病理学课件：第五章 肿瘤 1

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1、 第五章第五章 肿瘤肿瘤 Xian Jiaotong UniversityXIAN JIAOTONG UNIVERSITYPage 2 祖国医学对肿瘤的记载：祖国医学对肿瘤的记载：2000多年前多年前周礼周礼已有专治已有专治“肿瘍肿瘍”的医生，称疡医。的医生，称疡医。肿瘍泛指肿肿瘍泛指肿瘤和非瘤性肿块瘤和非瘤性肿块 500-300BC 内经内经，把肿瘤和大多数非瘤性，把肿瘤和大多数非瘤性肿块，称之为肿块，称之为“瘕瘕”、“癥癥”和和“积聚积聚”。病因病因解释为解释为“营卫不通营卫不通”，“七情郁结七情郁结”，“脾胃受脾胃受伤伤”，以致，以致“气血凝滞气血凝滞”所致所致 东汉许慎东汉许慎说文解字

2、说文解字解释解释“瘤瘤”谓谓“瘤，肿瘤，肿也也”。东汉刘熙。东汉刘熙释名释名释疾病释疾病说：说：“瘤，瘤肿瘤，瘤肿也，血液聚而生瘤肿也也，血液聚而生瘤肿也”XIAN JIAOTONG UNIVERSITYPage 3XIAN JIAOTONG UNIVERSITYPage 4 Hippocrates(460-375 BC),the father of medicine,was the first to divide tumors into two large groups according to their behavior（1）the innocuous tumors,which incl

3、uded swellings and lumps of various kinds(probably both non neoplasitic and neoplastic)（2）the dangerous tumors,which killed the patients (probably representing predominantly malignant neoplasms).XIAN JIAOTONG UNIVERSITYPage 5 Galen(AD 131-201 prominent Greek physician,surgeon and philosopher in the

4、Roman empire）divided tumors into three categories:(1)tumor according to nature,e.g.,pregnancy.(2)tumors exceeding nature e.g.,inflammatory and reparative tumors,callus around a bone fracture;and(3)tumor contrary to nature,e.g.,true neoplasms.Galen was aware of the phenomenon of tumor metastasis.He w

5、as also the first to theorize as to the possible cause of cancer,ascribing it to excess of black bile.It is said that he was the one who coined the term sarcoma(Gr.sarx,genitive sarkos,flesh)under which he included various tumors with a fleshy gross appearance.XIAN JIAOTONG UNIVERSITYPage 6第一节第一节 肿瘤

6、的概念肿瘤的概念 肿瘤是机体在各种致瘤因素的作用下肿瘤是机体在各种致瘤因素的作用下,局部组织的细胞异局部组织的细胞异常增生而形成的新生物常增生而形成的新生物,这种新生物常表现为肿块这种新生物常表现为肿块.肿瘤细胞是从肿瘤细胞是从正常细胞正常细胞转变而来的转变而来的,但当它变为肿瘤细但当它变为肿瘤细胞后就具有异常的形态、代谢及功能，它生长旺盛，呈相胞后就具有异常的形态、代谢及功能，它生长旺盛，呈相对无止境生长，与整个机体不协调，并在不同程度上失去对无止境生长，与整个机体不协调，并在不同程度上失去了发育成熟的能力，有些甚至具有接近幼稚的胚胎细胞的了发育成熟的能力，有些甚至具有接近幼稚的胚胎细胞的表

7、现。致瘤因子可能作用于细胞的遗传物质，使之产生结表现。致瘤因子可能作用于细胞的遗传物质，使之产生结构或构或/和功能的变异，随着细胞的分裂，这些遗传物质的改和功能的变异，随着细胞的分裂，这些遗传物质的改变仍能按照遗传法则不断传给子代细胞，这样，即便是致变仍能按照遗传法则不断传给子代细胞，这样，即便是致瘤因子不存在，肿瘤细胞的生长和代谢仍能继续保持下去瘤因子不存在，肿瘤细胞的生长和代谢仍能继续保持下去（病理学卫生部统编教材第一版1979）。）。XIAN JIAOTONG UNIVERSITYPage 7肿瘤概念肿瘤概念 Cancer is a genetic disease,arising fro

8、m an accumulation of mutations that promote clonal selection of cells with increasingly aggressive behavior.The vast majority of mutations in cancer are somatic and are found only in an individuals cancer cells.However,about 1%of all cancers arise in individuals with an unmistakable hereditary cance

