General Pathology Review - Presentation Transcript

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GENERAL PATHOLOGY REVIEW CRISBERT I. CUALTEROS,M.D. http://crisbertcualteros.page.tl

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Cellular Adaptations, Cell Injury, and Cell Death

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Pathology is literally the study (logos) of suffering (pathos)

The four aspects of a disease process that form the core of pathology are:

its cause ( etiology ) ,

the mechanisms of its development ( pathogenesis )

the structural alterations induced in the cells and organs of the body ( morphologic
changes )

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the functional consequences of the morphologic changes ( clinical significance ).

Overview: Cellular Responses to Stress and Noxious Stimuli

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Figure 1-1 Stages in the cellular response to stress and injurious stimuli.

Cellular Adaptations of Growth and Differentiation

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Cells respond to increased demand and external stimulation by hyperplasia or

hypertrophy , and they respond to reduced supply of nutrients and growth factors by
atrophy . In some situations, cells change from one type to another, a process called
metaplasia .

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Figure 1-2 The relationships between normal, adapted, reversibly injured, and dead
myocardial cells. The cellular adaptation depicted here is hypertrophy, and the type
of cell death is ischemic necrosis. In reversibly injured myocardium, generally effects
are only functional, without any readily apparent gross or even microscopic
changes. In the example of myocardial hypertrophy, the left ventricular wall is more
than 2 cm in thickness (normal is 1 to 1.5 cm). In the specimen showing necrosis,
the transmural light area in the posterolateral left ventricle represents an acute
myocardial infarction.

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HYPERPLASIA
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increase in the number of cells in an organ or tissue, usually resulting in increased

volume of the organ or tissue.

Ex. Hormonal hyperplasia- best exemplified by the proliferation of the glandular

epithelium of the female breast at puberty and during pregnancy and the
physiologic hyperplasia that occurs in the pregnant uterus.

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HYPERTROPHY

increase in the size of cells, resulting in an increase in the size of the organ .

Figure 1-3 Physiologic hypertrophy of the uterus during pregnancy. A , Gross

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appearance of a normal uterus (right) and a gravid uterus (removed for postpartum
bleeding) (left). B, Small spindle-shaped uterine smooth muscle cells from a normal
uterus (left) compared with large plump cells in gravid uterus (right) .

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ATROPHY
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Shrinkage in the size of the cell by loss of cell substance

The common causes of atrophy are the following:

1. Decreased workload (atrophy of disuse).

2.Loss of innervation (denervation atrophy).

3. Diminished blood supply.

4. Inadequate nutrition.

5. Loss of endocrine stimulation.

6. Aging (senile atrophy).

7. Pressure.

Figure 1-5 A, Atrophy of the brain in an 82-year-old male with atherosclerotic

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disease. Atrophy of the brain is due to aging and reduced blood supply. The
meninges have been stripped. B, Normal brain of a 36-year-old male. Note that loss
of brain substance narrows the gyri and widens the sulci.

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METAPLASIA
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reversible change in which one adult cell type (epithelial or mesenchymal) is

replaced by another adult cell type

adaptive substitution of cells that are sensitive to stress by cell types better able to
withstand the adverse environment.

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Figure 1-6 Metaplasia. A , Schematic diagram of columnar to squamous metaplasia.

B , Metaplastic transformation of esophageal stratified squamous epithelium ( left )
to mature columnar epithelium (so-called Barrett metaplasia).

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Overview of Cell Injury and Cell Death

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Reversible cell injury- if the damaging stimulus is removed.

Irreversible injury and cell death- w ith continuing damage, at which time the cell
cannot recover.

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Figure 1-7 Stages in the evolution of cell injury and death.

Figure 1-8 Schematic representation of a normal cell and the changes in reversible

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and irreversible cell injury.

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There are two types of cell death, necrosis and apoptosis

Whereas necrosis is always a pathologic process, apoptosis serves many normal

functions and is not necessarily associated with cell injury .

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Feature Necrosis Apoptosis

Cell size Enlarged (swelling) Reduced (shrinkage)

Nucleus Pyknosis -> karyorrhexis -> karyolysis Fragmentation into nucleosome size
fragments

Plasma Disrupted Intact; altered structure, especially

Membrane orientation of lipids

Cellular Enzymatic digestion; may leak out of cell Intact; may be released in
apoptotic bodies

Contents

Adjacent Frequent No

Inflammation

Physiologic Invariably pathologic Often physiologic, means of or

pathologic role (culmination of irreversible cell injury) eliminating unwanted cells;

may

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be pathologic after some forms of cell injury, especially DNA damage

Causes of Cell Injury

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Oxygen Deprivation

Physical Agents

Chemical Agents and Drugs

Infectious Agents

Immunologic Reactions

Genetic Derangements

Nutritional Imbalances

Mechanisms of Cell Injury

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There are, however, a number of principles that are relevant to most forms of cell
injury:

1.The cellular response to injurious stimuli depends on the type of injury, its
duration, and its severity.

2.The consequences of cell injury depend on the type, state, and adaptability of the
injured cell .

3.Cell injury results from functional and biochemical abnormalities in one or more of
several essential cellular components .

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The most important targets of injurious

stimuli are:

aerobic respiration involving mitochondrial oxidative phosphorylation and production

of ATP;

integrity of cell membranes , on which the ionic and osmotic homeostasis of the cell
and its organelles depends;

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protein synthesis ;

cytoskeleton ;

integrity of the genetic apparatus of the cell .

Morphology of Cell Injury and Necrosis

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Cells undergo sequential biochemical and morphologic changes as they are

progressively injured and ultimately die by necrosis.

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Reversible Injury

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Two patterns of reversible cell injury can be recognized under the light microscope:

1. cellular swelling - the first manifestation of almost all forms of injury to cells.

2. fatty change .

Necrosis
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refers to a spectrum of morphologic changes that follow cell death in living tissue,
largely resulting from the progressive degradative action of enzymes on the lethally
injured cell.

in the setting of irreversible exogenous injury.

result of denaturation of intracellular proteins and enzymatic digestion of the cell.

Necrotic cells show increased eosinophilia attributable in part to loss of the normal

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basophilia imparted by the RNA in the cytoplasm and in part to the increased
binding of eosin to denatured intracytoplasmic proteins
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Figure 1-18 Ischemic necrosis of the myocardium. A , Normal myocardium. B ,

Myocardium with coagulation necrosis (upper two thirds of figure), showing strongly
eosinophilic anucleate myocardial fibers. Leukocytes in the interstitium are an early
reaction to necrotic muscle. Compare with A and with normal fibers in the lower part
of the figure.

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Nuclear changes appear in the form of one of three patterns, all due to nonspecific
breakdown of DNA :

pyknosis , characterized by nuclear shrinkage and increased basophilia.

karyorrhexis , the pyknotic or partially pyknotic nucleus undergoes fragmentation.

karyolysis, t he basophilia of the chromatin may fade

Coagulative necrosis implies preservation of the basic outline of the coagulated cell

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for a span of at least some days
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-When denaturation is the primary pattern

Liquefactive necrosis is characteristic of focal bacterial or, occasionally, fungal

infections, because microbes stimulate the accumulation of inflammatory cells.

-In the instance of dominant enzyme digestion

Figure 1-19 Coagulative and liquefactive necrosis. A , Kidney infarct exhibiting

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coagulative necrosis, with loss of nuclei and clumping of cytoplasm but with
preservation of basic outlines of glomerular and tubular architecture. B , A focus of
liquefactive necrosis in the kidney caused by fungal infection. The focus is filled with
white cells and cellular debris, creating a renal abscess that obliterates the normal
architecture.

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Caseous necrosis , a distinctive form of coagulative necrosis, is encountered most

often in foci of tuberculous infection

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Figure 1-20 A tuberculous lung with a large area of caseous necrosis. The caseous
debris is yellow-white and cheesy.

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Fat necrosis , it is descriptive of focal areas of fat destruction, typically occurring as

a result of release of activated pancreatic lipases into the substance of the pancreas
and the peritoneal cavity.

-i.e. acute pancreatitis

Figure 1-21 Foci of fat necrosis with saponification in the mesentery. The areas of

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white chalky deposits represent calcium soap formation at sites of lipid breakdown.

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Apoptosis
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a pathway of cell death that is induced by a tightly regulated intracellular program

in which cells destined to die activate enzymes that degrade the cells' own nuclear
DNA and nuclear and cytoplasmic proteins.

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Death by apoptosis is a normal phenomenon that serves to eliminate cells that are
no longer needed, as, for example, during development, and to maintain a steady
number of various cell populations in tissues.

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Death by apoptosis is also responsible for loss of cells in a variety of pathologic

states

-i.e. Cell injury in certain viral diseases , such as viral hepatitis

The following morphologic features, characterize cells undergoing apoptosis

Cell shrinkage.

Chromatin condensation. the most characteristic feature of apoptosis.

Formation of cytoplasmic blebs and apoptotic bodies.

Phagocytosis of apoptotic cells or cell bodies, usually by macrophages.

Figure 1-26 A, Apoptosis of epidermal cells in an immune-mediated reaction. The

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apoptotic cells are visible in the epidermis with intensely eosinophilic cytoplasm and
small, dense nuclei. H&E stain. B , High power of apoptotic cell in liver in immunemediated hepatic cell injury.
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Intracellular Accumulations
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One of the manifestations of metabolic derangements in cells is the intracellular

accumulation of abnormal amounts of various substances.

The stockpiled substances fall into three categories:

a normal cellular constituent accumulated in excess , such as water, lipids, proteins,

and carbohydrates;

an abnormal substance , either exogenous, such as a mineral or products of

infectious agents, or endogenous, such as a product of abnormal synthesis or
metabolism;

a pigment .

Figure 1-34 A, The liver of alcohol abuse (chronic alcoholism). Hyaline inclusions in

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the hepatic parenchymal cell in the center appear as eosinophilic networks disposed
about the nuclei (arrow) . B, Electron micrograph of alcoholic hyalin. The material is
composed of intermediate (prekeratin) filaments and an amorphous matrix.

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Figure 1-35 Mechanisms of intracellular accumulations:

abnormal metabolism, as in fatty change in the liver;

mutations causing alterations in protein folding and transport, as in alpha1antitrypsin deficiency;

deficiency of critical enzymes that prevent breakdown of substrates that accumulate

in lysosomes, as in lysosomal storage diseases; and

inability to degrade phagocytosed particles, as in hemosiderosis and carbon

pigment accumulation.

