nóng)村：胃癌、肝癌、肺癌、食管 癌、腸癌,基 本 概 念,腫瘤的慨念腫瘤是機(jī)體中正常細(xì)胞，在不同始動與促進(jìn)因素長期作用下所產(chǎn)生的增生與異常分化所形成的新

2、生物。腫瘤的特點(diǎn)新生物一旦形成，不因病因消除而停止增生。它不受機(jī)體生理調(diào)節(jié)，而是破壞正常組織與器官。,Introduction:,Inflammatory, Degenerative & NeoplasticGrowth – Increase in size due to synthesis of tissue components.Proliferatation- Cell division.Differentia

3、tion: 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 suppres

4、sor genes – p53Oncogenes – c-onc, p-onc, v-onc etc.,Non-Neoplastic Proliferation:,*Controlled & ReversibleHypertrophy 肥大 – SizeHyperplasia 增生– NumberMetaplasia 化生– ChangeDysplasia 異常增生– Disordered,Neoplasia:,Pro

5、gressive, Purposeless, Pathologic, Proliferation of cells characterized by loss of control over cell division.DNA damage at growth control genes is central to development of neoplasm.Carcinogens – Chemical, physical &

6、amp; genetic ? DNA damage ? Neoplasm.,Pathogenesis of Neoplasia:,Normal ? Hyperplasia ? Metaplasia化生 ?(DNA damage) ? Dysplasia 異常增生 ? (DNA damage) ? (DNA damage) Anaplasia 間變? (DNA damage) Infiltration 浸潤? (DNA damage) ?

7、 Metastasis轉(zhuǎn)移….Progressive DNA Damage – features of neoplasia.,Pathogenesis of Neoplasia:,Non lethal DNA Damage leading to uncontrolled cell division.,病理,惡性腫瘤的發(fā)生發(fā)展過程一般致癌因素作用30~40年，經(jīng)10年左右的癌前階段惡變?yōu)樵话?。原位癌歷時3~5年，在促癌因素作用下

8、發(fā)展成浸潤癌。浸潤癌的病程一般1年左右。,2.腫瘤細(xì)胞的分化分為高分化、中分化、低（未）分化。組織化學(xué)的變化：(1)核酸增多(2)酶的改變(3)糖原減少,,,3. 生長方式： 4. 生長速度：良性腫瘤：外生性生長 良性腫瘤生長慢惡性腫瘤：浸潤性生長 惡性腫瘤生長快,,Non-Neoplastic Ne

9、oplastic (Polyclonal) (Monoclonal),Normal Adaptation Benign Malignant,Mechanism of Neoplams,,,,Structure of Neoplasm:,Neoplastic cells parenchyma.Non-neoplastic - stroma (Connective

10、 tissue & BV) Fast growth ? less stroma Less stroma ? more necrosis,,Biology of Neoplasm:,Cell of originRate of growthDifferentiationLocal InvasionMetastasis,Lung cancerGrade - low, highWell, Mod, P, Un.St

11、agingStaging,Lung cancer:Squamus cell carcinoma.Poorly differentiated, high grade, stage 4, Liver+,Benign Malignant:,Slow growing,capsulated, Non-invasive do not metastasize, well differentiated, suffix “oma”

12、 eg. Fibroma.,Fast growing, non capsulated, Invasive & Infiltrate Metastasize. poorly differentiated, Suffix “Carcinoma” or “Sarcoma”,,,,,Better Understanding of Cancer,1. Cancer Cancer cells,Cancer

13、 Research Cancer cell research,Cancer a tissue: Cancer cells Stromal cells Vascular cells ( endothelia, pericytes

14、 smooth muscle cells fibroblasts) Lymphatic vessel cells Immune cells,,,2. Do Cancer Stem Cells Exist in Caner ?,cancer cell heterogeneity,1. genetic

15、2.phenotypic,differentin,MorphologyGrowth behaviorMetastasis potentialChemo / radio resistanceOther phenotypes,,,,Do Cancer stem cells exist among cancer cell population ?,Cancer cells,Cancer stem cells: ( 10-2 to

