病理学课件：第五章 肿瘤 1

1、 第五章 肿瘤 Xian Jiaotong UniversityPage 2 祖国医学对肿瘤的记载： 2000多年前周礼已有专治“肿瘍”的医生，称疡医。 肿瘍泛指肿瘤和非瘤性肿块 500-300BC 内经，把肿瘤和大多数非瘤性肿块，称之为“瘕”、“癥”和“积聚”。 病因解释为“营卫不通”，“七情郁结”，“脾胃受伤”，以致“气血凝滞”所致 东汉许慎说文解字解释“瘤”谓“瘤，肿也”。东汉刘熙释名释疾病说：“瘤，瘤肿也，血液聚而生瘤肿也” Page 3Page 4 Hippocrates (460-375 BC), the father of medicine, was the first to d

2、ivide tumors into two large groups according to their behavior （1）the innocuous tumors, which included 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).Pa

3、ge 5 Galen (AD 131-201 prominent Greek physician, surgeon and philosopher in the 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 contra

4、ry to nature, e.g., true neoplasms. Galen was aware of the phenomenon of tumor metastasis. He was 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 wh

5、ich he included various tumors with a fleshy gross appearance.Page 6第一节 肿瘤的概念 肿瘤是机体在各种致瘤因素的作用下,局部组织的细胞异常增生而形成的新生物,这种新生物常表现为肿块. 肿瘤细胞是从正常细胞转变而来的,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/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

6、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 （病理学卫生部统编教材第一版1979）。 Page 7肿瘤概念 Cancer is a genetic disease, arising from 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 c

7、ancer cells. However, about 1% of all cancers arise in individuals with an unmistakable hereditary cancer 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 Page 8 肿瘤是机体在各种致瘤因素的作用下，局部组织的细胞在基因水平上失去对其

8、生长的正常调控，导致克隆性异常增生而形成的新生物（病理学卫生部统编教材第五版 2001） 。 肿瘤(tumor)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（neoplasia)。现在一般认为，肿瘤细胞是单克隆性（monoclonility)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（病理学卫生部统编教材(7/8年制第2版 2010）Page 9 Cancer is a genetic disorder caused by DNA mutations

9、 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 result, cells harboring these alterations are subject to Darwinian selection with cells bearing mutations that pr

10、ovide them with growth or survival advantages outcompeting their neighbors and thus coming to dominate the population. Page 10 Accumulation of mutations gives rise to a set of properties that have been called hallmarks of cancer. (1)self-sufficiency in growth . (2) lack of response to growth inhibit

11、ory signals that control non-neoplastic cellular proliferations such as hyperplasias; (3) evasion of cell death. (4) limitless replicative potential, immortalization; (5) development of angiogenesis to sustain the growth of cancer cells; (6) ability to invade local tissues and spread to distant site

12、s; (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 enabled by the development of genomic instability, adding fuel to the fire. ROBBINS BASIC PATHOLOGY 9th Edition 2013Page 1

13、1 No completely satisfactory definition of neoplasia exists， it has been surprisingly difficult to develop an accurate definition. In the Premolecular era, definition of the eminent British oncologist Willis remains one of the most widely cited and useful: A neoplasm is an abnormal mass of tissue, t

14、he 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(Willis B.A.: the spread of the tumors in the human body, London,1952. Butterworth & Co.)Page 12 In the modern era, a neopla

15、sm 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 . The causative mutations give the neoplastic cells a survival and growth advantage, resulting in excessive proliferation that is independent of physiolog

16、ic growth signals (Robbins & Cotran Pathologic Basis of Disease 9th Ed. 2015)Page 13Non-neoplastic Growth Disturbances Hypertrophy and Atrophy（肥大/萎缩） Hyperplasia （增生） Metaplasia （化生） Dysplasia （异型增生/不典型增生） （A synonym：Atypical hyperplasia）Page 14 The genetic alterations of cancer cells are heritable.