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Steatosis (Fatty Change)

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All major classes of lipids can accumulate in cells: triglycerides,

cholesterol/cholesterol esters, and phospholipids.

steatosis and fatty change -abnormal accumulations of triglycerides within

parenchymal cells often seen in the liver because it is the major organ involved in
fat metabolism. In industrialized nations, by far the most common cause of
significant fatty change in the liver (fatty liver) is alcohol abuse

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Figure 1-36 Fatty liver. A , Schematic diagram of the possible mechanisms leading to
accumulation of triglycerides in fatty liver. Defects in any of the steps of uptake,
catabolism, or secretion can result in lipid accumulation. B , High-power detail of
fatty change of the liver. In most cells, the well-preserved nucleus is squeezed into
the displaced rim of cytoplasm about the fat vacuole.

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Cholesterol and Cholesterol Esters

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Accumulations, manifested histologically by intracellular vacuoles, seen in several

pathologic processes.

-i.e. Cholesterolosis. Refers to the focal accumulations of cholesterol-laden

macrophages in the lamina propria of the gallbladder. The mechanism of
accumulation is unknown.

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Figure 1-37 Cholesterolosis. Cholesterol-laden macrophages (foam cells) from a

focus of gallbladder cholesterolosis ( arrow ).

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PROTEINS
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Intracellular accumulations of proteins usually appear as rounded, eosinophilic

droplets, vacuoles, or aggregates in the cytoplasm.

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Figure 1-38 Protein reabsorption droplets in the renal tubular epithelium.

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HYALINE CHANGE
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an alteration within cells or in the extracellular space, which gives a homogeneous,

glassy, pink appearance in routine histologic sections stained with hematoxylin and
eosin.

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does not represent a specific pattern of accumulation.

GLYCOGEN
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Excessive intracellular deposits of glycogen are seen in patients with an abnormality

in either glucose or glycogen metabolism.

the glycogen masses appear as clear vacuoles within the cytoplasm.

Staining with periodic acid schiff (PAS) reaction imparts a rose-to-violet color to the
glycogen,

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PIGMENTS
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colored substances, some of which are normal constituents of cells (e.g., melanin),
whereas others are abnormal and collect in cells only under special circumstances.

Exogenous Pigments. The most common exogenous pigment is carbon or coal dust ,
Accumulations of this pigment blacken the tissues of the lungs (anthracosis)

- Tattooing is a form of localized, exogenous pigmentation of the skin.

Endogenous Pigments . Lipofuscin is an insoluble pigment, also known as

lipochrome and wear-and-tear or aging pigment. Its importance lies in its being the
telltale sign of free radical injury and lipid peroxidation.

- Melanin , is the only endogenous brown-black pigment .

- Hemosiderin is a hemoglobin-derived, golden yellow-to-brown, granular or

crystalline pigment in which form iron is stored in cells.

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Figure 1-40 Lipofuscin granules in a cardiac myocyte as shown by A, light

microscopy (deposits indicated by arrows ), and B, electron microscopy (note the
perinuclear, intralysosomal location).

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Figure 1-41 Hemosiderin granules in liver cells. A , H&E section showing goldenbrown, finely granular pigment. B , Prussian blue reaction, specific for iron.

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Pathologic Calcification
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the abnormal tissue deposition of calcium salts, together with smaller amounts of
iron, magnesium, and other mineral salts.

There are two forms of pathologic calcification:

1. dystrophic calcification , when the deposition occurs locally in dying tissues ; it

occurs despite normal serum levels of calcium and in the absence of derangements
in calcium metabolism.

2.metastatic calcification , almost always results from hypercalcemia secondary to

some disturbance in calcium metabolism.

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Figure 1-42 View looking down onto the unopened aortic valve in a heart with
calcific aortic stenosis. The semilunar cusps are thickened and fibrotic. Behind each
cusp are seen irregular masses of piled-up dystrophic calcification

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END

Tissue Renewal and Repair: Regeneration, Healing, and Fibrosis

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The body's ability to replace injured or dead cells and to repair tissues after
inflammation is critical to survival.

When injurious agents damage cells and tissues, the host responds by setting in
motion a series of events that serve to eliminate these agents, contain the damage,
and prepare the surviving cells for replication.

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Figure 3-1 Tissue response to injury. Repair after injury can occur by regeneration,
which restores normal tissue, or by healing, which leads to scar formation and
fibrosis.

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Regeneration refers to growth of cells and tissues to replace lost structures

-the term is usually applied to processes such as liver and kidney growth after
partial hepatectomy and unilateral nephrectomy.

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Healing is usually a tissue response:

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to a wound (commonly in the skin)

to inflammatory processes in internal organs

to cell necrosis in organs incapable of regeneration.

Control of Normal Cell Proliferation and Tissue Growth

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Figure 3-2 Mechanisms regulating cell populations. Cell numbers can be altered by
increased or decreased rates of stem cell input, by cell death due to apoptosis, or by
changes in the rates of proliferation or differentiation.

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Mechanisms of Tissue Regeneration

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Figure 3-11 Liver regeneration after partial hepatectomy. Upper panel, The lobes of
the liver of a rat are shown (M, median; RL and LL, right and left lateral lobes; C,
caudate lobe). Partial hepatectomy removes two thirds of the liver (median and left
lateral lobes), and only the right lateral and caudate lobes remain. After 3 weeks,
the right lateral and caudate lobes enlarge to reach a mass equivalent to that of the
original liver. Note that there is no regrowth of the median and left lateral lobes
removed after partial hepatectomy. Lower panel, Timing of hepatocyte DNA
replication, hepatocyte mitosis, and expression of messenger RNAs during liver
regeneration. DNA replication is shown as the incorporation of tritiated thymidine
10-4 (right-side scale). Mitosis presented as the percentage of hepatocytes
undergoing mitosis ( right-side scale ). The expression of some of the many mRNAs
in the regenerating rat liver is presented as fold elevation above normal ( left-side
scale ). Expression of the proto-oncogenes c- fos, c- jun, and c- myc corresponds to
the immediate early gene phase of gene expression during liver regeneration.

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Figure 3-12 Regeneration of human liver. Computed tomography (CT) scans of the
donor liver in living-donor hepatic transplantation. left panel, The liver of the donor
before the operation. The right lobe, which will be used as a transplant, is outlined.
Right panel, A scan of the liver 1 week after performance of partial hepatectomy to
remove the right lobe. Note the great enlargement of the left lobe (outlined in the
panel) without regrowth of the right lobe

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growth occurs by enlargement of the lobes that remain after the operationcompensatory growth .

the end-point of liver regeneration after partial hepatectomy is the restitution of

functional mass rather than form.

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Extracellular Matrix (ECM) and Cell-Matrix Interactions

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Cells grow, move, and differentiate in intimate contact with macromolecules outside
the cell that constitute the ECM

The ECM is secreted locally and assembles into a network in the spaces surrounding
cells

relevant to regeneration, healing, and fibrosis.

Figure 3-14 Major components of the extracellular matrix (ECM), including collagens,

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proteoglycans, and adhesive glycoproteins. Both epithelial and mesenchymal cells
(e.g., fibroblasts) interact with ECM via integrins. To simplify the diagram, many ECM
components (e.g., elastin, fibrillin, hyaluronan, syndecan) are not included.

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COLLAGEN
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the most common protein in the animal world, providing the extracellular framework
for all multicellular organisms.

Without collagen, a human being would be reduced to a clump of cells,

interconnected by a few neurons.

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ELASTIN, FIBRILLIN, AND ELASTIC FIBERS

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found in the walls of large blood vessels, such as the aorta, and in the uterus, skin,
and ligaments - require elasticity for their function

Although tensile strength is provided by the proteins of the collagen family, the
ability of these tissues to recoil is provided by elastic fibers.

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CELL ADHESION PROTEINS

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Most adhesion proteins, also called CAMs (cell adhesion molecules), can be
classified into four main families:

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1.immunoglobulin family CAMs,

2.cadherins,

3.integrins,

4.selectins.

These proteins are located in the cell membrane, where they function as receptors

PROTEOGLYCANS
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make up the third type of component in the ECM

Some of the most common are heparan sulfate, chondroitin sulfate, and dermatan
sulfate.

They have diverse roles in regulating connective tissue structure and permeability.

integral membrane proteins and, act as modulators of cell growth and

differentiation.

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HYALURONIC ACID
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binds a large amount of water, forming a viscous hydrated gel that gives connective
tissue the ability to resist compression forces.

helps provide resilience and lubrication to many types of connective tissue, notably
for the cartilage in joints.

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Repair by Healing, Scar Formation, and Fibrosis

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regeneration involves the restitution of tissue components identical to those

removed or killed.

healing is a fibroproliferative response that " patches " rather than

restores a tissue.

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complex but orderly phenomenon involving a number of processes:

1.Induction of an inflammatory process in response to the initial injury, with removal

of damaged and dead tissue

2.Proliferation and migration of parenchymal and connective tissue cells

3.Formation of new blood vessels ( angiogenesis) and granulation tissue

4.Synthesis of ECM proteins and collagen deposition

5. Tissue remodeling

6. Wound contraction

7. Acquisition of wound strength

The repair process is influenced by many factors, including:

1.The tissue environment and the extent of tissue damage

2.The intensity and duration of the stimulus

3.Conditions that inhibit repair, such as the presence of foreign bodies or inadequate

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blood supply,
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4.Various diseases that inhibit repair (diabetes in particular), and treatment with
steroids.

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The goal of the repair process is to restore the tissue to its original state.

The inflammatory reaction set in motion by the injury:

1.contains the damage

2.eliminates the damaging stimulus

3.removes injured tissue

4.initiates the deposition of ECM components in the area of injury.

For tissues that are incapable of regeneration, repair is accomplished by connective

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tissue deposition, producing a scar.
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If damage persists, inflammation becomes chronic, and tissue damage and repair
may occur concurrently. Connective tissue deposition in these conditions is usually
referred to as fibrosis.

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fibroblasts and vascular endothelial cells begin proliferating to form a specialized

type of tissue that is the hallmark of healing, called granulation tissue

formation of new small blood vessels ( angiogenesis )

Figure 3-17 A, Granulation tissue showing numerous blood vessels, edema, and a

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loose ECM containing occasional inflammatory cells. This is a trichrome stain that
stains collagen blue; minimal mature collagen can be seen at this point. B,
Trichrome stain of mature scar, showing dense collagen, with only scattered
vascular channels.

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ANGIOGENESIS
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Figure 3-18 Angiogenesis by mobilization of endothelial precursor cells (EPCs) from

the bone marrow and from pre-existing vessels (capillary growth). EPCs are
mobilized from the bone marrow and may migrate to a site of injury or tumor growth
( upper panel ). The homing mechanisms have not yet been defined. At these sites,
EPCs differentiate and form a mature network by linking with existing vessels.

