Download Papilloma of the colon with finger

NEOPLASM
Zhu keqing 竺可青
Pathology Department
Zhejiang University School of Medicine
2008-12-1
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Neoplasia literally means the process of "new growth," and a new growth is called a
neoplasm.
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The term tumor was originally applied to the swelling caused by inflammation.
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Neoplasms also may induce swellings, but by long precedent, the non-neoplastic
usage of tumor has passed into limbo; thus, the term is now equated with neoplasm.
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Oncology (Greek oncos = tumor) is the study of tumors or neoplasms.
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Cancer is the common term for all malignant tumors. Although the ancient origins of
this term are somewhat uncertain, it probably derives from the Latin for crab, cancerpresumably because a cancer "adheres to any part that it seizes upon in an obstinate
manner like the crab."
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Tumor/neoplasm/neoplasia/Mass
Benign tumors
Malignant tumors/cancer
我国常见恶性肿瘤依次为：
• 胃癌、肝癌、肺癌、食管癌、大肠癌、白血病及
淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌
• 肿瘤是机体在各种致瘤因素作用下，局部组织的细胞在基因水平上失
去对其生长的正常调控，导致克隆性异常增生而形成的新生物。这种
新生物常形成局部肿块。
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Oncology
Neoplastic proliferation/clonal/clonality
Nonneoplastic proliferation/polyclonal
Tumorigenic agent/carcinogen
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定义 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.
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We know that the persistence of tumors, even after the inciting stimulus is
gone, results from heritable genetic alterations that are passed down to the
progeny of the tumor cells.
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These genetic changes allow excessive and unregulated proliferation that
becomes autonomous (independent of physiologic growth stimuli),
although tumors generally remain dependent on the host for their nutrition
and blood supply.
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The entire population of cells within a tumor arises from a single cell that
has incurred genetic change, and hence tumors are said to be clonal.
肿瘤性增生与非肿瘤性增生的区别
肿瘤性增生
与机体不协调
增生无止境
永生化，异型性
病因去除，继续增生
再生性、炎症性增生
协调一致
增生细胞数量虽多，但有限度
分化好，形态代谢功能正常
一般停止
Cancer incidence and mortality by site and sex.
Age-adjusted cancer death rates for selected sites in the United
States, adjusted for the 2000 U.S. population
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The change in incidence of various cancers with migration from Japan to the United
States provides evidence that the occurrence of cancers is related to components of the
environment that differ in the two countries.
The incidence of each kind of cancer is expressed as the ratio of the death rate in the
population being considered to that in a hypothetical population of California whites with
the same age distribution; the death rates for whites are thus defined as 1. The death
rates among immigrants and immigrants' sons tend consistently toward California norms.
Occupational Cancers
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Agents or Groups of Agents
Human Cancer Site for Which Reasonable Evidence Is Available
Typical Use or Occurrence
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Arsenic and arsenic compounds
Lung, skin, hemangiosarcoma
Byproduct of metal smelting. Component of alloys, electrical and semiconductor devices,
medications and herbicides, fungicides, and animal dips
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Asbestos
Lung, mesothelioma; gastrointestinal tract (esophagus, stomach, large intestine)
Formerly used for many applications because of fire, heat, and friction resistance; still found in
existing construction as well as fire-resistant textiles, friction materials (i.e., brake linings),
underlayment and roofing papers, and floor tiles
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Benzene
Leukemia, Hodgkin lymphoma
Principal component of light oil. Although use as solvent is discouraged, many applications exist in
printing and lithography, paint, rubber, dry cleaning, adhesives and coatings, and detergents.
Formerly widely used as solvent and fumigant
Inherited Predisposition to Cancer
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Inherited Cancer Syndromes (Autosomal Dominant)
Gene
Inherited Predisposition
RB
Retinoblastoma
P53
Li-Fraumeni syndrome (various tumors)
p16INK4A
Melanoma
APC
Familial adenomatous polyposis/colon cancer
NF1, NF2
Neurofibromatosis 1 and 2
BRCA1, BRCA2
Breast and ovarian tumors
MEN1, RET
Multiple endocrine neoplasia 1 and 2
MSH2, MLH1, MSH6 Hereditary nonpolyposis colon cancer
PATCH
Nevoid basal cell carcinoma syndrome
Inherited Predisposition to Cancer
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Familial Cancers
Familial clustering of cases, but role of inherited predisposition not clear for
each individual
Breast cancer
Ovarian cancer
Pancreatic cancer
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Inherited Autosomal Recessive Syndromes of Defective DNA Repair
Xeroderma pigmentosum
Ataxia-telangiectasia
Bloom syndrome
Fanconi anemia
1. 肿瘤的一般形态和结构
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数目
大小
形状
颜色
硬度
All tumors, benign and malignant, have two basic components:
(1) proliferating neoplastic cells that constitute their parenchyma
(2) supportive stroma made up of connective tissue and blood vessels.