9、r syndrome.These individuals carry a particular germline mutation in every cell of their body.Science Vol.278.no.5340,pp.1043 1050,7 November 1997 XIAN JIAOTONG UNIVERSITYPage 8 肿瘤是机体在各种致瘤因素的作用下，局部组织的细胞肿瘤是机体在各种致瘤因素的作用下，局部组织的细胞在在基因水平上失去对其生长的正常调控，导致克隆性异常基因水平上失去对其生长的正常调控，导致克隆性异常增生增生而形成的新生物而形成的新生物（病理学卫生

10、部统编教材第五版 2001）。肿瘤肿瘤(tumor)是机体在内外各种致瘤因素作用下，局部是机体在内外各种致瘤因素作用下，局部组织的某一个细胞在基因水平上失去对其生长分化的正常调组织的某一个细胞在基因水平上失去对其生长分化的正常调控，导致其克隆性异常增生而形成的新生物（控，导致其克隆性异常增生而形成的新生物（neoplasm)。这种新生物形成的过程称为肿瘤形成（这种新生物形成的过程称为肿瘤形成（neoplasia)。现在一。现在一般认为，肿瘤细胞是单克隆性（般认为，肿瘤细胞是单克隆性（monoclonility)的，即一个的，即一个肿瘤中的所有瘤细胞均是一个突变的细胞的后代肿瘤中的所有瘤细胞均是

11、一个突变的细胞的后代（病理学卫生部统编教材(7/8年制第2版 2010）XIAN JIAOTONG UNIVERSITYPage 9 Cancer is a genetic disorder caused by DNA mutations that are(for the most part)acquired spontaneously or induced by environmental insults.These genetic alterations are heritable,being passed to daughter cells upon cell division.As a

12、 result,cells harboring these alterations are subject to Darwinian selection with cells bearing mutations that provide them with growth or survival advantages outcompeting their neighbors and thus coming to dominate the population.XIAN JIAOTONG UNIVERSITYPage 10 Accumulation of mutations gives rise

13、to a set of properties that have been called hallmarks of cancer.(1)self-sufficiency in growth.(2)lack of response to growth inhibitory signals that control non-neoplastic cellular proliferations such as hyperplasias;(3)evasion of cell death.(4)limitless replicative potential,immortalization;(5)deve

14、lopment of angiogenesis to sustain the growth of cancer cells;(6)ability to invade local tissues and spread to distant sites;(7)reprogramming of metabolic,Warburg effect.(8)ability to evade the immune system.The genetic alterations that give rise to these hallmarks of cancers are sustained and enabl

15、ed by the development of genomic instability,adding fuel to the fire.ROBBINS BASIC PATHOLOGY 9th Edition 2013XIAN JIAOTONG UNIVERSITYPage 11 No completely satisfactory definition of neoplasia exists，it has been surprisingly difficult to develop an accurate definition.In the Premolecular era,definiti

16、on of the eminent British oncologist Willis remains one of the most widely cited and useful: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

17、the change(Willis B.A.:the spread of the tumors in the human body,London,1952.Butterworth&Co.)XIAN JIAOTONG UNIVERSITYPage 12 In the modern era,a neoplasm can be defined as a disorder of cell growth that is triggered by a series of acquired mutations affecting a single cell and its clonal progeny.Th

18、e causative mutations give the neoplastic cells a survival and growth advantage,resulting in excessive proliferation that is independent of physiologic growth signals(Robbins&Cotran Pathologic Basis of Disease 9th Ed.2015)XIAN JIAOTONG UNIVERSITYPage 13Non-neoplastic Growth Disturbances Hypertrophy

19、and Atrophy（肥大（肥大/萎缩）萎缩）Hyperplasia（增生）（增生）Metaplasia（化生）（化生）Dysplasia（异型增生（异型增生/不典型增生）不典型增生）（A synonym：Atypical hyperplasia）XIAN JIAOTONG UNIVERSITYPage 14 The genetic alterations of cancer cells are heritable.As a result,cells harboring these alterations are subject to Darwinian selection,with cel

20、ls bearing mutations that provide them with growth or survival advantages outcompeting their neighbors and thus coming to dominate the population.Because the selective advantages are conferred on a single cell that ultimately gives rise to the tumor,all tumors are clonal(i.e.,the progeny of one cell

21、).肿瘤是单克隆生长肿瘤是单克隆生长Monoclonality vs polyclonality of tumors二、肿瘤性增生的特点二、肿瘤性增生的特点XIAN JIAOTONG UNIVERSITYPage 15 glucose-6-phosphate dehydrogenase chromasome abrrationTo determine whether all the cells in a tumor mass share a common,highly unique genetic or biochemical marker.XIAN JIAOTONG UNIVERSITYPa