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Figure 3-18 In angiogenesis from pre-existing vessels, endothelial cells from these
vessels become motile and proliferate to form capillary sprouts ( lower panel ).
Regardless of the initiating mechanism, vessel maturation (stabilization) involves
the recruitment of pericytes and smooth muscle cells to form the periendothelial
layer.

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Growth Factors and Receptors Involved in Angiogenesis

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VEGF emerges as the most important growth factor in adult tissues undergoing
physiologic angiogenesis (e.g., proliferating endometrium) as well as pathologic

angiogenesis seen in chronic inflammation, wound healing, tumors, and diabetic

retinopathy.
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stimulates the mobilization of endothelial cell precursors and enhances the

proliferation and differentiation of these cells at the site of angiogenesis.

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SCAR FORMATION
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Growth factors and cytokines released at the site of injury induce fibroblast
proliferation and migration into the granulation tissue framework of new blood
vessels and loose ECM that initially forms at the repair site.

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three processes that participate in the formation of a scar:

emigration and proliferation of fibroblasts in the site of injury ,

deposition of ECM ,

tissue remodeling .

Cutaneous Wound Healing

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Figure 3-20 Phases of wound healing.

Skin wounds are classically described to heal by primary or secondary intention---

based on the nature of the wound rather

than the healing process itself.

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HEALING BY FIRST INTENTION (WOUNDS WITH OPPOSED EDGES)

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Figure 3-21 Steps in wound healing by first intention ( left ) and second intention
( right ). Note large amounts of granulation tissue and wound contraction in healing
by second intention.

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By the end of the first month , the scar is made up of a cellular connective tissue
devoid of inflammatory infiltrate, covered now by intact epidermis.

The dermal appendages that have been destroyed in the line of the incision are
permanently lost.

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Tensile strength of the wound increases thereafter

HEALING BY SECOND INTENTION (WOUNDS WITH SEPARATED EDGES)

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Figure 3-22 Healing of skin ulcers. A, Pressure ulcer of the skin, commonly found in
diabetic patients.

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Figure 3-22 The histology slides show B, a skin ulcer with a large gap between the
edges of the lesion;

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Figure 3-22 C, a thin layer of epidermal reepithelialization and extensive granulation

tissue formation in the dermis;

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Figure 3-22 D, continuing reepithelialization of the epidermis and wound contraction.

Figure 3-21 Steps in wound healing by first intention ( left ) and second intention

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( right ). Note large amounts of granulation tissue and wound contraction in healing
by second intention.
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there is more extensive loss of cells and tissue, surface wounds that create large
defects

Inevitably, large tissue defects generate a larger fibrin clot that fills the defect and
more necrotic debris and exudate that must be removed.

the inflammatory reaction is more intense.

Much larger amounts of granulation tissue are formed.

the feature that most clearly differentiates primary from secondary healing is the

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phenomenon of wound contraction
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The initial steps of wound contraction:

1. formation of a network of actin-containing fibroblasts at the edge of the wound.

2. action of myofibroblasts -altered fibroblasts that have the ultrastructural

characteristics of smooth muscle cells.

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LOCAL AND SYSTEMIC FACTORS THAT INFLUENCE WOUND HEALING

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Systemic factors include the following:

1.Nutrition

2.Metabolic status

3.Circulatory status

4.Hormones

Local factors that influence healing include the following:

1. Infection -the single most important cause of delay in healing

2.Mechanical factors

3.Foreign bodies

4.Size, location, and type of wound trauma.

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COMPLICATIONS IN CUTANEOUS WOUND HEALING

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Inadequate formation of granulation tissue or assembly of a scar can lead to two

types of complications: wound dehiscence and ulceration

accumulation of excessive amounts of collagen- a raised scar aka hypertrophic

scar ;

-if the scar tissue grows beyond the boundaries of the original wound and does not
regress, it is called a keloid

3. exaggeration of contraction- contracture and results in deformities

Figure 3-23 A, Keloid. Excess collagen deposition in the skin forming a raised scar

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known as keloid. B, Note the thick connective tissue deposition in the dermis.
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Hemodynamic Disorders, Thromboembolic Disease, and Shock

107.
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Normal fluid homeostasis encompasses maintenance of vessel wall integrity as well

as intravascular pressure and osmolarity within certain physiologic ranges .

Changes in vascular volume, pressure, or protein content, or alterations in

endothelial function, all affect the net movement of water across the vascular wall.

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Edema
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increased fluid in the interstitial tissue spaces.

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Table 4-1. Pathophysiologic Categories of Edema

Increased Hydrostatic Pressure

Impaired venous return

Congestive heart failure

Constrictive pericarditis

Ascites (liver cirrhosis)

Venous obstruction or compression

Thrombosis

External pressure (e.g., mass)

Lower extremity inactivity with prolonged dependency

Arteriolar dilation

Heat Neurohumoral dysregulation

Reduced Plasma Osmotic Pressure (Hypoproteinemia)

Protein-losing glomerulopathies (nephrotic syndrome)

Liver cirrhosis (ascites)

Malnutrition

Protein-losing gastroenteropathy

Lymphatic Obstruction

Inflammatory

Neoplastic

Postsurgical

Postirradiation

Sodium Retention

Excessive salt intake with renal insufficiency

Increased tubular reabsorption of sodium

Renal hypoperfusion

Increased renin-angiotensin-aldosterone secretion

Inflammation

Acute inflammation

Chronic inflammation

Angiogenesis

Figure 4-1 Factors affecting fluid balance across capillary walls . Capillary hydrostatic

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and osmotic forces are normally balanced so that there is no net loss or gain of fluid
across the capillary bed. However, increased hydrostatic pressure or diminished
plasma osmotic pressure leads to a net accumulation of extravascular fluid
(edema) . As the interstitial fluid pressure increases, tissue lymphatics remove much
of the excess volume, eventually returning it to the circulation via the thoracic duct.
If the ability of the lymphatics to drain tissue is exceeded, persistent tissue edema
results.

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Figure 4-2 Sequence of events leading to systemic edema due to primary heart
failure, primary renal failure, or reduced plasma osmotic pressure (as in
malnutrition, diminished hepatic protein synthesis, or loss of protein owing to the
nephrotic syndrome). ADH, antidiuretic hormone; GFR, glomerular filtration rate.

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Anasarca - generalized edema

Dependent edema - a prominent feature of congestive heart failure, particularly of

the right ventricle.

Edema as a result of renal dysfunction or nephrotic syndrome is generally more

severe than cardiac edema and affects all parts of the body equally .

periorbital edema -is a characteristic finding in severe renal disease.

pitting edema -finger pressure over substantially edematous subcutaneous tissue

displaces the interstitial fluid and leaves a finger-shaped depression

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Pulmonary edema most typically seen in the setting of left ventricular failure

Hyperemia and Congestion

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both indicate a local increased volume of blood in a particular tissue.

Figure 4-3 Hyperemia versus congestion. In both cases there is an increased volume

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and pressure of blood in a given tissue with associated capillary dilation and a
potential for fluid extravasation. In hyperemia, increased inflow leads to
engorgement with oxygenated blood, resulting in erythema . In congestion,
diminished outflow leads to a capillary bed swollen with deoxygenated venous blood
and resulting in cyanosis .
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Figure 4-4 Liver with chronic passive congestion and hemorrhagic necrosis. A ,
Central areas are red and slightly depressed compared with the surrounding tan
viable parenchyma, forming the so-called "nutmeg liver" pattern. B ,
Centrilobular necrosis with degenerating hepatocytes, hemorrhage, and sparse
acute inflammation.

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Hemorrhage
118.
o

indicates extravasation of blood due to vessel rupture

hematoma -accumulation of blood within tissue

Petechiae -m inute 1- to 2-mm hemorrhages into skin, mucous membranes, or

119.

serosal surfaces
o

purpura -s lightly larger (3 mm) hemorrhages

ecchymoses -larger (>1 to 2 cm) subcutaneous hematomas (i.e., bruises)

hemothorax, hemopericardium, hemoperitoneum , or hemarthrosis (in joints)

---Large accumulations of blood in one or another of the body cavities

120.
o

Figure 4-5 A , Punctate petechial hemorrhages of the colonic mucosa, seen here as a
consequence of thrombocytopenia. B , Fatal intracerebral bleed. Even relatively
inconsequential volumes of hemorrhage in a critical location, or into a closed space
(such as the cranium), can have fatal outcomes.

121.

Hemostasis and Thrombosis

o

Normal hemostasis -result of a set of well-regulated processes that accomplish two

important functions:

They maintain blood in a fluid, clot-free state in normal vessels;

They are poised to induce a rapid and localized hemostatic plug at a site of vascular
injury.

122.
o

Thrombosis - an inappropriate activation of normal hemostatic processes, such as

the formation of a blood clot (thrombus) in uninjured vasculature or thrombotic
occlusion of a vessel after relatively minor injury.

The pathologic opposite to hemostasis

Both hemostasis and thrombosis are regulated by three general components-1.the

123.
vascular wall

124.

2.platelets

3.the coagulation cascade.

NORMAL HEMOSTASIS
125.
o

Figure 4-6 Diagrammatic representation of the normal hemostatic process. A , After

vascular injury, local neurohumoral factors induce a transient vasoconstriction.

126.
o

Figure 4-6 Diagrammatic representation of the normal hemostatic process. B ,

Platelets adhere to exposed extracellular matrix (ECM) via von Willebrand factor
(vWF) and are activated, undergoing a shape change and granule release; released
adenosine diphosphate (ADP) and thromboxane A2 (TxA2) lead to further platelet
aggregation to form the primary hemostatic plug.

127.
o

Figure 4-6 Diagrammatic representation of the normal hemostatic process. C , Local

activation of the coagulation cascade (involving tissue factor and platelet
phospholipids) results in fibrin polymerization, "cementing" the platelets
into a definitive secondary hemostatic plug.

128.
o

Figure 4-6 Diagrammatic representation of the normal hemostatic process. D ,

Counter-regulatory mechanisms, such as release of tissue type plasminogen
activator (t-PA) (fibrinolytic) and thrombomodulin (interfering with the coagulation
cascade), limit the hemostatic process to the site of injury.

129.
o

The balance between endothelial antithrombotic and prothrombotic activities

critically determines whether thrombus formation, propagation, or dissolution occurs

130.