• Parenchyma
• 肿瘤细胞的总称，是肿瘤的主要成分
• 决定肿瘤的生物学行为，用于识别肿瘤的组织来源
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Mesenchyma/stroma
主要是结缔组织和血管
支持和营养肿瘤实质
与肿瘤转移有关
2. 肿瘤的异型性 atypia
• 肿瘤组织无论在细胞形态和组织结构上，都与其发源的正
常组织有不同程度的差异。
• 反映肿瘤组织的成熟程度（分化程度）
• 诊断肿瘤，确定其良恶性的主要组织学依据
Degree of differentiation分化
Differentiation refers to the extent to which neoplastic cells
resemble comparable normal cells, both morphologically
and functionally; lack of differentiation is called anaplasia.
• Well differentiated
• Poorly differentiated
• Undifferentiated
间变 anaplasia
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指恶性肿瘤细胞缺乏分化，异型性明显。
分化不良
形态的多样性
生长的活跃性
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• 幼稚
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分化
成熟
间变
Cellular atypia 异型性
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Lack of differentiation分化, or anaplasia间变, is marked by a number of
morphologic changes.
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Pleomorphism.
Abnormal nuclear morphology. (hyperchromatic).
Mitoses. Atypical, bizarre mitotic figures, sometimes producing tripolar,
quadripolar, or multipolar spindles.
Loss of polarity.
Other changes. Another feature of anaplasia is the formation of tumor giant
cells, some possessing only a single huge polymorphic nucleus and others
having two or more nuclei.
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正常细胞的特点
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核：浆=1：4-6
有极性
同类细胞大小形态一致
染色正常均匀
恶性细胞的特点
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1. 细胞的多形性：大小不一，形态不规则
2. 核的多形性：
核增大，核：浆比增加，甚至接近1：1
核大小、形状、染色不一，可见巨核、多核、奇异核
核染色深，核膜厚
核仁肥大，数目增多，极性消失
病理性核分裂像
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3. 细胞浆呈嗜碱性或胞浆内异常产物或分泌物
肿瘤组织结构的异型性
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结构排列异常
失去正常的层次、极向
大小形状不一
浸润性生长
3. 肿瘤的生长与扩散
• 肿瘤生长的动力学Growth kinetics
• 肿瘤细胞倍增时间Doubling time
• 生长分数growth fraction：肿瘤细胞群体中处于增值阶段
（S期+G2期）的细胞比例。
• 瘤细胞的生成与丢失
肿瘤血管形成
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恶性肿瘤诱导血管形成
肿瘤细胞和巨噬细胞产生血管生成因子VEGF,b-FGF
肿瘤细胞产生抗血管生成因子
肿瘤生长由血管生成因子和抗血管生成因子共同控制
抑制肿瘤血管生成是肿瘤治疗的一个途径
Biology of tumor growth
The left panel depicts minimal estimates of tumor cell doublings that precede the formation of a
clinically detectable tumor mass. It is evident that by the time a solid tumor is detected, it has already
completed a major portion of its life cycle as measured by cell doublings.
The right panel illustrates clonal evolution of tumors and generation of tumor cell heterogeneity. New
subclones arise from the descendants of the original transformed cell, and with progressive growth the
tumor mass becomes enriched for those variants that are more adept at evading host defenses and
are likely to be more aggressive.
One can begin the consideration of tumor cell kinetics by asking the question:
How long does it take to produce a clinically overt tumor mass?
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It can be readily calculated that the original transformed cell (approximately
10 μm in diameter) must undergo at least 30 population doublings to
produce 109 cells (weighing approximately 1 gm), which is the smallest
clinically detectable mass.
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In contrast, only 10 further doubling cycles are required to produce a tumor
containing 1012 cells (weighing approximately 1 kg), which is usually the
maximal size compatible with life.
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This calculation highlights an extremely important concept about tumor
growth: By the time a solid tumor is clinically detected, it has already
completed a major portion of its life cycle.
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This is a major impediment in the treatment of cancer, and underscores the
need to develop diagnostic markers to detect early cancers.
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The rate of growth of a tumor is determined by three main factors: the
doubling time of tumor cells, the fraction of tumor cells that are in the
replicative pool, and the rate at which cells are shed and lost in the growing
lesion.
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Because cell-cycle controls are deranged in most tumors, tumor cells can
be triggered into cycle more readily and without the usual restraints.
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The dividing cells, however, do not necessarily complete the cell cycle more
rapidly than do normal cells.
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In reality, total cell-cycle time for many tumors is equal to or longer than that
of corresponding normal cells. Thus, it can be safely concluded that growth
of tumors is not commonly associated with a shortening of cell-cycle time.
Schematic representation of tumor growth.
As the cell population expands, a progressively higher percentage of
tumor cells leaves the replicative pool by reversion to G0, differentiation,
and death.
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Fast-growing tumors may have a high cell turnover, implying that rates of both
proliferation and apoptosis are high. Obviously, for the tumor to grow, the rate of
proliferation should exceed that of apoptosis.
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The growth fraction of tumor cells has a profound effect on their susceptibility to
cancer chemotherapy.