22、ge 16不成熟性不成熟性 代谢、功能和结构的幼稚性代谢、功能和结构的幼稚性 遗传性遗传性 能将增生的特点传给子代细胞，病因能将增生的特点传给子代细胞，病因 消除后仍继续生长消除后仍继续生长 与机体不协调性与机体不协调性 持续性生长，破坏正常组织。持续性生长，破坏正常组织。肿瘤性增生的特点肿瘤性增生的特点XIAN JIAOTONG UNIVERSITY肿瘤性增生肿瘤性增生 非肿瘤性增生非肿瘤性增生 增生增生单克隆性单克隆性多克隆性多克隆性分化程度分化程度 失去分化成熟能力失去分化成熟能力 分化成熟分化成熟 与机体协调性与机体协调性 相对自主性相对自主性具有自限性具有自限性病因去除病因去除 持续

23、生长持续生长停止生长停止生长形态结构、功能形态结构、功能 异常异常正常正常对机体影响对机体影响 有害有害有利有利肿瘤性增生与非肿瘤性增生的区别肿瘤性增生与非肿瘤性增生的区别XIAN JIAOTONG UNIVERSITYPage 18一、肿瘤的大体形态（直观性）一、肿瘤的大体形态（直观性）数目：数目：一般一个，可多个一般一个，可多个大小：大小：大小悬殊大小悬殊 影响因素：影响因素：性质、生长时间、部位性质、生长时间、部位外形：外形：多种多样多种多样 影响因素：影响因素：部位、组织来源、性质、生长部位、组织来源、性质、生长方式方式XIAN JIAOTONG UNIVERSITY乳头状乳头状 囊状

24、囊状 多房性囊状多房性囊状 结节状结节状 乳头状乳头状 分叶状分叶状XIAN JIAOTONG UNIVERSITY 胆管细胞癌胆管细胞癌巨块状肝细胞癌巨块状肝细胞癌溃疡型直肠癌溃疡型直肠癌肥厚浸润型膀胱癌肥厚浸润型膀胱癌菜花样胃癌菜花样胃癌XIAN JIAOTONG UNIVERSITYPage 21颜色：颜色：多为灰白或灰红色，也可呈其它颜色多为灰白或灰红色，也可呈其它颜色 影响因素：影响因素：组织来源、含血量、继发改变组织来源、含血量、继发改变质地或硬度：质地或硬度：悬殊悬殊较大较大 影响因素影响因素:来源、实质与间质的比例等来源、实质与间质的比例等肿瘤的包膜：肿瘤的包膜：良性：大多数有

25、完整包膜良性：大多数有完整包膜 恶性：一般无包膜恶性：一般无包膜XIAN JIAOTONG UNIVERSITY二、肿瘤的组织形态二、肿瘤的组织形态 实质（实质（parenchyma）：）：即克隆性增生的即克隆性增生的肿瘤细胞，肿瘤细胞，是肿瘤的主要成分，决定肿瘤的生物学特点。其是肿瘤的主要成分，决定肿瘤的生物学特点。其分化程度和异型性大小可确定肿瘤的良、恶性及分化程度和异型性大小可确定肿瘤的良、恶性及恶性程度。恶性程度。间质（间质（stroma）：）：基本成分是基本成分是结缔组织和血管，结缔组织和血管，支持和营养肿瘤实质。其内浸润的免疫细胞是机支持和营养肿瘤实质。其内浸润的免疫细胞是机体对肿

26、瘤组织发生的免疫反应（体对肿瘤组织发生的免疫反应（双向性效应双向性效应）。）。XIAN JIAOTONG UNIVERSITYPage 23Recruitment of endothelial precursor cells by mammary CAFs desmoplastic stroma肿瘤间质是肿瘤性的肿瘤间质是肿瘤性的XIAN JIAOTONG UNIVERSITYPage 24Tumors and derived xenografted tumor cell linesXIAN JIAOTONG UNIVERSITY 第三节第三节 肿瘤的分化与异型性肿瘤的分化与异型性 一、概念一

27、、概念1.（肿瘤）分化：（肿瘤）分化：肿瘤实质细胞与其来源的正常实质肿瘤实质细胞与其来源的正常实质细胞在形态和功能上的相似程度细胞在形态和功能上的相似程度 分化（分化（differentiation）：）：个体发育中，由一种相同的细胞类型经细胞个体发育中，由一种相同的细胞类型经细胞分裂后逐渐在形态、结构和功能上形成稳定性差异，产生不同细胞类分裂后逐渐在形态、结构和功能上形成稳定性差异，产生不同细胞类群的过程。原始或幼稚的细胞发育成为成熟的细胞的过程群的过程。原始或幼稚的细胞发育成为成熟的细胞的过程2.间变（间变（Anaplasia)在病理学上指去分化或者缺乏在病理学上指去分化或者缺乏分化（分化