16、 10-4) Persistent proliferation Renewal Metastatic potentialPartial differentiated cancer cells Limited number of proliferation Differential extent of diffe

17、rentiation Bulk of cancer cells,,If the hypothesis is true Kill the cancer stem cells ? Abolish the whole tumorDifficult Problems: How to identify ? How to kill ? (Cancer stem cel

18、ls normal stem cells),,,?,Cancer stem cells reported: Breast cancer ( human ) Glioma ( human ) Lung cancer ( animal ) Gastric cancer ( animal ),Characteristics of report

19、ed “cancer stem cells”,,May be early event quiescent,3. Metastasis:,Early or late event ?Dissemination Metastasis.Dissemination: Migration of cancer cells to distant places:,Micro-satellit

20、e 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 progression:

21、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

22、 2, 2004 vol. 101: 15724-15729,分類,根據(jù)腫瘤的生物學(xué)行為主要分為：良性：稱為“瘤”惡性：來源于上皮組織稱為“癌” 來源于間葉組織稱為“肉瘤” 胚胎性腫瘤稱為“母細(xì)胞瘤”某些惡性腫瘤沿用傳統(tǒng)名稱：惡性淋巴瘤，精原細(xì)胞瘤，白血病，霍奇金氏病,1. 各種腫瘤根據(jù)其組織及器官來源而冠以不同名稱。2. 相同組織器官可發(fā)生不同細(xì)胞形態(tài)腫瘤。3. 同一細(xì)胞類型，

23、由于細(xì)胞分化程度不同，又分為高分化、中分化、低（未）分化。,,Nomenclature: Cell of origin + Suffix,Suffix - omaFibroma OsteomaAdenomaPapilloma Chondroma,Carcinoma / SarcomaFibrosarcomaOsteosarcomaAdenocarcinomaSquamous cell carcinomaChondr

24、osarcoma,Exceptions: Leukemia, Lymphoma, Glioma,,Bilateral Cystadenoma Ovary:,,,Lipoma Intestine:,meningioma,Lung carcinoma,Hepatic Adenoma:,,Carcinoma Breast:,,,,,,,,Carcinoma Lung:,,,Osteo - sarcoma:,,,Colon Polyp:,,,H

25、epatic Adenoma:,Normal Adenoma,,Anaplasia in Sarcoma:,Anaplasia:,Hepatic Adenocarcinoma:,Hepatic Adenocarcinoma:,,,Liver Metastasis:,,,分 級,Staging of Tumor,Grading – Cellular Differentiation (Microscopic),G

26、rading & 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 – Syste

27、mic Venous bloodLiver – GIT venous return, nutrition.Brain – End arteries.,5. 轉(zhuǎn)移①直接蔓延：胰頭癌侵及膽總管等②淋巴道轉(zhuǎn)移：多數(shù)情況為區(qū)域淋巴結(jié)轉(zhuǎn)移③種植性轉(zhuǎn)移：最多見的為胃癌種植到盆腔④血道轉(zhuǎn)移：如肝、肺、骨轉(zhuǎn)移,,轉(zhuǎn)移機(jī)制：①CD44，整合素：改變細(xì)胞粘附性②降解酶：形成瘤移動通道④運(yùn)動因子IGF-I，II：使腫瘤移動④VEGF：促

28、進(jìn)轉(zhuǎn)移灶形成,惡性腫瘤具有的表型,成瘤表型：與腫瘤生成有關(guān)的 基因所決定轉(zhuǎn)移表型：與腫瘤轉(zhuǎn)移有關(guān)的 基因所決定,體外研究成瘤性的生物學(xué)指標(biāo),倍增時間分裂指數(shù)生長曲線細(xì)胞周期PCNA表達(dá),體外研究轉(zhuǎn)移性的生物學(xué)指標(biāo),軟瓊脂集落形成數(shù)細(xì)胞爬片劃痕實(shí)驗(yàn)Tranwell (類似Boyden chember)細(xì)胞游走實(shí)驗(yàn)細(xì)胞穿膜（Metri