THROMBOSIS http://crisbertcualteros.page.tl
131.
o

Three primary influences predispose to thrombus formation, the so-called Virchow

triad :

132.

endothelial injury

stasis or turbulence of blood flow

blood hypercoagulability

Figure 4-13 Virchow triad in thrombosis. Endothelial integrity is the single most
important factor. Note that injury to endothelial cells can affect local blood flow
and/or coagulability; abnormal blood flow (stasis or turbulence) can, in turn, cause
endothelial injury. The elements of the triad may act independently or may combine
to cause thrombus formation.

133.
o

Alterations in Normal Blood Flow. i.e. Turbulence contributes to arterial and cardiac
thrombosis by causing endothelial injury or dysfunction

stasis is a major factor in the development of venous thrombi

Thrombi may develop anywhere in the cardiovascular system

An area of attachment to the underlying vessel or heart wall, frequently firmest at

134.

the point of origin, is characteristic of all thromboses.

135.
o

The propagating tail may not be well attached and, particularly in veins, is prone to
fragmentation, creating an embolus .

mural thrombi - arterial thrombi that arise in heart chambers or in the aortic lumen,
that usually adhere to the wall of the underlying structure

136.
o

Figure 4-14 Mural thrombi. A , Thrombus in the left and right ventricular apices,
overlying a white fibrous scar. B , Laminated thrombus in a dilated abdominal aortic
aneurysm.

137.
o

Fate of the Thrombus.

1.Propagation.

2. Embolization.

3. Dissolution.

4. Organization and recanalization.

Figure 4-15 Potential outcomes of venous thrombosis.

Figure 4-16 Low-power view of a thrombosed artery. A , H&E-stained section. B ,

138.

139.
Stain for elastic tissue. The original lumen is delineated by the internal elastic
lamina (arrows) and is totally filled with organized thrombus, now punctuated by a
number of small recanalized channels.

140.

Embolism
o

An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried

by the blood to a site distant from its point of origin.

emboli lodge in vessels too small to permit further passage, resulting in partial or
complete vascular occlusion

141.

PULMONARY THROMBOEMBOLISM
o

95% of instances, venous emboli originate from deep leg vein thrombi

Figure 4-17 Large embolus derived from a lower extremity deep venous thrombosis

142.
and now impacted in a pulmonary artery branch.

143.

144.

SYSTEMIC THROMBOEMBOLISM
o

emboli traveling within the arterial circulation.

Most (80%) arise from intracardiac mural thrombi,

two thirds of which are associated with left ventricular wall infarcts

The major sites for arteriolar embolization are:

1.lower extremities (75%)

2.brain (10%

FAT EMBOLISM
o

Microscopic fat globules may be found in the circulation after fractures of long bones
(which have fatty marrow) or, rarely, in the setting of soft tissue trauma and burns.

Fat embolism syndrome is characterized by pulmonary insufficiency, neurologic

symptoms, anemia, and thrombocytopenia .

145.
o

Figure 4-18 Bone marrow embolus in the pulmonary circulation. The cleared
vacuoles represent marrow fat that is now impacted in a distal vessel along with the
cellular hematopoietic precursors.

146.

AIR EMBOLISM
o

Gas bubbles within the circulation can obstruct vascular flow

enter the circulation during obstetric procedures or as a consequence of chest wall

injury.

in excess of 100 cc is required to have a clinical effect

147.
o

decompression sickness , occurs when individuals are exposed to sudden changes in

atmospheric pressure

i.e. Scuba and deep sea divers

-responsible for the painful condition

called the bends

-focal atelectasis or emphysema may appear, leading to respiratory distresschokes.

-more chronic form of decompression sickness - caisson disease (persistence of gas

emboli in the skeletal system )

148.

AMNIOTIC FLUID EMBOLISM

o

grave but fortunately uncommon complication of labor and the immediate

postpartum period

characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed

by seizures and coma.

underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal
circulation via a tear in the placental membranes or rupture of uterine veins.

149.

150.

The classic findings are therefore the presence in the pulmonary microcirculation of:

squamous cells shed from fetal skin,

lanugo hair,

fat from vernix caseosa,

mucin derived from the fetal respiratory or gastrointestinal tract.

Infarction
151.
o

An infarct is an area of ischemic necrosis caused by occlusion of either the arterial

supply or the venous drainage in a particular tissue.

Nearly 99% of all infarcts result from thrombotic or embolic events, and almost all
result from arterial occlusion.

152.
o

Infarcts are classified on the basis of their color (reflecting the amount of
hemorrhage) and the presence or absence of microbial infection

153.
o

Red (hemorrhagic) infarcts occur

with venous occlusions (such as in ovarian torsion);

in loose tissues (such as lung)

in tissues with dual circulations (e.g., lung and small intestine)

in tissues that were previously congested because of sluggish venous outflow

when flow is re-established to a site of previous arterial occlusion and necrosis (e.g.,
following fragmentation of an occlusive embolus or angioplasty of a thrombotic
lesion

154.
o

White (anemic) infarcts occur

with arterial occlusions in solid organs with end-arterial circulation (such as heart,
spleen, and kidney)

Solid tissues

Figure 4-19 Examples of infarcts. A , Hemorrhagic, roughly wedge-shaped pulmonary

155.
infarct. B , Sharply demarcated white infarct in the spleen.
156.
o

The dominant histologic characteristic of infarction is ischemic coagulative necrosis

most infarcts are ultimately replaced by scar tissue .

The brain is an exception to these generalizations; ischemic injury in the central

nervous system results in liquefactive necrosis

157.
o

Figure 4-20 Remote kidney infarct, now replaced by a large fibrotic cortical scar.

Septic infarctions may develop when embolization occurs by fragmentation of a

158.
bacterial vegetation from a heart valve or when microbes seed an area of necrotic
tissue.
159.

Clinical Correlations: Factors That Influence Development of an Infarct.

o

The consequences of a vascular occlusion can range from no or minimal effect, all
the way up to death of a tissue or even the individual.

160.

The major determinants include:

the nature of the vascular supply ;

the rate of development of the occlusion ;

the vulnerability of a given tissue to hypoxia ;

the blood oxygen content.

Shock

161.
o

Shock, or cardiovascular collapse , is the final common pathway for a number of

potentially lethal clinical events, including severe hemorrhage, extensive trauma or
burns, large myocardial infarction, massive pulmonary embolism, and microbial
sepsis

162.
o

gives rise to systemic hypoperfusion caused by reduction in:

1.cardiac output

2.the effective circulating blood volume.

The end results are hypotension , followed by impaired tissue perfusion and cellular
hypoxia.

163.
o

Table 4-3. Three Major Types of Shock

Type of Clinical Examples Principal Mechanisms

Shock

Cardiogenic

Myocardial infarction Failure of myocardial pump

owing to intrinsic myocardial

damage, extrinsic pressure,

or obstruction to outflow

Ventricular rupture

Arrhythmia

Cardiac tamponade

Pulmonary embolism

Hypovolemic

Hemorrhage Inadequate blood or plasma volume

Fluid loss, e.g., vomiting,

diarrhea, burns, or trauma

Septic

Overwhelming microbial Peripheral vasodilation and pooling of

infections blood; endothelial activation/injury;

leukocyte-induced damage; disseminated

intravascular coagulation; activation of cytokine

cascades

Endotoxic shock

Gram-positive septicemia

Fungal sepsis

Superantigens

Less commonly:

neurogenic shock -in the setting of anesthetic accident or spinal cord injury , owing

164.

to loss of vascular tone and peripheral pooling of blood.

o

Anaphylactic shock , initiated by a generalized IgE-mediated hypersensitivity

response, is associated with systemic vasodilation and increased vascular
permeability

165.

PATHOGENESIS OF SEPTIC SHOCK

o

25% to 50% mortality rate, ranks first among the causes of mortality in intensive
care units

results from spread and expansion of an initially localized infection (e.g., abscess,
peritonitis, pneumonia) into the bloodstream.

166.
o

Most cases of septic shock (approximately 70%) are caused by endotoxin-producing

gram-negative bacilli , hence the term endotoxic shock .

Endotoxins are bacterial wall lipopolysaccharides ( LPSs ) that are released when the
cell walls are degraded (e.g., in an inflammatory response

167.
o

Figure 4-21 Cytokine cascade in sepsis . After release of lipopolysaccharide (LPS)

from invading gram-negative microorganisms, there are successive waves of tumor
necrosis factor (TNF), interleukin-1 (IL-1), and IL-6 secretion.

168.
o

Figure 4-22 Effects of lipopolysaccharide (LPS) and secondarily induced effector

molecules. LPS initiates the cytokine cascade described in Figure 4-21 ; in addition,
LPS and the various factors can directly stimulate downstream cytokine production,
as indicated. Secondary effectors that become important include nitric oxide (NO)
and platelet-activating factor (PAF). At low levels, only local inflammatory effects are
seen. With moderate levels, more systemic events occur in addition to the local
vascular effects. At high concentrations, the syndrome of septic shock is seen. DIC,
disseminated intravascular coagulation; ARDS, adult respiratory distress syndrome.

169.
o

Finally, at higher levels of LPS, the syndrome of septic shock supervenes

the same cytokines and secondary mediators, now at high levels, result in:

Systemic vasodilation (hypotension)

Diminished myocardial contractility

Widespread endothelial injury and activation, causing systemic leukocyte

adhesion and pulmonary alveolar capillary damage ( acute respiratory
distress syndrome

Activation of the coagulation system, culminating in DIC

170.
o

hypoperfusion resulting from the combined effects of widespread vasodilation,

myocardial pump failure, and DIC induces multiorgan system failure affecting the
liver, kidneys, and central nervous system

171.

Clinical Course
o

The clinical manifestations depend on the precipitating insult.

In hypovolemic and cardiogenic shock , the patient presents with hypotension; a

weak, rapid pulse; tachypnea; and cool, clammy, cyanotic skin.

In septic shock , the skin may initially be warm and flushed because of peripheral
vasodilation.

172.
o

END

173.

NEOPLASIA http://crisbertcualteros.page.tl

174.

Definitions
o

Neoplasia literally means the process of "new growth,"

Oncology (Greek oncos = tumor) is the study of tumors or neoplasms.

Cancer is the common term for all malignant tumors.

A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is

175.
uncoordinated with that of the normal tissues and persists in the same excessive
manner after cessation of the stimuli which evoked the change."
176.

Nomenclature

177.

All tumors, benign and malignant, have two basic components:

proliferating neoplastic cells that constitute their parenchyma

supportive stroma made up of connective tissue and blood vessels.

The nomenclature of tumors is, however, based on the parenchymal component.