28、（Dedifferentiation/Undifferentiation）Differentiation and AtypiaXIAN JIAOTONG UNIVERSITYPage 26二、肿瘤的异型性二、肿瘤的异型性 肿瘤的异型性（肿瘤的异型性（atypia）:是指肿瘤组织在是指肿瘤组织在瘤细胞形瘤细胞形态态和和瘤组织结构瘤组织结构方面都与其发源的正常组织有不方面都与其发源的正常组织有不同程度的同程度的差异差异。异型性异型性可可反映肿瘤组织的成熟程度（分化程度）反映肿瘤组织的成熟程度（分化程度）良性肿瘤异型性小，恶性肿瘤异型性大。良性肿瘤异型性小，恶性肿瘤异型性大。是诊断肿瘤、区别良、恶性

29、肿瘤的主要组织学依据是诊断肿瘤、区别良、恶性肿瘤的主要组织学依据。XIAN JIAOTONG UNIVERSITYPage 271.1.肿瘤组织结构异型性肿瘤组织结构异型性 指瘤组织在指瘤组织在空间排列方式空间排列方式（极向性、器官（极向性、器官样结构及与间质的关系）上与其来源的正常样结构及与间质的关系）上与其来源的正常组织之间的差异。组织之间的差异。良性肿瘤：良性肿瘤：有一定的组织结构异型性，是良性肿瘤有一定的组织结构异型性，是良性肿瘤的重要诊断依据。的重要诊断依据。恶性肿瘤：恶性肿瘤：组织结构异型性更明星，瘤细胞排列更组织结构异型性更明星，瘤细胞排列更紊乱、无正常的层次、层序和极向。紊乱、

30、无正常的层次、层序和极向。XIAN JIAOTONG UNIVERSITYPage 28 High-grade squamous intraepithelial lesion.An abrupt transition(arrow)is visible between Normal (left)and dysplastic(right)epithelium.The epithelium at right shows a persistence of immature cells (large nuclei and high N/C ratios)up to the surface.Compare

31、 this to the clear distinction between basal cells and maturing cells seen at left.XIAN JIAOTONG UNIVERSITYPage 29Normal colon.Section through colonic mucosa showing parallel crypts(C),lamina propria(LP),muscularis mucosa(MM),and submucosal arteries(A),veins(V),and lymphatics(L).XIAN JIAOTONG UNIVER

32、SITYPage 30Tubular adenoma.This section shows an early tubular adenoma in which low-grade dysplasia is seen in the surface glands(arrow),while the deeper glands are uninvolved(arrowhead).The adenomatous epithelium is dark due to crowded and hyperchromatic nuclei and loss of mucinous goblet cells.Mit

33、otic activity and neutrophils are common in adenomas but may also be seen in benign epitheliumXIAN JIAOTONG UNIVERSITYPage 31 Invasive adenocarcinoma.Poorly formed glands and single cells(arrow)infiltrate through a desmoplastic stroma(arrowhead).Cells show marked pleomorphism and prominent nucleoli.

34、High-grade dysplasia in an adenoma.The diagnosis is largely based on architectural features,such as cribriform growth(arrow).XIAN JIAOTONG UNIVERSITY2.2.肿瘤细胞的异型性肿瘤细胞的异型性n良性肿瘤细胞良性肿瘤细胞与其起源的细胞形态十分相似，与其起源的细胞形态十分相似，异型异型性小性小。n恶性肿瘤瘤细胞异型性显著恶性肿瘤瘤细胞异型性显著，有以下特点：有以下特点：(1)(1)瘤细胞的多形性：瘤细胞的多形性：大小形态不一，一般较大，可大小形态不一，一

35、般较大，可出现瘤巨细胞，细胞极性缺失。亦有小细胞（如小出现瘤巨细胞，细胞极性缺失。亦有小细胞（如小细胞肺癌），细胞肺癌），(2)(2)瘤细胞核的多形性：瘤细胞核的多形性：对诊断恶性肿瘤至关重要。对诊断恶性肿瘤至关重要。XIAN JIAOTONG UNIVERSITY核形态异常，核核形态异常，核-浆比例增大，核大小浆比例增大，核大小/形态不一，形态不一，核不规则。一般较大，出现巨核、多核和畸异核不规则。一般较大，出现巨核、多核和畸异核；核；核膜厚，染色质粗大呈块状分布不均，核深染。核膜厚，染色质粗大呈块状分布不均，核深染。核仁大、多；核仁大、多；核分裂像多、出现核分裂像多、出现病理性核分裂像病理