29、gel膜）浸潤實(shí)驗(yàn),體內(nèi)腫瘤轉(zhuǎn)移實(shí)驗(yàn),自發(fā)性腫瘤轉(zhuǎn)移實(shí)驗(yàn)實(shí)驗(yàn)性腫瘤轉(zhuǎn)移實(shí)驗(yàn),少數(shù)腫瘤形態(tài)上屬于良性，但常浸潤性生長，切除后易復(fù)發(fā)，多次復(fù)發(fā)有的出現(xiàn)轉(zhuǎn)移，生物行為上顯示良性與惡性之間的類型，故稱交界性或臨界性腫瘤。,,Clinical Features.,Tumor Impingement on nearby structuresPancreatic ca on bile duct ? Obst. Jaund.Ulceration/

30、bleedingColon, Gastric, and Renal cell carcinomasInfection (often due to obstruction)Pneumonia, Urinary inf.Rupture or InfarctionOvarian, Bladder, colon,,病因（1）外界因素（2）內(nèi)在因素臨床表現(xiàn)（1）局部表現(xiàn)（2）全身癥狀診斷（1）病史（2）體格檢查（3）實(shí)驗(yàn)室檢查（

31、4）影 像學(xué)檢查（5）內(nèi)鏡檢查（6）病理形態(tài)學(xué)檢查預(yù)防治療（1）手術(shù)治療（2）化學(xué)療法（3）放射療法 （4）生物治療（5）中醫(yī)中藥治療,,Tumor Diagnosis:,History and Clinical examinationImaging - X-Ray, US, CT, MRITumor markers Laboratory analysis Cytology –Pap s

32、mear, FNABBiopsy - Histopathology, markers.Molecular Tech – Gene detection.,CT: metastatic adenocarcinoma,Biopsy – Slide preparation,staining,病因,（一）外界因素：化學(xué)因素:(1)烷化劑：如有機(jī)農(nóng)藥、硫芥等(2) 多環(huán)芳香烴化合物：3，4-苯并芘(3)氨基偶氮類：染料類(4)亞硝胺類

33、(5)真菌毒素和植物毒素：黃曲霉菌、蘇鐵素等(6)其他：重金屬,,2. 物理因素(1)電離輻射(2)紫外線(3)其他：慢性病變，石棉纖維，滑石粉3. 生物因素 主要是病毒感染：如EB病毒，單純皰疹 病毒,,（二）內(nèi)在因素遺傳因素內(nèi)分泌因素免疫因素,臨床表現(xiàn),(一)局部表現(xiàn)腫塊疼痛潰瘍出血梗阻轉(zhuǎn)移癥狀,,（二）全身癥狀（1）多

34、無明顯全身癥狀，或僅有非特異性全身癥狀：貧血，低熱，消瘦，乏力。（2）惡病質(zhì)常是惡性腫瘤晚期全身衰竭表現(xiàn)。（3）某些部位的腫瘤可引起相應(yīng)的功能亢進(jìn)或低下，繼發(fā)全身改變：如嗜鉻細(xì)胞瘤，甲狀旁腺瘤。,診斷,目的：確定有無腫瘤，明確其性質(zhì)，了解其范圍和程度，以便擬訂治療方案。目前仍缺乏理想的特異性強(qiáng)的早期診斷方法。,（一）病史年齡：兒童腫瘤多為胚胎性腫瘤或白血??；青少年腫瘤多為肉瘤；癌多發(fā)于中年以上。病程：良性者病程較長，惡性者較

35、短。過去史：（1）有無家族史或遺傳史（2）有無癌前病變或相關(guān)疾病病史（3）注意個人史中，行為與環(huán)境相關(guān)情況,,（二）體格檢查全身體檢：注意淺表淋巴結(jié)是否腫大；是否有腫塊。局部檢查：1.腫塊的部位：有助于分析腫塊的組織來源與性 質(zhì)2.腫瘤的性狀：有助于分析診斷。3.區(qū)域淋巴結(jié)或轉(zhuǎn)移灶的檢查,,,（三）實(shí)驗(yàn)室檢查常規(guī)化驗(yàn)：并非特異性檢查，但可提供診斷線索。血清學(xué)檢查