Benign Tumors

-In general, benign tumors are designated by attaching the suffix - oma to the cell of
origin. Tumors of mesenchymal cells generally follow this rule. i.e. fibroma,
chondroma, osteoma.

nomenclature of benign epithelial tumors is more complex. They are variously

178.
classified based on:
o

their cells of origin

on microscopic architecture

on their macroscopic patterns.

Figure 7-1 Papilloma of the colon with finger-like projections into the lumen.

Figure 7-2 Colonic polyp. A, This benign glandular tumor (adenoma) is projecting

179.

180.
into the colonic lumen and is attached to the mucosa by a distinct stalk. B, Gross
appearance of several colonic polyps.
181.
o

Malignant Tumors

- Malignant tumors arising in mesenchymal tissue are usually called sarcomas

(Greek sar = fleshy) because they have little connective tissue stroma and so are
fleshy e.g., fibrosarcoma, liposarcoma, leiomyosarcoma and rhabdomyosarcoma

Malignant neoplasms of epithelial cell origin, derived from any of the three germ

182.
layers, are called carcinomas .
183.
o

divergent differentiation of a single line of parenchymal cells into another tissue

creates what are called mixed tumors . The best example of this is the mixed tumor
of salivary gland origin.

184.
o

Figure 7-3 This mixed tumor of the parotid gland contains epithelial cells forming
ducts and myxoid stroma that resembles cartilage. (Courtesy of Dr. Trace Worrell,
University of Texas Southwestern Medical School, Dallas, TX.)

185.
o

The great majority of neoplasms, even mixed tumors, are composed of cells
representative of a single germ layer. Teratomas , in contrast, are made up of a

variety of parenchymal cell types representative of more than one germ layer,
usually all three.
186.
o

Figure 7-4 A, Gross appearance of an opened cystic teratoma of the ovary. Note the
presence of hair, sebaceous material, and tooth.

187.
o

B, A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and
a tract of neural tissue ( arrow ).

188.
o

choristoma - an ectopic rest of normal tissue

i.e. a rest of adrenal cells under the kidney capsule

Hamartoma - aberrant differentiation may produce a mass of disorganized but

mature specialized cells or tissue indigenous to the particular site.

i.e. a hamartoma in the lung may contain islands of cartilage, blood vessels,
bronchial-type structures, and lymphoid tissue.

189.

Biology of Tumor Growth: Benign and Malignant Neoplasms

190.

191.

The natural history of most malignant tumors can be divided into four phases:

malignant change in the target cell, referred to as transformation ;

growth of the transformed cells;

local invasion ;

distant metastases .

DIFFERENTIATION AND ANAPLASIA

o

Differentiation -refers to the extent to which neoplastic cells resemble comparable

normal cells, both morphologically and functionally

anaplasia -lack of differentiation

Well-differentiated tumors are composed of cells resembling the mature normal cells

192.
of the tissue of origin of the neoplasm
193.
o

Figure 7-5 Leiomyoma of the uterus. This benign, well-differentiated tumor contains
interlacing bundles of neoplastic smooth muscle cells that are virtually identical in
appearance to normal smooth muscle cells in the myometrium.

194.
o
195.

In general, benign tumors are well differentiated

Figure 7-6 Benign tumor (adenoma) of the thyroid. Note the normal-looking (welldifferentiated), colloid-filled thyroid follicles.

196.
o

Malignant neoplasms, in contrast, range from well differentiated to undifferentiated.

Malignant neoplasms composed of undifferentiated cells are said to be anaplastic.

Lack of differentiation, or anaplasia , is considered a hallmark of malignant

transformation.

197.
o

Figure 7-7 Malignant tumor (adenocarcinoma) of the colon. Note that compared with
the well-formed and normal-looking glands characteristic of a benign tumor (see Fig.
7-6), the cancerous glands are irregular in shape and size and do not resemble the
normal colonic glands. This tumor is considered differentiated because gland
formation can be seen. The malignant glands have invaded the muscular layer of
the colon.

198.

Lack of differentiation, or anaplasia, is marked by a number of morphologic changes:

o

Pleomorphism. Both the cells and the nuclei characteristically display pleomorphism
-variation in size and shape ( Fig. 7-8 ).

199.
o

Figure 7-8 Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the
marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant
cells.

200.
o

Abnormal nuclear morphology. The nuclei contain an abundance of DNA and are
extremely dark staining ( hyperchromatic ). The nucleus-to-cytoplasm ratio may
approach 1:1 instead of the normal 1:4 or 1:6. The chromatin is often coarsely
clumped and distributed along the nuclear membrane. Large nucleoli are usually
present.

201.
o

Mitoses. Large numbers of mitoses, reflecting the higher proliferative activity of the
parenchymal cells. More important as a morphologic feature of malignant neoplasia
are atypical, bizarre mitotic figures , sometimes producing tripolar, quadripolar, or
multipolar spindles

202.
o

Figure 7-9 Anaplastic tumor showing cellular and nuclear variation in size and shape.
The prominent cell in the center field has an abnormal tripolar spindle.

203.
o

Loss of polarity. The orientation of anaplastic cells is markedly disturbed (i.e., they
lose normal polarity).

o
204.

-grow in an anarchic, disorganized fashion.

Other changes. Formation of tumor giant cells.

Figure 7-10 Well-differentiated squamous cell carcinoma of the skin. The tumor cells

205.
are strikingly similar to normal squamous epithelial cells, with intercellular bridges
and nests of keratin pearls ( arrow ).
206.
o

dysplasia, literally means disordered growth. Encountered principally in epithelia,

and it is characterized by:

loss in the uniformity of the individual cells

loss in their architectural orientation.

exhibit pleomorphism

contain hyperchromatic nuclei.

Mitotic figures are more abundant

When dysplastic changes are marked and involve the entire thickness of the

207.
epithelium, but the lesion remains confined to the normal tissue, it is considered a
preinvasive neoplasm and is referred to as carcinoma in situ ( Fig. 7-11 ). Once the
tumor cells move beyond the normal confines, the tumor is said to be invasive .
208.
o

Figure 7-11 A, Carcinoma in situ. This low-power view shows that the entire
thickness of the epithelium is replaced by atypical dysplastic cells. There is no
orderly differentiation of squamous cells. The basement membrane is intact and
there is no tumor in the subepithelial stroma. B, A high-power view of another region
shows failure of normal differentiation, marked nuclear and cellular pleomorphism,
and numerous mitotic figures extending toward the surface. The basement
membrane ( below ) is not seen in this section.

209.

RATES OF GROWTH
o

How long does it take to produce a clinically overt tumor mass? The original
transformed cell (approximately 10 m in diameter) must undergo at least 30
population doublings to produce 109 cells (weighing approximately 1 gm ), which is
the smallest clinically detectable mass. 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

210.
o

Figure 7-12 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.
211.
o

The rate of growth of a tumor is determined by three main factors:

1.The doubling time of tumor cells

2. The fraction of tumor cells that are in the replicative pool

3.The rate at which cells are shed and lost in the growing lesion.

Figure 7-13 Schematic representation of tumor growth. As the cell population

212.
expands, a progressively higher percentage of tumor cells leaves the replicative
pool by reversion to G0, differentiation, and death.
213.
o

the progressive growth of tumors and the rate at which they grow are determined by
an excess of cell production over cell loss .

214.

215.

Factors that may affect their growth:

1.hormonal stimulation

2.adequacy of blood supply

3.unknown influences

CANCER STEM CELLS AND CANCER CELL LINEAGES

o

A clinically detectable tumor contains a heterogeneous population of cells, which

originated from the clonal growth of the progeny of a single cell- stem cells

216.

initiate and sustain the tumor.

Ex. T-IC(tumor initiating cells)

LOCAL INVASION
o

Nearly all benign tumors:

grow as cohesive expansile masses that remain localized to their site of origin

do not have the capacity to infiltrate, invade, or metastasize to distant sites

They grow and expand slowly, they usually develop a rim of compressed connective
tissue, called a fibrous capsule, which separates them from the host tissue.

217.
o

Figure 7-14 Fibroadenoma of the breast. The tan-colored, encapsulated small tumor
is sharply demarcated from the whiter breast tissue.

218.
o

Figure 7-15 Microscopic view of fibroadenoma of the breast seen in Figure 7-14 . The
fibrous capsule ( right ) delimits the tumor from the surrounding tissue.

219.
o

The growth of cancers is accompanied by:

progressive infiltration

Invasion

destruction of the surrounding tissue

poorly demarcated from the surrounding normal tissue

a well-defined cleavage plane is lacking

Figure 7-16 Cut section of an invasive ductal carcinoma of the breast. The lesion is

220.
retracted, infiltrating the surrounding breast substance, and would be stony hard on
palpation.
221.
222.
o

Figure 7-17 The microscopic view of the breast carcinoma seen in Figure 7-16
illustrates the invasion of breast stroma and fat by nests and cords of tumor cells
(compare with fibroadenoma shown in Fig. 7-15 ). The absence of a well-defined
capsule should be noted.

223.
224.
o

Next to the development of metastases , invasiveness is the most reliable feature

that differentiates malignant from benign tumors.

225.

METASTASIS
o

are tumor implants discontinuous with the primary tumor.

unequivocally marks a tumor as malignant because benign neoplasms do not

metastasize.

The invasiveness of cancers permits them to penetrate into blood vessels,

lymphatics, and body cavities, providing the opportunity for spread.

226.
o

With few exceptions, all cancers can metastasize. The major exceptions are:

most malignant neoplasms of the glial cells in the central nervous system, called
gliomas

o
227.

basal cell carcinomas of the skin.

In general, the more aggressive , the more rapidly growing , and the larger the
primary neoplasm, the greater the likelihood that it will metastasize or already has
metastasized.

228.
o

Approximately 30% of newly diagnosed patients with solid tumors (excluding skin
cancers other than melanomas) present with metastases.

229.
o

Pathways of Spread

-Dissemination of cancers may occur

through one of three pathways:

1. Seeding of Body Cavities and Surfaces. May occur whenever a malignant

neoplasm penetrates into a natural "open field." Most often involved is
the peritoneal cavity ( Fig. 7-18 ), but any other cavity-pleural, pericardial,
subarachnoid, and joint space-may be affected.

230.
o

Figure 7-18 Colon carcinoma invading pericolonic adipose tissue.

2. Lymphatic Spread. Transport through lymphatics is the most common pathway for

231.
the initial dissemination of carcinomas ( Fig. 7-19 ), and sarcomas may also use this
route. The pattern of lymph node involvement follows the natural routes of
lymphatic drainage.
232.
o

Figure 7-19 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.

233.
o

3. Hematogenous Spread. Hematogenous spread is typical of sarcomas but is also

seen with carcinomas. Arteries, with their thicker walls, are less readily penetrated
than are veins.