36、性核分裂像（对恶性肿（对恶性肿 瘤有诊断意义）。瘤有诊断意义）。“核多形性核多形性”主要包括：主要包括：XIAN JIAOTONG UNIVERSITYPage 34XIAN JIAOTONG UNIVERSITYPage 35 瘤细胞质的改变：瘤细胞质的改变：胞浆少，核蛋白体增多胞浆少，核蛋白体增多胞浆嗜碱（稍蓝染）；可出现分泌物或代胞浆嗜碱（稍蓝染）；可出现分泌物或代谢物的储留（有助判断肿瘤来源）。谢物的储留（有助判断肿瘤来源）。其他改变：其他改变：瘤性坏死瘤性坏死XIAN JIAOTONG UNIVERSITYXIAN JIAOTONG UNIVERSITYPage 37 Leiomyo

37、ma of the uterus.A.A bisected uterus displays a prominent,sharply circumscribed,fleshy tumor.B.Microscopically,smooth muscle cells intertwine in bundles,some of which are cut longitudinally(elongated nuclei)andothers transversely.XIAN JIAOTONG UNIVERSITYPage 38Leiomyosarcoma of the uterus.A.The uter

38、us has been opened to reveal a large,soft leiomyosarcoma with extensive necrosis that replaces the entire myometrium.B.A zoneof coagulative tumor necrosis(arrows)appears demarcated from the viable tumor.C.The tumor shows considerable nuclear atypia and abundant mitotic activity.XIAN JIAOTONG UNIVERS

39、ITYPage 39Chondrosarcoma of bone.The tumor is composed of malignant chondrocytes,which have bizarre shapes and irregular hyperchromaticnuclei,embedded in a cartilaginous matrix.Benign chondroma.A.Normal cartilage.B.A benign chondroma closely resembles normal cartilage.XIAN JIAOTONG UNIVERSITYPage 40

40、 Undifferentiated pleomorphic sarcoma(“malignant fibrous histiocytoma”).An anaplastic tumor exhibits spindle cells,plump polygonal cells,bizarre tumor giant cells,an abnormal mitosis(center)XIAN JIAOTONG UNIVERSITY第四节第四节 肿瘤的生长和扩散肿瘤的生长和扩散一、一、肿瘤的生长肿瘤的生长（一）肿瘤的生长方式（一）肿瘤的生长方式膨胀性、外生性、浸润性膨胀性、外生性、浸润性 1.膨胀性生

41、长膨胀性生长（expansive growth）:多发生在多发生在深部组织良性肿瘤的生长方式，形成的肿瘤一般深部组织良性肿瘤的生长方式，形成的肿瘤一般有完整包膜、界清、活动、易摘除。有完整包膜、界清、活动、易摘除。XIAN JIAOTONG UNIVERSITY 2.外生性生长外生性生长（exophytic growth）：生长在体表、体腔或管道器官表面的肿瘤，常生长在体表、体腔或管道器官表面的肿瘤，常向表面生长形成不同肉眼形态的肿物。良性肿瘤向表面生长形成不同肉眼形态的肿物。良性肿瘤-仅向表面生长。恶性肿瘤仅向表面生长。恶性肿瘤-表面生长同时兼有向深表面生长同时兼有向深部组织浸润生长部组织浸

42、润生长XIAN JIAOTONG UNIVERSITY 3.浸润性生长（浸润性生长（invasive growth）：大多数恶性肿瘤的生长方式。大多数恶性肿瘤的生长方式。瘤细胞瘤细胞长入长入周围周围组织间隙、血管或神经束衣组织间隙、血管或神经束衣并破坏并破坏周围组织（周围组织（浸润浸润 invasiveinvasive）。瘤性肿块无包膜、界不清、固定、难。瘤性肿块无包膜、界不清、固定、难于切净，因而手术后容易复发。于切净，因而手术后容易复发。XIAN JIAOTONG UNIVERSITYPage 44Adenocarcinoma of the colon with intestinal ob