17、 As a 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. Because the selective advantages are conferred on a single ce

18、ll that ultimately gives rise to the tumor, all tumors are clonal (i.e., the progeny of one cell). 肿瘤是单克隆生长Monoclonality vs polyclonality of tumors二、肿瘤性增生的特点Page 15 glucose-6-phosphate dehydrogenase chromasome abrrationTo determine whether all the cells in a tumor mass share a common, highly unique

19、genetic or biochemical marker.Page 16不成熟性 代谢、功能和结构的幼稚性 遗传性 能将增生的特点传给子代细胞，病因 消除后仍继续生长 与机体不协调性 持续性生长，破坏正常组织。 肿瘤性增生的特点肿瘤性增生 非肿瘤性增生 增生单克隆性多克隆性分化程度 失去分化成熟能力 分化成熟 与机体协调性 相对自主性具有自限性病因去除 持续生长停止生长形态结构、功能 异常正常对机体影响 有害有利肿瘤性增生与非肿瘤性增生的区别Page 18一、肿瘤的大体形态（直观性）数目：一般一个，可多个大小：大小悬殊 影响因素：性质、生长时间、部位外形：多种多样 影响因素：部位、组织来源、

20、性质、生长方式第二节 肿瘤的形态乳头状 囊状 多房性囊状 结节状 乳头状 分叶状 胆管细胞癌巨块状肝细胞癌溃疡型直肠癌肥厚浸润型膀胱癌菜花样胃癌Page 21颜色：多为灰白或灰红色，也可呈其它颜色 影响因素：组织来源、含血量、继发改变质地或硬度：悬殊较大 影响因素: 来源、实质与间质的比例等肿瘤的包膜： 良性：大多数有完整包膜恶性：一般无包膜二、肿瘤的组织形态 实质（parenchyma）：即克隆性增生的肿瘤细胞，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、恶性及恶性程度。 间质（stroma）：基本成分是结缔组织和血管，支持和营养肿瘤实质。其内浸润的免疫细胞

21、是机体对肿瘤组织发生的免疫反应（双向性效应）。Page 23Recruitment of endothelial precursor cells by mammary CAFs desmoplastic stroma肿瘤间质是肿瘤性的Page 24Tumors and derived xenografted tumor cell lines 第三节 肿瘤的分化与异型性 一、概念1.（肿瘤）分化：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 分化（differentiation）：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，产生不同细胞类群的

22、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（Anaplasia) 在病理学上指去分化或者缺乏分化（Dedifferentiation/ Undifferentiation）Differentiation and AtypiaPage 26二、肿瘤的异型性 肿瘤的异型性（atypia）:是指肿瘤组织在瘤细胞形态和瘤组织结构方面都与其发源的正常组织有不同程度的差异。 异型性可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。 是诊断肿瘤、区别良、恶性肿瘤的主要组织学依据。Page 271.肿瘤组织结构异型性 指瘤组织在空间排列方式（极向性、器官样结构及与间质的关

23、系）上与其来源的正常组织之间的差异。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。恶性肿瘤：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。Page 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 (la

24、rge nuclei and high N/C ratios) up to the surface. Compare this to the clear distinction between basal cells and maturing cells seen at left.Page 29Normal colon. Section through colonic mucosa showing parallel crypts (C), lamina propria (LP), muscularis mucosa (MM), and submucosal arteries (A), vein

25、s (V), and lymphatics (L).Page 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 o

26、f mucinous goblet cells. Mitotic activity and neutrophils are common in adenomas but may also be seen in benign epitheliumPage 31 Invasive adenocarcinoma. Poorly formed glands and single cells (arrow) infiltrate through a desmoplastic stroma (arrowhead). Cells show marked pleomorphism and prominent

27、nucleoli.High-grade dysplasia in an adenoma. The diagnosis is largely based on architectural features,such as cribriform growth (arrow).2.肿瘤细胞的异型性良性肿瘤细胞与其起源的细胞形态十分相似，异型性小。恶性肿瘤瘤细胞异型性显著，有以下特点：(1)瘤细胞的多形性：大小形态不一，一般较大，可出现瘤巨细胞，细胞极性缺失。亦有小细胞（如小细胞肺癌），(2)瘤细胞核的多形性：对诊断恶性肿瘤至关重要。核形态异常，核-浆比例增大，核大小/形态不一，核不规则。一般较大，出

28、现巨核、多核和畸异核；核膜厚，染色质粗大呈块状分布不均，核深染。核仁大、多；核分裂像多、出现病理性核分裂像（对恶性肿 瘤有诊断意义）。“核多形性”主要包括：Page 34Page 35 瘤细胞质的改变：胞浆少，核蛋白体增多胞浆嗜碱（稍蓝染）；可出现分泌物或代谢物的储留（有助判断肿瘤来源）。 其他改变：瘤性坏死Page 37 Leiomyoma of the uterus. A. A bisected uterus displays a prominent, sharply circumscribed, fleshy tumor.B. Microscopically, smooth muscle