-Understandably the liver and lungs are most frequently involved secondarily in
such hematogenous dissemination

234.
o

Figure 7-20 A liver studded with metastatic cancer.

Figure 7-21 Microscopic view of liver metastasis. A pancreatic adenocarcinoma has

235.
formed a metastatic nodule in the liver.
236.
o

Certain cancers have a propensity for invasion of veins.

Ex. Renal cell carcinoma,

Hepatocellular carcinomas

- Histologic evidence of penetration of small vessels at the site of the primary

neoplasm is obviously an ominous feature.

237.
o

The distinguishing features of benign and malignant tumors discussed in this

overview are summarized in Table 7-2 (see p. 281) and Figure 7-22 .

238.
o

Figure 7-22 Comparison between a benign tumor of the myometrium (leiomyoma)

and a malignant tumor of similar origin (leiomyosarcoma).

239.

Epidemiology
o

Study of cancer patterns in populations, can contribute substantially to knowledge

about the origins of cancer.

major insights into the cause of cancer can be obtained by epidemiologic studies
that relate particular environmental, hereditary, and cultural influences to the
occurrence of malignant neoplasms.

240.
o

Figure 7-23 Cancer incidence and mortality by site and sex. Excludes basal cell and
squamous cell skin cancers and in situ carcinomas, except urinary bladder. (Adapted
from Jemal A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5, 2003.)

241.
o

Figure 7-24 Age-adjusted cancer death rates for selected sites in the United States,
adjusted for the 2000 U.S. population. (Adapted from Jemal A, et al: Cancer
statistics, 2003. CA Cancer J Clin 53:5, 2003.)

242.
o

overall age-adjusted cancer death rate has significantly increased in men, whereas
it has fallen slightly in women.

o
243.

Striking is the alarming increase in deaths from carcinoma of the lung in both sexes .

GEOGRAPHIC AND ENVIRONMENTAL FACTORS

o

death rate for stomach carcinoma in both men and women is seven to eight times
higher in Japan than in the United States

the death rate from carcinoma of the lung is slightly more than twice as great in the
United States as in Japan.

Skin cancer deaths, largely caused by melanomas, are six times more frequent in
New Zealand than in Iceland, which is probably attributable to differences in sun
exposure.

most of these geographic differences are the consequence of environmental

influences.

244.

There is no paucity of environmental factors: they are found in the ambient

environment, in the workplace, in food, and in personal practices

examples of occupational hazards, and many others are listed in Table 7-3

most overweight individuals in the U.S. population have a 52% (men) and 62%
(women) higher death rate from cancer than do their slimmer counterparts.

245.
o

Alcohol abuse alone increases the risk of carcinomas of the oropharynx (excluding
lip), larynx, and esophagus and, through the intermediation of alcoholic cirrhosis,
carcinoma of the liver.

Smoking, particularly of cigarettes, has been implicated in cancer of the mouth,

pharynx, larynx, esophagus, pancreas, and bladder -single most important
environmental factor contributing to premature death in the United States

246.
o

It begins to appear that almost everything one does to gain a livelihood or for
pleasure is fattening, immoral, illegal, or, even worse, oncogenic.

247.

AGE
o

Most carcinomas occur in the later years of life ( 55 years). Cancer is the main
cause of death among women aged 40 to 79 and among men aged 60 to 79.

o
248.

Please see Tables 7-4 and 7-5 pp.286-287

GENETIC PREDISPOSITION TO CANCER

o

"My mother and father both died of cancer. Does that mean I am doomed to
get it?"

249.
o

Less than 10% of cancer patients have inherited mutations that predispose to
cancer, and the frequency is even lower (around 0.1%) for certain types of tumors.

250.
o

Genetic predisposition to cancer can be divided into three categories ( Table 7-6 )

Autosomal Dominant Inherited Cancer Syndromes.

Defective DNA Repair Syndromes.

Familial Cancers.

Autosomal Dominant Inherited Cancer Syndromes- include several well-defined

251.
cancers in which inheritance of a single mutant gene greatly increases the risk of
developing a tumor.
o

-The inherited mutation is usually a point mutation occurring in a single allele of a

tumor suppressor gene.

-Childhood retinoblastoma is the most striking example

Defective DNA Repair Syndromes

- characterized by defects in DNA repair and resultant DNA instability.

- These conditions generally have an autosomal recessive pattern of inheritance.

Familial Cancers- occur at higher frequency in certain families without a clearly

252.

253.
defined pattern of transmission.
o

- Features that characterize familial cancers include early age at onset, tumors
arising in two or more close relatives of the index case, and sometimes, multiple or
bilateral tumors .

254.

NONHEREDITARY PREDISPOSING CONDITIONS

o

The only certain way of avoiding cancer is not to be born; to live is to incur the risk.

Because cell replication is involved in neoplastic transformation, regenerative,

hyperplastic, and dysplastic proliferations are fertile soil for the origin of a malignant
tumor.

255.
o

Chronic Inflammation and Cancer- --

- Virchow proposed that cancer develops at sites of chronic inflammation

- Chronic inflammatory reactions may result in the production of cytokines, which

stimulate the growth of transformed cells.

- exemplified by the increased risk of cancer development in patients affected by a

variety of chronic inflammatory diseases of the gastrointestinal tract.

256.
o

2. Precancerous Conditions- the chronic atrophic gastritis of pernicious anemia, solar

keratosis of the skin, chronic ulcerative colitis, and leukoplakia of the oral cavity,
vulva, and penis- have such a well-defined association with cancer

-Is there not a risk with all benign neoplasms? Although some risk may be inherent,
a large cumulative experience indicates that most benign neoplasms do not become
cancerous.

257.

Carcinogenic Agents and Their Cellular Interactions

o

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.

258.

CHEMICAL CARCINOGENESIS

we owe largely to Sir Percival Pott our awareness of the potential carcinogenicity of
chemical agents.

increased incidence of scrotal skin cancer in chimney sweeps to chronic exposure to

soot.

259.

Steps Involved in Chemical Carcinogenesis

o

the stages of initiation and progression during cancer development have been
described

the classic experiments that allowed the distinction between initiation and
promotion were performed on mouse skin and are outlined in Figure 7-48 .

260.
o

Figure 7-48 Experiments demonstrating the initiation and promotion phases of

carcinogenesis in mice. Group 2: application of promoter repeated at twice-weekly
intervals for several months. Group 3: application of promoter delayed for several
months and then applied twice weekly. Group 6: promoter applied at monthly
intervals.

261.
o

The following concepts relating to the initiation-promotion sequence:

-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)

- 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.

- 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).

-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.

262.
o

Figure 7-49 General schema of events in chemical carcinogenesis. Note that

promoters cause clonal expansion of the initiated cell, thus producing a
preneoplastic clone. Further proliferation induced by the promoter or other factors
causes accumulation of additional mutations and emergence of a malignant tumor.

263.

Initiation of Chemical Carcinogenesis

They fall into one of two categories: (1) direct-acting compounds , which do not
require chemical transformation for their carcinogenicity, and (2) indirect-acting
compounds or procarcinogens , which require metabolic conversion in vivo to
produce ultimate carcinogens capable of transforming cells. ( Table 7-11 ).

264.
o

have one property in common: They are highly reactive electrophiles (have electrondeficient atoms) that can react with nucleophilic (electron-rich) sites in the cell.

265.
o

Metabolic Activation of Carcinogens- most chemical carcinogens require metabolic

activation for conversion into ultimate carcinogens ( Fig. 7-49 ).

-the carcinogenic potency of a chemical is determined by the balance between

metabolic activation and inactivation reactions.

-Most of the known carcinogens are metabolized by cytochrome P-450-dependent

mono-oxygenases.

266.
o

Molecular Targets of Chemical Carcinogens -malignant transformation results from

mutations that affect oncogenes, tumor suppressor genes, genes that regulate
apoptosis, and genes involved in DNA repair

-the majority of initiating chemicals are mutagenic- investigated, most commonly

using the Ames test- uses the ability of a chemical to induce mutations in the
bacterium Salmonella typhimurium.

267.
o

most but not all chemicals that are mutagenic in vitro are carcinogenic in vivo

That DNA is the primary target for chemical carcinogens seems fairly well
established

It should be emphasized that carcinogen-induced changes in DNA do not necessarily

lead to initiation because most types of DNA damage can be repaired by cellular
enzymes.

268.
o

Initiated Cell- unrepaired alterations in the DNA are essential first steps in the
process of initiation. For the change to be heritable, the damaged DNA template
must be replicated. Thus, for initiation to occur, carcinogen-altered cells must
undergo at least one cycle of proliferation so that the change in DNA becomes fixed
or permanent.

-cell proliferation may be induced by concurrent exposure to biologic agents such as

viruses and parasites, dietary factors, or hormonal influences.

269.

Promotion of Chemical Carcinogenesis

o

Application of promoters leads to proliferation and clonal expansion of initiated

(mutated) cells

Forced to proliferate, the initiated clone of cells suffers additional mutations,

developing eventually into a malignant tumor

270.

Carcinogenic Chemicals
o

Direct-Acting Alkylating Agents- are activation independent and are weak

carcinogens. Nonetheless, they are important because many are therapeutic agents
(e.g., cyclophosphamide , chlorambucil , busulfan , and melphalan ) These are used
as anticancer drugs but have been documented to induce lymphoid neoplasms,
leukemia, and other forms of cancer.

271.
o

Polycyclic Aromatic Hydrocarbons- represent some of the most potent carcinogens

known

-require metabolic activation and can induce tumors in a wide variety of tissues and
species.

Ex. Painted on the skin, they cause skin cancers;

injected subcutaneously, they induce sarcomas;

-The polycyclic hydrocarbons are of particular interest as carcinogens because they

are produced in the combustion of tobacco, particularly with cigarette smoking, and
are thought to contribute to the causation of lung and bladder cancers

272.
o

Aromatic Amines and Azo Dyes- The carcinogenicity of most aromatic amines and
azo dyes is exerted mainly in the liver, where the "ultimate carcinogen"
is formed by the action of the cytochrome P-450 oxygenase systems.

-Thus, fed to rats, acetylaminofluorene and the azo dyes induce hepatocellular
carcinomas

273.
o

Naturally Occurring Carcinogens- the potent hepatic carcinogen aflatoxin B1 is

particularly important.

-This mycotoxin is produced by some strains of the fungus Aspergillus flavus that
thrive on improperly stored corn, rice, and peanuts.

274.
o

Nitrosamines and Amides- possibility that they are formed in the gastrointestinal
tract of humans and so may contribute to the induction of gastric carcinoma. They
are derived in the stomach from the reaction of nitrostable amines and nitrate used
as a preservative, which is converted to nitrites by bacteria.