36、：特異性較差，但可用作輔助診斷。 酶學(xué)檢查：①堿性磷酸酶：肝癌，骨肉瘤時↑　　　　?、谒嵝粤姿崦福呵傲邢侔　　　　、廴樗崦摎涿福焊伟┘皭盒粤馨土觥堑鞍祝合到y(tǒng)腫瘤激素類：絨毛膜上皮癌→絨毛膜促性腺激素↑ 垂體腫瘤→抗利尿激素↑ 胰島細(xì)胞瘤→胰島素↑,,3. 免疫學(xué)檢查：常用放射免疫測定法。常用的有：①癌胚抗原（CEA），結(jié)腸癌、胃癌、肺癌、乳癌↑②α

37、-胚胎抗原（AFP），肝癌、惡性畸胎瘤↑③腫瘤相關(guān)抗原：抗EB病毒抗原的IgA抗體（VCA-IgA）→鼻咽癌↑時間分辨熒光分析技術(shù)（TRF）以稀土離子極其螯合物進(jìn)行標(biāo)記。靈敏度高，特異性強(qiáng)，無污染。,,4. 流式細(xì)胞分析術(shù)：用以判斷腫瘤惡性程度及推測其預(yù)后。5. 基因診斷：腫瘤的發(fā)生是由于細(xì)胞中基因改變積累的結(jié)果，包括（1）癌基因的激活、過度表達(dá)。（2）抑癌基因的突變、丟失。（3）微衛(wèi)星不穩(wěn)定，出現(xiàn)核苷酸異常的串聯(lián)重復(fù)分布于基因

38、組（4）錯配修復(fù)基因突變，導(dǎo)致細(xì)胞遺傳不穩(wěn)定或致腫瘤易感性。,,,,（四）影像學(xué)檢查X線檢查（1）透視與平片,Skull in Myeloma:,,（2）造影①鋇餐，鋇灌腸,,②器官造影IVP口服膽囊造影逆行腎盂造影膽道與胰管逆行造影,,③血管造影,（3）特殊X線顯影術(shù)干板攝影鉬靶X線球管攝影主要用于軟組織和乳腺組織,,2. 電子計(jì)算機(jī)斷掃描（CT）,,螺旋CT與三維成像,,3. 超聲顯像：對判斷囊性與實(shí)質(zhì)性腫塊很

39、有價(jià)值,,4. 放射性核素成像,,5. MRI,,（五）內(nèi)鏡檢查,,（六）病理形態(tài)學(xué)檢查1.臨床細(xì)胞學(xué)檢查①自然脫落細(xì)胞②粘膜細(xì)胞③細(xì)針穿刺涂片,,2. 病理組織學(xué)檢查 對色素性結(jié)節(jié)或痣，應(yīng)完整切除檢查,腫瘤分期,I期：T1N0M0II期：T0-1N1M0III期：T1-2N2M0或T3N0-2M0IV期：T1-3N0-2M1或T0N0-2M1,預(yù)防,一級預(yù)防：消除或減少可能致癌的因素，防止癌癥的發(fā)

40、生。二級預(yù)防：早期發(fā)現(xiàn)，及時治療。對高危區(qū)及高危人群定期檢查，從中發(fā)現(xiàn)癌前期病變及時治療。三級預(yù)防：改善生存質(zhì)量，對癥治療。（1）最初用非嗎啡類藥（2）小劑量開始（3）口服為主（4）定期給藥。,治療,良性腫瘤或臨界性腫瘤以手術(shù)切除為主。惡性腫瘤I期：手術(shù)治療為主II期：切除或放療原發(fā)腫瘤，輔以有效的全身化療III期：手術(shù)前、后及術(shù)中放療或化療。IV期：全身治療為主，輔以局部對癥治療,（一）手術(shù)治療①根治手術(shù)：包括原發(fā)癌