29、 cells intertwine in bundles, some of which are cut longitudinally (elongated nuclei) andothers transversely.Page 38Leiomyosarcoma of the uterus.A. The uterus has been opened to reveal a large, soft leiomyosarcoma with extensive necrosis that replaces the entire myometrium. B. A zoneof coagulative t

30、umor necrosis (arrows) appears demarcated from the viable tumor. C. The tumor shows considerable nuclear atypia and abundant mitotic activity.Page 39Chondrosarcoma of bone. The tumor is composed of malignant chondrocytes, which have bizarre shapes and irregular hyperchromaticnuclei, embedded in a ca

31、rtilaginous matrix.Benign chondroma. A. Normal cartilage. B. A benign chondroma closely resembles normal cartilage.Page 40 Undifferentiated pleomorphic sarcoma (“malignant fibrous histiocytoma”). An anaplastic tumor exhibits spindle cells, plump polygonal cells, bizarre tumor giant cells, an abnorma

32、l mitosis (center) 第四节 肿瘤的生长和扩散一、 肿瘤的生长（一）肿瘤的生长方式膨胀性、外生性、浸润性 1. 膨胀性生长（expansive growth）:多发生在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。 2. 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。恶性肿瘤表面生长同时兼有向深部组织浸润生长 3. 浸润性生长（invasive growth）： 大多数恶性肿瘤的生长方式。瘤细胞长入周围组织间隙、血管或神经束衣并破坏周围组织（浸润 in

33、vasive）。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。Page 44Adenocarcinoma of the colon with intestinal obstruction.The lumen of the colon at the site of the cancer is narrow. The colonabove the obstruction is dilated.Page 45（二）肿瘤的生长速度不同肿瘤的生长速度不同。 慢（良性）、 快（恶性）、由慢变快（良性恶性变） 影响肿瘤生长速度的因素很多。肿瘤生长速度相关因素1. 肿瘤细胞倍增的时间2. 生长分

34、数=进入细胞周期的细胞肿瘤细胞群体总数3. 瘤细胞的生成与丢失Page 46细胞种类周期（小时）细胞种类周期（小时）食道上皮144食道癌250.8胃上皮66胃癌80.8结肠上皮24-48结肠癌22-125骨髓细胞24-40 急性白血病48-96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Page 47（三） 肿瘤血管形成Page 48Page 49Promotion of angiogenesis by immunosuppressive cells Page 50血管拟态（vasculogenic mimicry）：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

35、管状结构，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。Page 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 angiogenesis, splitting of an existing

36、 vessel, starts with the formation of an intraluminal vascular pillar.Page 52Micrographs and schema illustrating time-course of the angiogenic switch during tumor recovery.Page 53（四）肿瘤的演进和异质性肿瘤的演进(progression)：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现象。肿瘤的异质性(heterogeneity)：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、生长速度、对

37、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。克隆演进/肿瘤干细胞/表观遗传修饰Page 54Darwinian evolution and clonal successionsPage 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。正常腺体重建干细胞定位在乳腺导管的基底层

38、；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Page 56Stochastic State Transitions Give Rise to Phenotypic Equilibrium In Populations of Cancer Cells Cell 146:633, August 19, 2011Page 57二、肿瘤扩散（spread of tumor)肿瘤扩散是恶性肿瘤特有的生物学行为 直接蔓延(direct spreading by local invasion: progressive infiltration, invasion, destructio

39、n of the surrounding tissue)转移(Metastasis)： 淋巴道、血道和种植 指瘤细胞连续不断地沿着组织间隙、血管、淋巴管或神经束衣浸润，破坏邻近的正常组织或器官并继续生长，使肿瘤范围扩大。1. 直接蔓延：Page 592. 转移（metastasis）概念： 恶性瘤细胞从原发部位侵入淋巴管、血管或体腔，不连续地迁徙到远隔部位并继续生长，形成与原发瘤同类型肿瘤（转移性肿瘤或继发肿瘤）的过程。常见的转移途径有直接种植，淋巴道转移和血道转移。 Linear and parallel progression modelsPage 60（1）淋巴道转移(Lymphatic