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Because most anticancer agents act on cells that are in cycle, it is not difficult to
imagine that a tumor that contains 5% of all cells in the replicative pool will be slow
growing but relatively refractory to treatment with drugs that kill dividing cells.
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One strategy employed in the treatment of tumors with low growth fraction (e.g.,
cancer of colon and breast) is first to shift tumor cells from G0 into the cell cycle. This
can be accomplished by debulking the tumor with surgery or radiation. The surviving
tumor cells tend to enter the cell cycle and thus become susceptible to drug therapy.
Such considerations form the basis of combined modality treatment.
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Some aggressive tumors (such as certain lymphomas) that contain a large pool of
dividing cells literally melt away with chemotherapy and cures may even be effected.
肿瘤的演进和异质化
• 演进 progression：恶性肿瘤在生长过程中越来越富有侵袭性.
• 异质化 heterogeneity：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、对激素反应、对抗癌药的敏感性等方面有
所不同的亚克隆的过程。
• 抗原性较低的亚克隆可以逃避机体的免疫监视。
Diagram depicting the use of X-linked isoenzyme cell markers as evidence of
the monoclonality of neoplasms 肿瘤细胞的单克隆性
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In reality, the latent period before which a tumor becomes clinically
detectable is unpredictable but typically much longer than 90 days, up to
many years for most solid tumors, emphasizing once again that human
cancers are diagnosed only after they are fairly advanced in their life cycle.
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After they become clinically detectable, the average volume-doubling time
for such common killers as cancer of the lung and colon is about 2 to 3
months.
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The range of doubling time values is extremely broad, varying from less
than 1 month for some childhood cancers to more than 1 year for certain
salivary gland tumors.
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Cancer is indeed an unpredictable disorder.
肿瘤的生长方式
• Expansile growth
• Exophytic growth
• Invasive growth
肿瘤生长方式
膨胀性生长
• 大多数良性肿瘤的生长方式
• 生长缓慢，无侵袭性
• 周围有完整包膜，分界清
• 一般不破坏器官的结构和功能
外生性生长
• 常见体表、体腔表面或管道器官表面
• 良恶性肿瘤均可发生
• 恶性肿瘤易形成恶性溃疡
浸润性生长
• 大多数恶性肿瘤的生长方式
• 浸润破坏周围组织
• 无包膜，无明显分界
• 手术切除时应扩大范围
Fibroadenoma of the breast.
The tan-colored, encapsulated small tumor is sharply demarcated
from the whiter breast tissue.
Microscopic view of fibroadenoma of the breast
The fibrous capsule (right) delimits the tumor from the surrounding tissue.
Cut section of an invasive ductal carcinoma of the breast.
The lesion is retracted, infiltrating the surrounding breast substance, and would be
stony hard on palpation.
肿瘤的扩散
• 直接蔓延：瘤细胞沿着组织间隙、淋巴管、血管或神经束衣浸润，破
坏邻近正常器官或组织，并继续生长。
• 转移 metastasis：瘤细胞从原发部位侵入淋巴管、血管或体腔，迁移
到他处继续生长，形成与原发瘤同样类型的肿瘤。
• 良性肿瘤不转移，只有恶性肿瘤才可能发生转移。
• Pathways of Spread
• Dissemination of cancers may occur through one of three pathways:
(1) direct seeding of body cavities or surfaces, (2) lymphatic spread,
and (3) hematogenous spread.
The microscopic view of the breast carcinoma seen in illustrates the
invasion of breast stroma and fat by nests and cords of tumor cells
Axillary lymph node with metastatic breast carcinoma.
The subcapsular sinus (top) is distended with tumor cells. Nests of tumor cells have also
invaded the subcapsular cortex.
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In many cases, the regional nodes serve as effective barriers to further
dissemination of the tumor, at least for a time.
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Conceivably the cells, after arrest within the node, may be destroyed by a
tumor-specific immune response.
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Drainage of tumor cell debris or tumor antigens, or both, also induces
reactive changes within nodes.
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Thus, enlargement of nodes may be caused by (1) the spread and growth of
cancer cells or (2) reactive hyperplasia.
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Therefore, nodal enlargement in proximity to a cancer does not
necessarily mean dissemination of the primary lesion.