43、struction.The lumen of the colon at the site of the cancer is narrow.The colonabove the obstruction is dilated.XIAN JIAOTONG UNIVERSITYPage 45（二）肿瘤的生长速度（二）肿瘤的生长速度不同肿瘤的生长速度不同不同肿瘤的生长速度不同。慢（良性）、慢（良性）、快（恶性）、快（恶性）、由慢变快（良性恶性变）由慢变快（良性恶性变）影响肿瘤生长速度的因素很多。影响肿瘤生长速度的因素很多。肿瘤生长肿瘤生长速度相关速度相关因素因素1.肿瘤细胞倍增的时间肿瘤细胞倍增的时间2

44、.生长分数生长分数=进入细胞周期的细胞进入细胞周期的细胞肿瘤细胞群体总数肿瘤细胞群体总数3.瘤细胞的生成与丢失瘤细胞的生成与丢失XIAN JIAOTONG UNIVERSITYPage 46细胞种类细胞种类周期（小时）周期（小时）细胞种类细胞种类周期（小时周期（小时）食道上皮食道上皮144食道癌食道癌250.8胃上皮胃上皮66胃癌胃癌80.8结肠上皮结肠上皮24-48结肠癌结肠癌22-125骨髓细胞骨髓细胞24-40 急性白血病急性白血病48-96人正常细胞与肿瘤细胞增殖周期的比较人正常细胞与肿瘤细胞增殖周期的比较细胞周期长短几乎不影响肿瘤生长速率细胞周期长短几乎不影响肿瘤生长速率XIAN J

45、IAOTONG UNIVERSITYPage 47（三）（三）肿瘤血管形成肿瘤血管形成XIAN JIAOTONG UNIVERSITYPage 48XIAN JIAOTONG UNIVERSITYPage 49Promotion of angiogenesis by immunosuppressive cells XIAN JIAOTONG UNIVERSITYPage 50u血管拟态血管拟态（vasculogenic mimicry）：）：肿瘤细胞本身肿瘤细胞本身和细胞外基质形成类似血管、具有基底膜的小管状结构，和细胞外基质形成类似血管、具有基底膜的小管状结构，可与血管交通，作为不依赖血管生

46、成的肿瘤微循环或微环可与血管交通，作为不依赖血管生成的肿瘤微循环或微环境成分。境成分。XIAN JIAOTONG UNIVERSITYPage 51Intussusceptive angiogenesis There are two types of angiogenesis,sprouting angiogenesis and intussusceptive angiogenesis.Sprouting angiogenesis is the outgrowth of a new branch from an existing vessel.Intussusceptive angiogene

47、sis,splitting of an existing vessel,starts with the formation of an intraluminal vascular pillar.XIAN JIAOTONG UNIVERSITYPage 52Micrographs and schema illustrating time-course of the angiogenic switch during tumor recovery.XIAN JIAOTONG UNIVERSITYPage 53（四）肿瘤的演进和异质性（四）肿瘤的演进和异质性肿瘤的演进肿瘤的演进(progression

48、)：指恶性肿瘤在生长指恶性肿瘤在生长过程中变得越来越富有侵袭性和获得更大恶性潜能的过程中变得越来越富有侵袭性和获得更大恶性潜能的现象。现象。肿瘤的异质性肿瘤的异质性(heterogeneity)：指由一个克隆指由一个克隆来源的肿瘤细胞在生长过程中，形成在侵袭能力、生来源的肿瘤细胞在生长过程中，形成在侵袭能力、生长速度、对激素反应和抗癌药物的敏感性、抗原表达长速度、对激素反应和抗癌药物的敏感性、抗原表达以及转移潜能等方面有所不同的亚克隆的过程。以及转移潜能等方面有所不同的亚克隆的过程。克隆演进克隆演进/肿瘤干细胞肿瘤干细胞/表观遗传修饰表观遗传修饰XIAN JIAOTONG UNIVERSITY

49、Page 54Darwinian evolution and clonal successionsXIAN JIAOTONG UNIVERSITYPage 55Xin Ye.Robert A.Weinberg Distinct EMT programs control normal mammary stem cells and tumour-initiating cells Nature，525:256,Sep.10,2015 Snail阳性癌干细胞与正常干细胞起源于不同的细胞群。正阳性癌干细胞与正常干细胞起源于不同的细胞群。正常腺体重建干细胞定位在乳腺导管的基底层；癌干细胞出现在常腺体重建干

50、细胞定位在乳腺导管的基底层；癌干细胞出现在腔面层。这意味着癌干细胞和正常干细胞调控的机制不同腔面层。这意味着癌干细胞和正常干细胞调控的机制不同XIAN JIAOTONG UNIVERSITYPage 56Cell 146:633,August 19,2011XIAN JIAOTONG UNIVERSITYPage 57二、肿瘤扩散（二、肿瘤扩散（spread of tumor)肿瘤扩散是恶性肿瘤特有的生物学行为肿瘤扩散是恶性肿瘤特有的生物学行为 直接蔓延直接蔓延(direct spreading by local invasion:progressive infiltration,invasi