40、 spread): 是癌初始播散最常见的路径转移过程：局部Ln 远隔Ln 胸导管 血流。 转移瘤的特点：Ln肿大、灰白、质硬，晚期融合 哨兵淋巴结 Sentinel lymph nodes Page 61Metastatic carcinoma in periaortic lymph nodes Page 62肉瘤最常见的转移途径 转移过程： 从细静脉或毛细血管或胸导管入血，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。常见的转移部位： 肺(最常见)、肝、骨。也可转移到脑（可伴肺转移或不伴肺转移）和脊髓、甚至全身各部位。(2)血道转移 (Hematogenous spread):Pag

41、e 63Hematogenous spread of cancer. A malignant tumor (bottom) has invaded adipose tissue and penetrated into a small veinPage 64 血道转移瘤的特点：多个、界清、散在的瘤结节。一般位于近包膜处,靠近器官表面时可形成“癌脐” Page 65The invasion-metastasis cascadeThe invasion-metastasis cascadeLocalized invasion- intravasation-transport and arrest i

42、n microvessels of 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 steps体腔内肿瘤蔓延

43、至器官表面时,瘤细胞脱落种植在同一体腔其它器官的表面,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。腹腔内器官的癌肿（如胃癌）常发生广泛的种植性转移,在女性患者可形成 Krukenberg瘤（卵巢的种植性转移性粘液腺癌）。(3)种植性转移(seeding of body cavities and surfaces)：Page 67Peritoneal carcinomatosis. The mesentery attached to aloop of small bowel is studded with small nodules of metastatic ovariancar

44、cinoma.Page 68 原发肿瘤 常见的继发转移器官 乳腺癌 骨、脑、肾上腺 前列腺癌 骨 肺小细胞癌 骨、脑、肝 皮肤黑色素瘤 肺（95%）、脑 眼脉络膜黑色素瘤 肝（100%） 甲状腺癌 骨 肾透明细胞癌 骨、肝、甲状腺 睾丸癌 肝 膀胱癌 脑 神经母细胞瘤 肝、肾上腺 肿瘤细胞的血行转移或淋巴道转移并不总是循着血流或淋巴液流动方向到达相应的脏器，即使通过渗透进入人体腔的肿瘤细胞也不循自然沉淀规律继发生长。肿瘤转移的器官选择性 恶性肿瘤转移的临床特点“种子土壤”学说 “What is it that decides what organs shall suffer a case of

45、 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 histories that led to the visionary soil and seed hypothesis of metastasis.Page 70 Prepari

46、ng 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 enlargement of the lymph sinuses is correlated with the primary tumor weight. The newly emerged functional blo

47、od 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 characterized in the axillary lymph nodes from human breast cancer patients without the evidence of metastasis. T

48、hese 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 independent of the physical presence of metastatic cancer cells. the signals? Page 71Evolving View Of The

49、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 factors and prime distant sites of metastasis to form the pre-metastatic niche. Disseminated tumor cells(DTCs)( either from

50、 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 The traditional view of cancer metastasis in which primary tumor cells escape their site of origin, travel in a uni

51、directional path away from the primary site and ultimately colonize distant organs to give rise to systemic disease.Page 72Basement membrane proteincytokeratin18Page 73良性肿瘤恶性肿瘤组织分化程度分化好，异型性小，与原有组织的形态相似分化不好，异型性大，与原有组织的形态差别大核分裂无或稀少，不见病理性核分裂多见，可见病理性分裂像生长速度缓慢较快继发改变很少发生坏死、出血常发生出血坏死，溃疡形成良性肿瘤与恶性肿瘤的区别Page 7

52、4良性肿瘤恶性肿瘤生长方式膨胀性或外生性，前者常有包膜形成，与周围组织一般分界清楚，故通常可推动。浸润性或外生性生长，前者无包膜，一般与周围组织分界不清，不能推动。后者常伴有浸润转移不转移常有转移复发切除后很少复发切除等治疗后常有复发对机体影响较小，主要是局部压迫或阻塞。较大，压迫、阻塞、破坏组织。恶病质，副肿瘤综合征注意：相对性、交界性肿瘤的概念、瘤样病变、恶变、不同程度的恶性肿瘤Page 75良恶性肿瘤的区别（小结） 分化程度、生长速率、局部侵袭和远隔转移 1、良性肿瘤与来源组织相似，异型性小，分化好； 恶性肿瘤 分化差，甚至完全未分化（间变），异型性大。2、良性肿瘤生长缓慢，恶性肿瘤一般