metastasis
• Lymphatic metastasis
• Hematogenous metastasis
• Seeding transcoelomic metastaisis
淋巴道转移
• 一般随淋巴流向转移
• 癌细胞侵入淋巴管，进入局部淋巴结，淋巴结肿大、质地变硬，灰白色
• 进入下一级淋巴结，也可跳跃转移
• 最后进入血道，发生血道转移
血道转移
• 癌细胞侵入血管后随血流到远端器官继续生长，形成转移瘤
• 转移路径与血栓相似
• 多见于肺，其次为肝
• 边界清、边缘性、散在性、多发性
种植性转移
• 体腔内器官的肿瘤浸及器官表面后脱离，像播种一样种植于体腔内器官表面
• 常见与腹腔器官的肿瘤
• 胃癌种植转移到卵巢称Krukenberg瘤
The metastatic cascade
Colon carcinoma invading pericolonic adipose tissue
A liver studded with metastatic cancer
Numerous metastases from a renal cell carcinoma
Microscopic view of liver metastasis
• 目前尚未发现单独的转移基因
• 转移抑制基因：上皮粘连素、金属蛋白酶抑制剂
• 肿瘤抑制基因nm23与肿瘤转移负相关
恶性肿瘤浸润机制
Invasion of the ECM is an active process that can be resolved into 4 steps
• Detachment ("loosening up") of the tumor cells from each other
• 癌细胞粘附力降低
• Attachment to matrix components
• 癌细胞附着基底膜
• Degradation of ECM
• 细胞外基质降解
• Migration of tumor cells
• 癌细胞移出
Schematic illustration of the sequence of events in the invasion of
epithelial basement membranes by tumor cells.
Mechanisms of metastasis development within a primary tumor
肿瘤分级 grading
• 根据肿瘤分化程度的高低、异型性的大小及核分裂数的多数来确定恶
性肿瘤的级别。
• 1级 Well differentiated 低恶
• 2级 Moderately differentiated 中恶
• 3级 Poorly differentiated 高恶
Staging分期
• 根据原发瘤的大小，浸润深度和范围以及是否累及邻近器官，有无局
部淋巴结的转移，有无血缘性或其他远处转移等来确定肿瘤发展的分
期或早晚。
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TNM classification
T: 原发灶大小 T1-T4
N: 淋巴结累及情况 N0-N3
M: 血行转移情况 M0-M2
4 肿瘤对机体的影响
• Cachexia
• Ectopic endocrine syndrome
• Paraneoplastic syndrome
良性肿瘤
• 一般对机体影响较小
• 局部压迫阻塞症状
• 继发性改变：出血、感染和内分泌失如acidophilic adenoma垂体前叶肿瘤导致
Gigantism/acromegaly
恶性肿瘤
• 浸润破坏器官的结构和功能
• 发生转移
• 局部压迫、阻塞，出血、感染，发热、疼痛
• 恶病质cachexia：机体严重消瘦、无力、贫血和全身衰竭的状态。
恶性肿瘤在机体引起的继发病变
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导致内分泌功能紊乱，引起异位内分泌综合症。大多为恶性肿瘤。如肺癌。
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APUD(amine precursor uptake and decarbosylation)系统的肿瘤，也可引起
异位内分泌紊乱。如类癌、神经内分泌癌、嗜铬细胞瘤和副神经节瘤。
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副肿瘤综合征paraneoplastic syndrome：由于肿瘤产物（包括异位激素产生）
或异位免疫反应或其他不明原因，引起内分泌、神经、消化、造血、骨关节、
肾脏及皮肤等系统发生病变，出现相应临床表现，非原发肿瘤或转移灶直接
引起。
Paraneoplastic syndromes are important to recognize, for several reasons:
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They may represent the earliest manifestation of an occult neoplasm.
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In affected patients, they may represent significant clinical problems and
may even be lethal.
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They may mimic metastatic disease and therefore confound treatment.
Paraneoplastic syndromes
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Endocrinopathies
Hypercalcemia
Neuromyopathic paraneoplastic syndromes
Acanthosis nigricans
Hypertrophic osteoarthropathy
Several vascular and hematologic manifestations
良性肿瘤和恶性肿瘤的区别
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组织分化程度，异型性
核分裂像
生长速度
生长方式
继发改变
转移
复发
对机体影响
Comparisons Between Benign and Malignant Tumors
Characteristics
Benign
Malignant
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Differentiation/anaplasia
B:Well differentiated; structure may be typical of tissue of origin
M:Some lack of differentiation with anaplasia; structure is often atypical
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Rate of growth
B:Usually progressive and slow; may come to a standstill or regress; mitotic figures
are rare and normal
M:Erratic and may be slow to rapid; mitotic figures may be numerous and abnormal
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Local invasion
B:Usually cohesive and expansile well-demarcated masses that do not invade or
infiltrate surrounding normal tissues
M:Locally invasive, infiltrating the surrounding normal tissues; sometimes may be
seemingly cohesive and expansile
Metastasis
B:Absent
M:Frequently present; the larger and more undifferentiated the primary, the more
likely are metastases
• Borderline tumor 交界性肿瘤
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组织形态介于良恶性肿瘤之间的肿瘤
有恶变倾向Malignant potential、Malignant change
良恶性并非一成不变。
如卵巢交界性浆液性乳头状囊腺瘤。
Comparison between a benign tumor of the myometrium (leiomyoma)
and a malignant tumor of similar origin (leiomyosarcoma).