41、所在器官的部分或全部，連同周圍正常組織和區(qū)域淋巴結(jié)整塊切除。②擴(kuò)大根治術(shù)：在原根治范圍基礎(chǔ)上適當(dāng)切除附近器官及區(qū)域淋巴結(jié)。③對癥手術(shù)或姑息手術(shù)：以手術(shù)解除或減輕癥狀，延長生命，爭取綜合治療機(jī)會，改進(jìn)生存質(zhì)量。④激光手術(shù)或冷凍手術(shù),,（二）化學(xué)治療藥物分類（1）細(xì)胞毒素類藥物：烷化劑，作用于DNA和RNA、酶、蛋白質(zhì)導(dǎo)致細(xì)胞死亡。如環(huán)磷酰胺、氮芥。（2）抗代謝類：對核酸代謝物與酶結(jié)合反應(yīng)有相互競爭作用，影響與阻斷了核酸的合成。

42、如5-FU，甲氨蝶呤。（3）抗生素類：如放線菌素D，絲裂霉素。（4）生物堿類：干擾細(xì)胞內(nèi)紡錘體的形成，使細(xì)胞停留在有絲分裂中期。如長春新堿，羥基喜樹堿。,,（5）激素類：能改變內(nèi)環(huán)境進(jìn)而影響腫瘤生長。如乙烯雌酚黃體酮等。（6）其他：如順鉑，卡鉑等根據(jù)藥物對細(xì)胞周期作用分類：細(xì)胞周期非特異性藥物細(xì)胞周期特異性藥物細(xì)胞周期時相特異藥物,,,2. 給藥方式：靜脈點(diǎn)滴或注射，口服，肌肉注射。靜脈給藥：大劑量沖擊治療中劑量間

43、斷治療小劑量維持治療,3. 化療副作用①白細(xì)胞血小板減少②消化道反應(yīng)③毛發(fā)脫落④血尿⑤免疫功能降低，易并發(fā)感染,,(三）放射治療器械： ①光子類：深度X線、γ射線，各種同位素②粒子類：粒子加速器，感應(yīng)加速器，中子加速器方法外照射，內(nèi)照射副作用骨髓抑制，皮膚粘膜改變，胃腸反應(yīng),,（四）生物治療免疫治療（1）生物反應(yīng)調(diào)節(jié)因子（BRM） BRM是一些在自然和特異性免疫的效應(yīng)階段起調(diào)節(jié)作用的激素蛋

44、白質(zhì)。（2）過繼性免疫治療2. 基因治療,,BRM的臨床療效（以腎細(xì)胞癌為例）,BRM治療的毒副作用,高熱，寒戰(zhàn)，嘔吐，腹瀉，伴有心、肺、肝及腎功能不全。,過繼性免疫治療的幾種方法,腫瘤浸潤淋巴細(xì)胞（TIL）激活的T淋巴細(xì)胞（ALT）活化的腫瘤特異性CTLs,過繼性免疫治療的療效,基因治療方法,轉(zhuǎn)基因腫瘤細(xì)胞（腫瘤疫苗）基因?qū)氲某Ｓ梅椒ǎ耗孓D(zhuǎn)錄病毒，脂質(zhì)體，基因槍病灶內(nèi)注射基因治療常用方法：腺病毒，脂質(zhì)體，基因槍,B

45、ottle Necks of Cancer Gene Therapy,Vectors targeting to cancer cellsGene expression controlEffective Therapeutic Genes,Key Issue: Better understanding of Cancer,Therapeutic Genes Currently Used In

46、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）中醫(yī)中藥治療 對腫瘤患者應(yīng)定期隨診。 常用3年，

47、5年，10年生存率表示治療效果生存者的百分率包括帶瘤生存者；無瘤生存的百分率是治愈率。影響轉(zhuǎn)歸和預(yù)后的主要因素是腫瘤的性質(zhì)和治療的徹底性。腫瘤的治療以綜合治療為主。,,summary,neoplasia- uncontrolled cell division non responsive to growth controls.Benign and MalignantNaming – Cell of origin + Suffi

48、x Oma, Carcinoma, Sarcomabenign ? slow-growing, well-differentiated, localized, do not metastasize, amenable to surgery.,summary,malignant neoplasms tend to be fast-growing lesions which invade normal structuresmalig

49、nant 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 depen

50、ds on a number 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 gen

51、eral health of the patient.,NEOPLASM Uncontrolled cell Division(DNA abnormality),Self Assessment Questions:,What is a neoplasm? Write two special characters? What is a papilloma, adenomaWhat is dysplasia, Metapla

52、sia, 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