275.
o

Miscellaneous Agents - asbestos has been associated with bronchogenic

carcinomas, mesotheliomas, and gastrointestinal cancers

-cigarette smoking heightens the risk of bronchogenic carcinoma

276.

RADIATION CARCINOGENESIS
o

Radiant energy, whether in the form of the UV rays of sunlight or as ionizing

electromagnetic and particulate radiation, can transform virtually all cell types in
vitro and induce neoplasms in vivo in both humans and experimental animals.

277.

Ex. UV light is clearly implicated in the

causation of skin cancers

Ultraviolet Rays
o

UV rays derived from the sun induce an increased incidence of squamous cell
carcinoma, basal cell carcinoma, and possibly malignant melanoma of the skin

UVB (280 to 320 nm) is believed to be responsible for the induction of cutaneous
cancers.

UVC (200 to 280 nm) , although a potent mutagen, is not considered significant
because it is filtered out by the ozone shield around the earth (hence the concern
about ozone depletion).

278.
o

The carcinogenicity of UVB light is attributed to its formation of pyrimidine dimers in

DNA. This type of DNA damage is repaired by the nucleotide excision repair (NER)
pathway.

The molecular basis of the degenerative changes in sun-exposed skin and

occurrence of cutaneous tumors rests on an inherited inability to repair UV-induced
DNA damage

o
279.

UVB also causes mutations in oncogenes and tumor suppressor genes.

Ionizing Radiation
o

Electromagnetic (x-rays, rays) and particulate ( particles, particles, protons,

neutrons) radiations are all carcinogenic.

Ex . skin cancers, lung cancers

radiant energy-whether absorbed in the pleasant form of sunlight, through the best

280.
intentions of a physician, or by tragic exposure to an atomic bomb blast or radiation
released by nuclear plant accidents-has awesome carcinogenic potential.
o

Even therapeutic irradiation has been documented to be carcinogenic.

hierarchy of vulnerability of different tissues to radiation-induced cancers: 1.

281.
leukemias, except for chronic lymphocytic leukemia. 2. Cancer of the thyroid but
only in the young. 3. cancers of the breast 4. lungs and 5. salivary glands.
o

-skin, bone, and the gastrointestinal tract are relatively resistant to radiationinduced neoplasia

-the physician dare not forget: practically any cell can be transformed into a cancer
cell by sufficient exposure to radiant energy.

282.

MICROBIAL CARCINOGENESIS
o

I. Oncogenic DNA Viruses

Of the various human DNA viruses, four are of particular interest because they have
been implicated in the causation of human cancer:

1. papillomaviruses [HPV], 2. Epstein-Barr virus [EBV], 3. hepatitis B virus [HBV], and

4. Kaposi sarcoma herpesvirus [KSHV])

Although not a DNA virus, hepatitis C virus (HCV) is also associated with cancer.

general comments relating to transformation by DNA viruses:

---The genomes of oncogenic DNA viruses integrate into and form stable

283.

associations with the host cell genome.

o

---Those viral genes that are transcribed early in the viral life cycle (early genes) are
important for transformation, and are expressed in transformed cells.

284.
o

Human Papillomavirus- Some types (e.g., 1, 2, 4, and 7) cause benign squamous

papillomas (warts) in humans. -have been implicated in the genesis of several
cancers, particularly squamous cell carcinoma of the cervix and anogenital region,
and in some cases, to the causation of oral and laryngeal cancers

285.
o

carcinoma of the cervix is caused by a sexually transmitted agent, and HPV is the
culprit. DNA sequences of HPV 16 and 18 and, less commonly, HPV 31, 33, 35, and
51 are found in approximately 85% of invasive squamous cell cancers and their
presumed precursors (severe dysplasias and carcinoma in situ).

286.
o

genital warts with low malignant potential are associated with distinct HPV types,
predominantly HPV 6 and HPV 11 ("low-risk" types).

287.
o

In benign warts and in preneoplastic lesions, the HPV genome is maintained in an

episomal (nonintegrated) form, whereas in cancers, the viral DNA is usually
integrated into the host cell genome.

integration of viral DNA is important in malignant transformation.

the pattern of integration is clonal; that is, the site of integration is identical within
all cells of a given cancer.

288.
o

infection with HPV acts as an initiating event and that additional somatic mutations
are essential for malignant transformation.

The occurrence of such changes is facilitated by cigarette smoking, coexisting

microbial infections, dietary deficiencies, and hormonal changes, all of which have
been implicated as cofactors in the pathogenesis of cervical cancers.

289.
o

Epstein-Barr Virus . EBV, a member of the herpes family, has been implicated in the
pathogenesis of four types of human tumors:

1. the African form of Burkitt lymphoma;

2. B-cell lymphomas in immunosuppressed individuals (particularly in those with

human immunodeficiency virus infection and those undergoing immunosuppressive
therapy after organ transplantation);

3. Hodgkin lymphoma; and

4. nasopharyngeal carcinomas

EBV infects epithelial cells of the oropharynx and B lymphocytes. It gains entry into

290.
B cells via the CD21 molecule, which is expressed on all B cells.
o

The infection of B cells is latent; that is, there is no replication of the virus and the
cells are not killed, but the latently infected B cells are immortalized and acquire the
ability to propagate indefinitely in vitro.

291.
o

several viral genes collaborate to render B cells immortal.

Burkitt lymphoma is a neoplasm of B lymphocytes that is the most common

childhood tumor in Central Africa and New Guinea. The association between African
Burkitt lymphoma and EBV is quite strong:

292.

-More than 90% of African tumors carry the EBV

genome.

-One hundred percent of the patients have elevated

antibody titers against viral capsid antigens.

-Serum antibody titers against viral capsid antigens

are correlated with the risk of developing the tumor.

several other observations suggest that additional factors must also be involved:
o

1) EBV infection is not limited to the geographic locales where Burkitt lymphoma is
found. EBV is a ubiquitous virus.

2) EBV is known to cause infectious mononucleosis

3) The EBV genome is found in only 15% to 20% of cases of Burkitt lymphoma
outside Africa, but both the endemic (African) and the sporadic cases of Burkitt

lymphoma have a t(8;14) or, less commonly, variant translocations that lead to
dysregulated expression of the c- MYC oncogene.
o

4) Although EBV infection immortalizes B cells in vitro, these cells do not form
tumors when injected into immunosuppressed mice in vivo.

(5) There are significant differences in the patterns of viral gene expression in EBVtransformed (but not tumorigenic) B-cell lines and Burkitt lymphoma cells.

293.
o

It appears, therefore, that EBV serves as one factor in the multistep development of
Burkitt lymphoma

EBV is not directly oncogenic, but by acting as a polyclonal B-cell mitogen, it sets
the stage for the acquisition of the t(8;14) translocation and other mutations, which
ultimately release the cells from normal growth regulation.

294.
o

The role played by the host immune response in controlling EBV-transformed B cells
is illustrated dramatically by the occurrence of B-cell lymphomas in
immunosuppressed patients (acquired immunodeficiency syndrome (AIDS) and
those who receive long-term immunosuppressive therapy)

295.
o

Nasopharyngeal carcinoma is the other tumor associated with EBV infection. This
endemic in Southern China

100% of nasopharyngeal carcinomas obtained from all parts of the world contain
EBV DNA.

The viral integration in the host cells is clonal

Hepatitis B Virus. Close association between HBV infection and the occurrence of

296.
liver cancer
o

-HBV is endemic in countries of the Far East and Africa; correspondingly, these areas
have the highest incidence of hepatocellular carcinoma.

297.
o

the precise role of HBV in the causation of human liver cancer is not clear.

the viral DNA is integrated into the host cell genome and, as with HPV, the tumors
are clonal with respect to these insertions.

298.
o

Although not a DNA virus, hepatitis C virus (HCV) is also strongly linked to the
pathogenesis of hepatocellular carcinoma.

The role of this virus in the pathogenesis of liver cancer seems to be related to its
ability to cause chronic liver cell injury and inflammation that is accompanied by
liver regeneration. Mitotically active hepatocytes, surrounded by an altered
environment, are presumably prone to genetic instability and cancer development.

299.
o

II. Oncogenic RNA Viruses

-only one human retrovirus, human T-cell leukemia virus type 1 (HTLV-1), is firmly
implicated in the causation of cancer.

300.
o

Human T-Cell Leukemia Virus Type 1. HTLV-1 is associated with a form of T-cell
leukemia/lymphoma

-endemic in certain parts of Japan and the Caribbean

-Similar to the AIDS virus, HTLV-1 has tropism for

CD4+ T cells- is the major target for neoplastic

transformation.

-requires transmission of infected T cells via sexual

intercourse, blood products, or breast-feeding.

-Leukemia develops in only 3% to 5% of the infected

individuals after a long latent period of 40 to 60 years.

-is also associated with tropical spastic paraparesis- a

demyelinating neurologic disorder

the secrets of its transforming activity are locked in the TAX gene- the product of

301.
this gene is essential for viral replication because it stimulates transcription of viral
mRNA by acting on the 5' LTR.
o

-the TAX protein can also activate the transcription of several host cell genes
involved in proliferation and differentiation of T cells

302.
o

main steps may be summarized as follows:

1. Infection by HTLV-1 causes the expansion of a nonmalignant polyclonal cell

population through stimulatory effects of TAX on cell proliferation.

2. The proliferating T cells are at increased risk of mutations and genomic instability
induced by TAX.

3. Eventually a monoclonal neoplastic T-cell population emerges from clonally

expanding nonmalignant cells.

303.

4. The malignant cells replicate independent of IL-2 and

contain molecular and chromosomal abnormalities.

Helicobacter pylori

causation of gastric carcinomas and gastric lymphomas.

present in 90% of patients with chronic gastritis

in 20% to 30% of cases the infection leads to gastric ulcers

The disease-causing strains contain a "pathogenicity island" containing

the CagA ( c ytotoxin a ssociated g ene A ) gene and a secretory system, which
injects the CagA protein into the host cells.

304.
o

The infection is associated with gastric adenocarcinomas of the intestinal type

through a sequence that involves: chronic gastritis multifocal atrophy with lower
gastric acid secretion intestinal metaplasia dysplasia carcinoma

305.
o

Gastric lymphomas arise in mucosa-associated lymphoid tissue (MALT)

The B cells that give rise to these tumors normally reside in the marginal zones of
lymphoid follicles

chronic infection with H. pylori leads to formation of lymphoid infiltrates in which B

cells actively proliferate and may acquire genetic abnormalities, such as a t(11;18)
translocation.