6 肿瘤的命名和分类
命名原则
• 根据其组织来源和生物学行为命名
• 良性肿瘤—组织来源+瘤
• 恶性肿瘤---组织来源+癌（上皮来源）
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组织来源+肉瘤（间叶来源）
• 结合形态特点命名
• 少数肿瘤的命名
肿瘤分类原则
• 以组织发生为依据
• 根据分化成熟程度
• 对机体影响
Nomenclature and classification
• -oma:adenoma,leiomyoma
• Carcinoma:squamous cell carcinoma, adenocarcinoma,
Sarcoma: undifferentiated sarcoma
• Carcinosarcoma
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-blastoma:osteoblastoma, neuroblastoma, medulloblastoma
Seminoma, leukemia
Ewing’s sarcoma, Hodgkin lymphoma
Neurofibromatosis, lipomatosis, angiomatosis
Teratoma
Nomenclature of Tumors
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Tissue of Origin
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Tumors of epithelial origin
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Stratified squamous
Squamous cell papilloma
carcinoma
Basal cells of skin or adnexa
Epithelial lining of glands or ducts Adenoma
Papilloma
Cystadenoma
Respiratory passages
Bronchial adenoma
Renal epithelium
Renal tubular adenoma
Liver cells
Liver cell adenoma
Urinary tract epithelium (transitional) Transitional cell papilloma
Placental epithelium
Hydatidiform mole
Testicular epithelium (germ cells)
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Tumors of melanocytes
Benign
Nevus
Malignant
Squamous cell or epidermoid
Basal cell carcinoma
Adenocarcinoma
Papillary carcinomas
Cystadenocarcinoma
Bronchogenic carcinoma
Renal cell carcinoma
Hepatocellular carcinoma
Transitional cell carcinoma
Choriocarcinoma
Seminoma
Embryonal carcinoma
Malignant melanoma
Nomenclature of Tumors
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Tissue of Origin
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Composed of One Parenchymal Cell Type
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Tumors of mesenchymal origin
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Connective tissue and derivatives
Endothelial and related tissues
Blood vessels
Lymph vessels
Synovium
Mesothelium
Brain coverings
Blood cells and related cells
Hematopoietic cells
Lymphoid tissue
Muscle
Smooth
Striated
Benign
Fibroma
Lipoma
Chondroma
Osteoma
Hemangioma
Lymphangioma
Meningioma
Malignant
Fibrosarcoma
Liposarcoma
Chondrosarcoma
Osteogenic sarcoma
Angiosarcoma
Lymphangiosarcoma
Synovial sarcoma
Mesothelioma
Invasive meningioma
Leukemias
Lymphomas
Leiomyoma
Rhabdomyoma
Leiomyosarcoma
Rhabdomyosarcoma
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Tissue of Origin
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More Than One Neoplastic Cell Type-Mixed Tumors, Usually Derived from One Germ Cell Layer
Salivary glands
Pleomorphic adenoma (mixed tumor of salivary origin)
Malignant mixed tumor of salivary gland
origin
Renal anlage
Wilms tumor
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More Than One Neoplastic Cell Type Derived from More Than One Germ Cell Layer-Teratogenous
Totipotential cells in gonads or in embryonic rests Mature teratoma, dermoid cyst Immature teratoma, teratocarcinoma
Benign
Malignant
肿瘤分类
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上皮组织来源的肿瘤
间叶组织来源的肿瘤
淋巴造血组织来源的肿瘤
神经组织来源的肿瘤
其他肿瘤
7. 常见肿瘤举例
上皮性肿瘤
• 良性上皮性肿瘤
• 乳头状瘤 papilloma
• 腺瘤 adenoma
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囊腺瘤
纤维腺瘤
多形性腺瘤
息肉状腺瘤
乳头状瘤 papilloma
• 好发部位：皮肤、胃肠道、泌尿道
• 眼观：向表面呈外生性生长，乳头状或指状突起，并可呈菜花状或绒
毛状
• 镜下：每一乳头由具有血管的分支状结缔组织间质构成轴心（中心
索），表面覆盖上皮可为鳞状上皮、柱状上皮、移行上皮
• 外耳道、阴茎、膀胱、结肠的乳头状瘤易恶变为乳头状癌
Papilloma of the colon with finger-like projections into the lumen
Colonic polyp
腺瘤 adenoma
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多见于甲状腺、卵巢、乳腺、唾液腺、肠道
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眼观：位于粘膜面多呈息肉状或绒毛状；腺器官内多呈结节状，且有包膜、边界清。
常有分泌功能。
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镜下：腺上皮伴不同程度的异型性，腺体大小形状不规则，排列较密集
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类型：
囊腺瘤
纤维腺瘤
多形性腺瘤
息肉状腺瘤
囊腺瘤 cystadenoma
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多见于卵巢、偶见甲状腺及胰腺
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肉眼：腺体分泌物淤积，腺腔扩大融合呈囊状，可见大小不等的囊腔
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镜下：浆液性乳头状囊腺瘤 serous papillary cystadenoma ，粘液性囊腺瘤
mucinous cystadenoma
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浆液性乳头状囊腺瘤易恶变
纤维腺瘤 fibroadenoma
• 女性乳腺
• 镜下：除腺上皮细胞增生形成腺体外，同时伴大量纤维结
缔组织增生，共同构成实质
A, This mammogram shows a well-circumscribed mass. (Courtesy of Dr. Jack Meyer, Brigham
and Women's Hospital, Boston, MA.) Although the most common lesion would be a
fibroadenoma, other benign (e.g., fibrous lesions or PASH) and malignant (e.g., medullary or
mucinous carcinomas) lesions can also have this appearance. B, Fibroadenoma. A rubbery,
white, well-circumscribed mass is clearly demarcated from the surrounding yellow adipose
tissue. The fibroadenoma does not contain adipose tissue and therefore appears denser than
the surrounding normal tissue on mammogram.