51、on,destruction of the surrounding tissue)转移转移(Metastasis)：淋巴道、血道和种植淋巴道、血道和种植 XIAN JIAOTONG UNIVERSITY 指瘤细胞指瘤细胞连续不断连续不断地地沿着组织间隙、血管、沿着组织间隙、血管、淋巴管或神经束衣浸淋巴管或神经束衣浸润，破坏邻近的正常润，破坏邻近的正常组织或器官并继续生组织或器官并继续生长，使肿瘤范围扩大。长，使肿瘤范围扩大。1.直接蔓延：直接蔓延：XIAN JIAOTONG UNIVERSITYPage 592.转移（转移（metastasis）概念：概念：恶性瘤细胞从原发部位侵入淋巴管、血管

52、恶性瘤细胞从原发部位侵入淋巴管、血管或体腔，不连续地或体腔，不连续地迁徙到远隔部位迁徙到远隔部位并继续生长，并继续生长，形成与形成与原发瘤同类型原发瘤同类型肿瘤肿瘤（转移性肿瘤或继发肿（转移性肿瘤或继发肿瘤）瘤）的过程。的过程。常见的转移途径有直接种植，淋巴常见的转移途径有直接种植，淋巴道转移和血道转移。道转移和血道转移。Linear and parallel progression modelsXIAN JIAOTONG UNIVERSITYPage 60（1 1）淋巴道转移）淋巴道转移(Lymphatic spread):(Lymphatic spread):是癌初始播散最常见的路径是癌初

53、始播散最常见的路径转移过程：转移过程：局部局部Ln 远隔远隔Ln 胸导管胸导管 血流。血流。转移瘤的特点：转移瘤的特点：Ln肿大、灰白、质硬，晚期融合肿大、灰白、质硬，晚期融合 哨兵淋巴结哨兵淋巴结 Sentinel lymph nodes XIAN JIAOTONG UNIVERSITYPage 61Metastatic carcinoma in periaortic lymph nodes XIAN JIAOTONG UNIVERSITYPage 62肉瘤最常见的转移途径肉瘤最常见的转移途径 转移过程：转移过程：从细静脉或毛细血管或胸导管从细静脉或毛细血管或胸导管入血，顺血流运行，并穿过血

54、管壁入血，顺血流运行，并穿过血管壁在其它部位继续生长形成转移瘤。在其它部位继续生长形成转移瘤。常见的转移部位：常见的转移部位：肺肺(最常见最常见)、肝、骨、肝、骨。也可转移也可转移到脑（可伴肺转移或不伴肺转移）到脑（可伴肺转移或不伴肺转移）和脊髓、甚至全身各部位。和脊髓、甚至全身各部位。(2)(2)血道转移血道转移 (Hematogenous spread):(Hematogenous spread):XIAN JIAOTONG UNIVERSITYPage 63Hematogenous spread of cancer.A malignant tumor(bottom)has invaded

55、 adipose tissue and penetrated into a small veinXIAN JIAOTONG UNIVERSITYPage 64 血道转移瘤的特点：血道转移瘤的特点：多个、界清、散在的瘤结多个、界清、散在的瘤结节。一般位于近包膜处节。一般位于近包膜处,靠近器官表面时可形成靠近器官表面时可形成“癌脐癌脐”XIAN JIAOTONG UNIVERSITYPage 65The invasion-metastasis cascadeLocalized invasion-intravasation-transport and arrest in microvessels o

56、f various organ-extravasation-(diapedesis)formation of a dormant micrometastasis-colonization of a macromatastasis(anoikis/hydrodynamic shear force/.)Travel of cancer cells from a primary tumor to a site of potential metastasis depends on a series of complex biological stepsXIAN JIAOTONG UNIVERSITYp

57、体腔内肿瘤蔓延至器官表面时体腔内肿瘤蔓延至器官表面时,瘤细胞脱落种植在瘤细胞脱落种植在同一体腔其它器官的表面同一体腔其它器官的表面,继续生长形成多数转移继续生长形成多数转移瘤。此种转移相应的浆膜腔常有血性积液。瘤。此种转移相应的浆膜腔常有血性积液。p腹腔内器官的癌肿（如胃癌）常发生广泛的种植腹腔内器官的癌肿（如胃癌）常发生广泛的种植性转移性转移,在女性患者可形成在女性患者可形成 Krukenberg瘤（卵巢瘤（卵巢的种植性转移性粘液腺癌）。的种植性转移性粘液腺癌）。(3)(3)种植性转移种植性转移(seeding of body cavities and surfaces)：XIAN JIAO