53、生长较快 3、良性肿瘤 与相邻组织界清有包膜， 恶性肿瘤与邻近 组织界限不清，常侵入临近正常组织 4、良性肿瘤局限于发生部位， 恶性肿瘤局部侵袭并远隔部位转移。 Page 76一. 肿瘤对机体的影响(一）良性肿瘤（benign tumor, BT）1.局部影响：压迫、阻塞出血感染少见2.全身影响：主要指发生在内分泌腺的良性肿瘤，瘤细胞通过产生过多的内分泌激素作用于更广泛的部位引起全身影响。 垂体腺瘤、胰岛细胞瘤等。第五节. 肿瘤与宿主相互作用 Page 77（二）恶性肿瘤(malignant tumor, MT)1.局部影响：压迫、阻塞；破坏组织结构、造成溃疡和穿孔等病变；出血和感染常见；疼痛

54、。2.全身影响：发热、体重下降、贫血、夜汗、恶病质、副肿瘤综合征、异位内分泌综合征 。 Page 78恶病质(cachexia)：指严重消瘦、无力、贫血和全身衰竭的状态。 机制：出血、感染、发热、中毒、消耗、进食减少、睡眠差、代谢紊乱；TNF的作用。Page 79异位内分泌综合征 概念：指非内分泌腺肿瘤产生和分泌的激素类物质所引起的内分泌紊乱综合征。 常见肿瘤：以癌多见，例如肺、胃、肝、胰腺和结肠癌；也可见纤维肉瘤、平滑肌肉瘤等。副肿瘤综合征(paraneoplastic syndrome) 概念：由肿瘤产物、异常免疫反应或不明原因引起的非原发瘤和继发瘤所在部位的病变和相应临床表现。 意义：发

55、现早期肿瘤；避免误诊为转移而放弃治疗。Page 80二、肿瘤与宿主的相互作用-肿瘤免疫（一）肿瘤免疫存在的证据肿瘤浸润淋巴细胞（TILs）肿瘤组织中浸润淋巴细胞的数量与预后相关肿瘤局部引流淋巴结免疫组织学反应类型与预后 西安医学院第一附属医院病理科 乳癌时腋淋巴结改变与预后的关系 肿瘤防治研究 1978, 4:67 Rui Li, et Analysis of the immunological microenvironment at the tumor site in patients with non-small cell lung cancer Langenbecks Arch Surg

56、. 2003 , 388(6):406Page 81 Bernhard Mlecnik, et. al. Histopathologic-Based Prognostic Factors of Colorectal Cancers Are Associated With the State of the Local Immune Reaction J Clin Oncol 28 2011 Jrme Galon, et.al Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Cli

57、nical Outcome SCIENCE 29 SEPTEMBER 2006 VOL 313TNM Staging in Colorectal Cancer: T Is for T Celland M Is for Memory JCO editorial s , 29(6) , 2011 Page 82 SITC (Society for Immunotherapy of Cancer) : BaseCamp Expert Centers : , Immunoscore Worldwide Task ForceEvaluation Of The Prognostic Value Of Th

58、e Immunoscore In Patients With Colon CancerPage 83 Immunoscore Worldwide Task Force: Cancer classification using the Immunoscore: a worldwide task force J Transl Med. 2012,10:205. doi: 10.1186/1479-5876-10-205 Immunoscore Worldwide Task Force: Towards the introduction of the Immunoscore in the class

59、ification of malignant tumors J Pathol 2014; 232: 199209 Page 84 Constructed over decades, it has begun to demonstrate such promising results in cancer patients that we have selected it as the Breakthrough of the Year for 2013.Page 85肿瘤免疫治疗-免疫检测点阻断策略 Page 86 A, CTLA-4 is upregulated after antigen-sp

60、ecific activation of a nave or memory T cell in lymphatic tissue, leading to decreased effector function (early activation phase). B, PD-1 is mainly expressed on antigen experienced memory T cells in peripheral tissues cells. The immune modulation mediated by this pathway ensures protection of tissu