Fibroadenoma
多形性腺瘤 pleomorphic adenoma
• 由腺组织、粘液样及软骨样组织等多种成分混合组成
• 常发生于唾液腺（腮腺），又称混合瘤
• 生长缓慢，但易侵犯包膜，切除后易复发
This mixed tumor of the parotid gland contains epithelial cells
forming ducts and myxoid stroma that resembles cartilage
息肉状腺瘤 polypous adenoma
• 又称腺瘤性息肉
• 多见直肠，也见于结肠、胃
• 表面乳头状恶变率高
• 结肠多发性腺瘤性息肉病有家族遗传性，癌变率高，易早期癌变。
Hyperplastic polyp
Familial adenomatous polyposis in an 18-year-old woman
恶性上皮组织肿瘤
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人类最常见恶性肿瘤，统称为癌
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浸润性生长
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质地硬，切面灰白色，干燥
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形成癌巢，早期淋巴道转移
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常见类型
Squamous cell carcinoma
Basal cell carcinoma
Transitional cell carcinoma
Adenocarcinoma
Undifferentiated carcinoma
Squamous cell carcinoma
• 披覆鳞状上皮如皮肤、口腔、唇、子宫颈、阴道、食管、喉、阴茎
• 通过鳞化：支气管、胆囊、肾盂
• 眼观：菜花状或结节状，中央可坏死脱落形成溃疡。切面向深处浸润
性生长。
• 镜检：细胞间桥和角化珠 keratin pearl,低分化者无
Well-differentiated squamous cell carcinoma of the skin.
Basal cell carcinoma
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好发于老年人面部如眼睑、脸颊、鼻翼
起源于表皮原始上皮或基底细胞层
眼观：扁平斑块
中央坏死形成溃疡
癌巢由浓染的基底细胞样癌细胞构成
生长缓慢，很少转移
对放疗敏感，低度恶性
Transitional cell carcinoma
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好发部位：膀胱、肾盂
乳头状，多发性
似移行上皮，多层排列，异型性明显
易复发
Adenocarcinoma
• 胃肠、甲状腺、胆囊、乳腺
• 腺上皮发生
• 类型
• 腺癌 adenocarcinoma：乳头状腺癌、囊腺癌、乳头状囊腺癌
• 粘液癌 mucoid carcinoma：胶样癌colloid carcinoma、印戒细胞癌
signet ring cell carcinoma、粘液腺癌 mucinous adenocarcinoma
• 实体癌solid carcinoma：单纯癌 carcinoma simplex、硬癌 scirrhous
carcinoma、髓样癌 medullary carcinoma
Malignant tumor (adenocarcinoma) of the colon
Benign tumor (adenoma) of the thyroid. Note the normal-looking
(well-differentiated), colloid-filled thyroid follicles
Invasive ductal carcinoma
A, Well-differentiated invasive carcinoma of no special type. Well-formed
tubules and nests of cells with small monomorphic nuclei invade into the
stroma with a surrounding desmoplastic response. B, Poorly
differentiated invasive carcinoma of no special type. Ragged sheets of
pleomorphic cells without tubule formation infiltrate into the adjacent
stroma.
Invasive lobular carcinoma. Parallel arrays of small, regular cells with
scant cytoplasm infiltrate singly in linear arrays or as small clusters of
cells. There is often associated LCIS
Medullary carcinoma.
The cells are highly pleomorphic with frequent mitoses and grow as
sheets of cohesive cells. A lymphoplasmacytic infiltrate is prominent.
Mucinous (colloid) carcinoma.
The tumor cells are present as small clusters within large pools of mucin. The borders are
typically well circumscribed, and these cancers often mimic benign masses.
Tubular carcinoma.
The carcinoma must be completely composed of well-formed tubules lined by a
single layer of well-differentiated cells
Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma).
Anaplastic tumor showing cellular and nuclear variation in size and shape.
Histologic appearance of lung carcinoma
Carcinoma of the cecum
Carcinoma of the descending colon
Invasive adenocarcinoma of colon
Precancerous lesions
具有癌变潜在可能性，长期存在可能转变为癌
粘膜白斑，慢性子宫颈炎伴子宫颈糜烂，乳腺增生性纤维性囊性变，结
肠直肠息肉状腺瘤，慢性萎缩性胃炎及胃溃疡，慢性溃疡性结肠炎，慢
性皮肤溃疡，肝硬化
Atypical hyperplasia, dysplasia
• 增生的上皮细胞形态有一定程度异型性，但不足以诊断为
癌。轻、中、重度不典型增生。
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Intraepithelial neoplasia 上皮内瘤变
1级 = 轻度不典型增生
2级 = 中度不典型增生
3级 = 重度不典型增生，原位癌
Carcinoma in situ, CIS
原位癌
• 粘膜鳞状上皮层或皮肤表皮层内的重度不典型增生几乎累及或累及上
皮的全层（上皮内瘤变3级）
Carcinoma in situ
A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence
of hair, sebaceous material, and tooth. B, A microscopic view of a similar tumor
shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).