58、TONG UNIVERSITYPage 67Peritoneal carcinomatosis.The mesentery attached to aloop of small bowel is studded with small nodules of metastatic ovariancarcinoma.XIAN JIAOTONG UNIVERSITYPage 68 原发肿瘤原发肿瘤 常见的继发转移器官常见的继发转移器官 乳腺癌乳腺癌 骨、脑、肾上腺骨、脑、肾上腺 前列腺癌前列腺癌 骨骨 肺小细胞癌肺小细胞癌 骨、脑、肝骨、脑、肝 皮肤黑色素瘤皮肤黑色素瘤 肺（肺（95%）、脑）、脑 眼

59、脉络膜黑色素瘤眼脉络膜黑色素瘤 肝（肝（100%）甲状腺癌甲状腺癌 骨骨 肾透明细胞癌肾透明细胞癌 骨、肝、甲状腺骨、肝、甲状腺 睾丸癌睾丸癌 肝肝 膀胱癌膀胱癌 脑脑 神经母细胞瘤神经母细胞瘤 肝、肾上腺肝、肾上腺 肿瘤细胞的血行转肿瘤细胞的血行转移或淋巴道转移并不总移或淋巴道转移并不总是循着血流或淋巴液流是循着血流或淋巴液流动方向到达相应的脏器，动方向到达相应的脏器，即使通过渗透进入人体即使通过渗透进入人体腔的肿瘤细胞也不循自腔的肿瘤细胞也不循自然沉淀规律继发生长。然沉淀规律继发生长。肿瘤转移的器官肿瘤转移的器官选择性选择性 XIAN JIAOTONG UNIVERSITY 恶性肿瘤转移的

60、临床特点恶性肿瘤转移的临床特点“种子土壤种子土壤”学说学说“What is it that decides what organs shall suffer a case of disseminated cancer?”This question intrigued Stephen Paget,assistant surgeon to the West London hospital and the Metropolitan hospital,whose self-effacing paper of 1889 records his careful analyses of case histo

61、ries that led to the visionary soil and seed hypothesis of metastasis.XIAN JIAOTONG UNIVERSITYPage 70 Preparing the Soil:The Primary Tumor Induces Vasculature Reorganization in the Sentinel Lymph Node before the arrival of Metastatic Cancer Cells Qian,C N et al Cancer Res 2006;66(21):10365 The enlar

62、gement of the lymph sinuses is correlated with the primary tumor weight.The newly emerged functional blood vessels develop from high endothelial venules(HEV),in which the proliferation rate of the endothelial cells is also significantly increased.Similar alterations of the HEVs are also characterize

63、d in the axillary lymph nodes from human breast cancer patients without the evidence of metastasis.These findings support the hypothesis that modification of the microenvironment for a secondary tumor(i.e.,vasculature reorganization in the SLN)can be initiated by a primary tumor before and independe

64、nt of the physical presence of metastatic cancer cells.the signals?XIAN JIAOTONG UNIVERSITYPage 71Evolving View Of The Dynamic Relationship Between The Primary Tumor And Metastasis A dynamic view of cancer metastasis in which bone marrow-derived cells are mobilized by tumor derived inflammatory fact

65、ors and prime distant sites of metastasis to form the pre-metastatic niche.Disseminated tumor cells(DTCs)(either from primary or from metastasis)that have been selected with enhanced malignancy can colonize distant organs,as well as repopulate the primary site through the phenomenon of self-seeding

66、The traditional view of cancer metastasis in which primary tumor cells escape their site of origin,travel in a unidirectional path away from the primary site and ultimately colonize distant organs to give rise to systemic disease.XIAN JIAOTONG UNIVERSITYPage 72Basement membrane proteincytokeratin18XIAN JIAOTONG UNIVERSITYPage 73良性肿瘤良性肿瘤恶性肿瘤恶性肿瘤组织分化程度组织分化程度分化好，异型性分化好，异型性小，与原有组织小，与原有组织的形态相似的形态相似分化不好，异型性分化不好，异型性大，与原有组织的大，与原有组织的形态差别大形态差别大核分裂核分裂无或稀少，不见无或稀少，不见病理性核分裂病理性核分裂多见，可见病多见，可见病理性分裂像理性分裂像生长速度生长速度