Leiomyoma of the uterus
Lifecycle changes
Molecular Basis of Cancer
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Nonlethal genetic damage lies at the heart of carcinogenesis.
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A tumor is formed by the clonal expansion of a single precursor cell that has
incurred the genetic damage.
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Four classes of normal regulatory genes-the growth-promoting
protooncogenes, the growth-inhibiting tumor suppressor genes, genes that
regulate programmed cell death (apoptosis), and genes involved in DNA
repair-are the principal targets of genetic damage.
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DNA repair genes affect cell proliferation or survival indirectly by influencing
the ability of the organism to repair nonlethal damage in other genes,
including protooncogenes, tumor suppressor genes, and genes that
regulate apoptosis.
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Carcinogenesis is a multistep process at both the phenotypic and the
genetic levels.
Diagram depicting the use of X-linked isoenzyme cell markers as evidence of
the monoclonality of neoplasms
Seven fundamental changes in cell physiology that together determine malignant phenotype
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Self-sufficiency in growth signals: Tumors have the capacity to proliferate without
external stimuli, usually as a consequence of oncogene activation.
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Insensitivity to growth-inhibitory signals: Tumors may not respond to molecules that
are inhibitory to the proliferation of normal cells such as transforming growth factor-β
(TGF-β), and direct inhibitors of cyclin-dependent kinases.
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Evasion of apoptosis: Tumors may be resistant to programmed cell death, as a
consequence of inactivation of p53 or other changes.
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Defects in DNA repair: Tumors may fail to repair DNA damage caused by
carcinogens or unregulated cellular proliferation.
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Limitless replicative potential: Tumor cells have unrestricted proliferative capacity,
associated with maintenance of telomere length and function.
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Sustained angiogenesis: Tumors are not able to grow without formation of a vascular
supply, which is induced by various factors, the most important being vascular
endothelial growth factor (VEGF).
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Ability to invade and metastasize: Tumor metastases are the cause of the vast
majority of cancer deaths and depend on processes that are intrinsic to the cell or are
initiated by signals from the tissue environment.
Flow chart depicting a simplified scheme of the molecular basis of cancer
Expression of cyclin-cyclin-dependent kinase (CDK) complexes during the cell cycle
Schematic illustration of the role of cyclins, CDKs, and cyclin-dependent
kinase inhibitors in regulating the G1/S cell-cycle transition
Mechanism of cell-cycle regulation by RB
Subcellular localization and functions of major classes of cancer-associated genes.
The protooncogenes are colored red, cancer suppressor genes blue, DNA repair
genes green, and genes that regulate apoptosis purple.
Model for action of RAS genes
The chromosomal translocation and associated oncogenes in
Burkitt lymphoma and chronic myelogenous leukemia
Amplification of the N-MYC gene in human neuroblastomas
Pathogenesis of retinoblastoma. Two mutations of the RB locus on chromosome
13q14 lead to neoplastic proliferation of the retinal cells.
Retinoblastoma as a Paradigm for the Two-Hit Hypothesis of Oncogenesis.
Role of RB as a cell-cycle regulator
The role of p53 in maintaining the integrity of the genome
p53 has been rightfully called a "guardian of the genome."
• To summarize, p53 links cell damage with DNA repair, cell-cycle
arrest, and apoptosis.
• In response to DNA damage, it is phosphorylated by genes that
sense the damage and are involved in DNA repair.
• p53 assists in DNA repair by causing G1 arrest and inducing DNA
repair genes.
• A cell with damaged DNA that cannot be repaired is directed by p53
to undergo apoptosis.
• With homozygous loss of p53, DNA damage goes unrepaired,
mutations become fixed in dividing cells, and the cell turns onto a
one-way street leading to malignant transformation.
A, The role of APC in regulating the stability and function of β-catenin. APC and β-catenin are components of the WNT
signaling pathway. In resting cells (not exposed to WNT), β-catenin forms a macromolecular complex containing the
APC protein. This complex leads to the destruction of β-catenin, and intracellular levels of β-catenin are low. B, When
cells are stimulated by secreted WNT molecules, the destruction complex is deactivated, β-catenin degradation does
not occur, and cytoplasmic levels increase. β-catenin translocates to the nucleus, where it binds to TCF, a transcription
factor that activates several genes involved in the cell cycle. C, When APC is mutated or absent, the destruction of βcatenin cannot occur. β-Catenin translocates to the nucleus and coactivates genes that promote the cell cycle, and
cells behave as if they are under constant stimulation by the WNT pathway.
Interaction between cancer susceptibility genes and DNA repair
Cellular responses to telomere shortening
Molecular Basis of Multistep Carcinogenesis
Schematic illustration of the pathways of malignancy initated by mutation of the
gatekeeper genes (e.g., APC, NF-1, RB) or caretaker genes (e.g., hMSH2, BRCA-1, BRCA-2).
Carcinogenic Agents and Their Cellular Interactions
• A large number of agents cause genetic damage and
induce neoplastic transformation of cells.
• They include (1) chemical carcinogens, (2) radiant
energy, and (3) oncogenic viruses and some other
microbes.
Steps Involved in Chemical Carcinogenesis
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Initiation results from exposure of cells to a sufficient dose of a carcinogenic agent
(initiator); an initiated cell is altered, making it potentially capable of giving rise to a
tumor (groups 2 and 3). Initiation alone, however, is not sufficient for tumor formation
(group 1).
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Initiation causes permanent DNA damage (mutations). It is therefore rapid and
irreversible and has "memory." This is illustrated by group 3, in which tumors were
produced even if the application of the promoting agent was delayed for several
months after a single application of the initiator.
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Promoters can induce tumors in initiated cells, but they are nontumorigenic by
themselves (group 5). Furthermore, tumors do not result when the promoting agent is
applied before, rather than after, the initiating agent (group 4). This indicates that, in
contrast to the effects of initiators, the cellular changes resulting from the application
of promoters do not affect DNA directly and are reversible. As discussed later,
promoters enhance the proliferation of initiated cells, an effect that may contribute to
the development of additional mutations in these cells. That the effects of promoters
are reversible is further documented in group 6, in which tumors failed to develop in
initiated cells if the time between multiple applications of the promoter was sufficiently
extended.
Experiments demonstrating the initiation and promotion phases of carcinogenesis in mice
General schema of events in chemical carcinogenesis.
Effect of HPV proteins E6 and E7 on the cell cycle. The net effect of HPV E6 and E7
proteins is to block apoptosis and remove the restrains to cell proliferation
Schema depicting the possible evolution of Epstein-Barr virus (EBV)-induced
Burkitt lymphoma
Tumor antigens recognized by CD8+ T cells
Tumor cells must develop mechanisms to escape or evade the
immune system in immunocompetent hosts
• Selective outgrowth of antigen-negative variants
• Loss or reduced expression of MHC molecules
• Lack of costimulation
• Immunosuppression
• Antigen masking
• Apoptosis of cytotoxic T cells
Mechanisms by which tumors evade the immune system
Normal cervicovaginal smear shows large, flattened squamous cells and groups of
metaplastic cells; interspersed are some neutrophils. There are no malignant cells.
An abnormal cervicovaginal smear shows numerous malignant cells that have pleomorphic,
hyperchromatic nuclei; interspersed are some normal polymorphonuclear leukocytes.
Immunohistochemistry
• Categorization of undifferentiated malignant
tumors
• Categorization of leukemias and lymphomas
• Determination of site of origin of metastatic
tumors
• Detection of molecules that have prognostic or
therapeutic significance
Anticytokeratin immunoperoxidase stain of a tumor of epithelial origin (carcinoma).
Molecular diagnosis
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Diagnosis of malignant neoplasms
Prognosis of malignant neoplasms
Detection of minimal residual disease
Diagnosis of hereditary predisposition to cancer
DNA microarray analysis and proteomics
Schematic representation of the steps required for the
analysis of global gene expression by DNA microarray
1、掌握肿瘤的概念；肿瘤增生与非肿瘤增生的区别；
2、掌握肿瘤的一般形态、肿瘤的组织结构、肿瘤细胞的异型性、肿瘤组织结
构的异型性、肿瘤中分化和间变的概念；
3、了解肿瘤的生长动力学、肿瘤血管的形成、肿瘤的演进和异质化。了解
肿瘤的生长速度和肿瘤转移的机制；掌握肿瘤的生长方式：膨胀性生长、外
生性生长、浸润性生长；掌握肿瘤的扩散：直接蔓延、肿瘤转移（转移的概
念、转移的途径）；掌握肿瘤的分级和分期、肿瘤复发的概念；
4、掌握恶病质、副肿瘤综合征；了解机体对肿瘤的影响；
5、掌握良性肿瘤与恶性肿瘤的区别；
6、掌握肿瘤的分类和命名原则，肿瘤的分类；
7、掌握乳头状瘤、腺瘤及其常见类型；鳞状细胞癌、腺癌及其常见类型、移
行上皮细胞癌；癌前病变及原位癌的概念；癌与肉瘤的区别；了解间叶肿瘤
的一般特点，神经外胚叶源性肿瘤的一般特点，多种组织构成肿瘤的一般特
点，妊娠滋养层细胞肿瘤的一般特点；了解肿瘤的病因学和发病；
8、了解肿瘤的发病学，肿瘤的病因学，影响肿瘤发生、发展的内在因素及其
作用机制。