306.

GRADING AND STAGING OF TUMORS

o

developed to express, at least in semiquantitative terms, the level of differentiation,

or grade, and extent of spread of a cancer within the patient, or stage, as
parameters of the clinical gravity of the disease.

307.
o

Grading of a cancer is based on the degree of differentiation of the tumor cells and
the number of mitoses within the tumor as presumed correlates of the neoplasm's
aggressiveness.

classified as grades I to IV with increasing anaplasia

the correlation between histologic appearance and biologic behavior is less than
perfect.

308.
o

In general, with a few exceptions, such as soft tissue sarcomas, grading of cancers
has proved of less clinical value than has staging.

309.
o

The staging of cancers is based on the size of the primary lesion, its extent of
spread to regional lymph nodes, and the presence or absence of blood-borne
metastases.

310.
o

Two major staging systems:

TNM system - T for primary tumor, N for regional lymph node involvement, and M for
metastases.

-Use by the Union Internationale Contre

Cancer (UICC)

2. American Joint Committee (AJC) Cancer Staging system- divides all cancers into
stages 0 to IV, incorporating within each of these stages the size of the primary
lesion as well as the presence of nodal spread and distant metastases

311.
o

staging of neoplastic disease has assumed great importance in the selection of the
best form of therapy for the patient.

It bears repeating that staging has proved to be of greater clinical value than
grading.

312.

LABORATORY DIAGNOSIS OF CANCER

o

Every year the approach to laboratory diagnosis of cancer becomes more complex,
more sophisticated, and more specialized.

313.
o

Histologic and Cytologic Methods.

- The laboratory diagnosis of cancer is, in most instances, not difficult.

- The two ends of the benign-malignant spectrum pose no problems; however, in the
middle lies a gray zone where one should tread cautiously.

- The focus here is on the roles of the clinician

(often a surgeon) and the pathologist in

facilitating the correct diagnosis.

Clinical data are invaluable for optimal pathologic diagnosis, but often clinicians

314.
tend to underestimate the value of the clinical data.
o

The laboratory evaluation of a lesion can be only as good as the specimen made
available for examination.

It must be adequate, representative, and properly preserved.

Several sampling approaches are available: (1) excision or biopsy,

(2) needle aspiration, and

(3) cytologic smears.

315.

316.

Excision or biopsy- Appropriate preservation of the specimen is obvious, yet it

involves such actions as prompt immersion in a usual fixative (commonly formalin
solution)

quick-frozen section - is sometimes desirable, for example, in determining the

nature of a mass lesion or in evaluating the margins of an excised cancer. This
permits histologic evaluation within minutes. In experienced, competent hands, it is
highly accurate,

317.
o

Fine-needle aspiration of tumors -involves aspirating cells and attendant fluid with a
small-bore needle, followed by cytologic examination of the stained smear.

- used most commonly for the assessment of readily palpable lesions in sites such
as the breast, thyroid, and lymph nodes.

- is less invasive and more rapidly performed than are needle biopsies. In
experienced hands, it is an extremely reliable, rapid, and useful technique.

318.
o

Cytologic (Pap) smears- This approach is widely used for the discovery of carcinoma
of the cervix, often at an in situ stage

- also used with many other forms of suspected malignancy, such as endometrial
carcinoma, bronchogenic carcinoma, bladder and prostatic tumors, and gastric
carcinomas; for the identification of tumor cells in abdominal, pleural, joint, and
cerebrospinal fluids

319.
o

Cytologic (Pap) smears- shed cells can be evaluated for the features of anaplasia
indicative of their origin in a cancer ( Figs. 7-54 and 7-55 )

judgment here must be rendered based on the features of individual cells or, at
most, a clump of a few cells, without the supporting evidence of architectural
disarray, loss of orientation of one cell to another, and (perhaps most important)
evidence of invasion.

320.
o

Cytologic (Pap) smears- permits differentiation among normal, dysplastic, and

cancerous cells and in addition permits the recognition of cellular changes
characteristic of carcinoma in situ.

321.
o

Figure 7-54 A normal cervicovaginal smear shows large, flattened squamous cells
and groups of metaplastic cells; interspersed are some neutrophils. There are no
malignant cells. (Courtesy of Dr. P.K. Gupta, University of Pennsylvania, Philadelphia,
PA.)

322.
o

Figure 7-55 An abnormal cervicovaginal smear shows numerous malignant cells that
have pleomorphic, hyperchromatic nuclei; interspersed are some normal

polymorphonuclear leukocytes. (Courtesy of Dr. P.K. Gupta, University of

Pennsylvania, Philadelphia, PA.)

323.
o

Immunohistochemistry. The availability of specific monoclonal antibodies has greatly

facilitated the identification of cell products or surface markers.

324.
o

Immunohistochemistry. Examples of the utility of immunohistochemistry in the

diagnosis or management of malignant neoplasms:

Categorization of undifferentiated malignant tumors.

-malignant tumors of diverse origin resemble each other because of poor

differentiation

Example: the presence of cytokeratins, detected by immunohistochemistry, points

to an epithelial origin (carcinoma) ( Fig. 7-56 ), whereas desmin is specific for
neoplasms of muscle cell origin

325.
o

Figure 7-56 Anticytokeratin immunoperoxidase stain of a tumor of epithelial origin

(carcinoma). (Courtesy of Dr. Melissa Upton, University of Washington, Seattle, WA.)

326.
o

Immunohistochemistry.

2. Categorization of leukemias and lymphomas.

3. Determination of site of origin of metastatic tumors.

- detection of tissue-specific or organ-specific antigens in a biopsy specimen of the

metastatic deposit can lead to the identification of the tumor source.

-Example: prostate-specific antigen and thyroglobulin are markers of tumors of the

prostate and thyroid, respectively.

327.
o

Immunohistochemistry.

4. Detection of molecules that have prognostic or therapeutic significance.

- detection of hormone (estrogen/progesterone) receptors in breast cancer cells is of

prognostic and therapeutic value because these cancers are susceptible to
antiestrogen therapy.

- receptor-positive breast cancers have a better prognosis.

- Breast cancers with overexpression of ERBB2 protein generally have a poor

prognosis

328.
o

Molecular Diagnosis.

Diagnosis of malignant neoplasms

- useful in differentiating benign (polyclonal) proliferations of T or B cells from

malignant (monoclonal) proliferations.

- by routine cytogenetic analysis, FISH

technique

- Detection of specific translocations that

activate oncogenes, Ex. PCR (CML- detects

BCR-ABL transcripts)

2. Prognosis of malignant neoplasms: allows stratification of patients for therapy.

-Ex. Amplification of the N -MYC gene and deletions of 1p- bode poorly for patients

329.

with neuroblastoma. (detected by routine cytogenetics, FISH or PCR assays.

330.
o

3. Detection of minimal residual disease: After treatment of patients with leukemia

or lymphoma, the presence of minimal disease or the onset of relapse can be
monitored by PCR-based amplification of unique nucleic acid sequences generated
by the translocation.

-Ex. detection of BCR-ABL transcripts by PCR gives a measure of the residual

leukemia cells in treated patients with chronic myeloid leukemia.

331.
o

4. Diagnosis of hereditary predisposition to cancer: germ line mutations in several

tumor suppressor genes, including BRCA1 , BRCA2 , and the RET protooncogene, are
associated with a high risk of developing specific cancers.

- ethical issues are involved

(presymptomatic diagnosis)

5. DNA microarray analysis and proteomics: - used to obtain gene expression

332.
signatures (molecular profiles) of cancer cells using gene chip technology
o

-has identified new subtypes with potential prognostic significance among breast
cancers, acute lymphoblastic leukemias, and gliomas

o
333.

- has identified new tumor markers for human malignancies

Flow Cytometry. Can rapidly and quantitatively measure several individual cell
characteristics, such as membrane antigens and the DNA content of tumor cells.

-Identification of cell-surface antigens by flow cytometry is widely used in the

classification of leukemias and lymphomas.

-Flow cytometric detection of ploidy is applied

Ex. Aneuploidy- associated with poorer

prognosis in early-stage breast cancer, carcinoma of

the urinary bladder, lung cancer, colorectal cancer,

and prostate cancer.

Tumor Markers. - are biochemical indicators of the presence of a tumor.

- includes cell-surface antigens, cytoplasmic proteins, enzymes, and hormones.

334.

( Table 7-13 )
o

-Their main utility in clinical medicine has been

as a laboratory test to support the diagnosis.

- Some tumor markers are also of value in determining the response to therapy

Tumor Markers

Ex. CEA, normally produced in embryonic tissue of the gut, pancreas, and liver, is a

335.

complex glycoprotein that is elaborated by many different neoplasms.

o

- positive in 60% to 90% of colorectal, 50% to 80% of pancreatic, and 25% to 50% of
gastric and breast carcinomas.

- have some bearing on prognosis because the level of elevation is correlated with
body burden of tumor.

336.
o

Tumor Markers

AFP is a well-established tumor marker

- This is synthesized normally early in fetal life by the yolk sac, fetal liver, and fetal
gastrointestinal tract.

- Abnormal plasma elevations are encountered in adults with cancer arising

principally in the liver and germ cells of the testis.

-marked elevations of the plasma AFP level have proved to be a useful indicator of
hepatocellular carcinomas and germ cell tumors of the testis.

337.

Tumor Markers

Other widely used markers include:

- PSA and PSMA (prostate-specific antigen and prostate-specific membrane antigen)prostate cancers

338.

- human chorionic gonadotropin- testicular tumors

- CA125- ovarian tumors.

Molecular Basis of Cancer

o

fundamental principles before going into the details of the molecular

basis of cancer:

Nonlethal genetic damage lies at the heart of carcinogenesis. Such genetic damage
(or mutation) may be acquired by the action of environmental agents, such as
chemicals, radiation, or viruses, or it may be inherited in the germ line.

A tumor is formed by the clonal expansion of a single precursor cell that has
incurred the genetic damage (i.e., tumors are monoclonal) . The most commonly
used method to determine tumor clonality involves the analysis of methylation
patterns adjacent to the highly polymorphic locus of the human androgen receptor
gene (HUMARA).

339.
o

Figure 7-26 Diagram depicting the use of X-linked isoenzyme cell markers as
evidence of the monoclonality of neoplasms. Because of random X inactivation, all
females are mosaics with two cell populations (with G6PD isoenzyme A or B in this
case). When neoplasms that arise in women who are heterozygous for X-linked
markers are analyzed, they are made up of cells that contain the active maternal
(XA) or the paternal (XB) X chromosome but not both.

340.
o

Four classes of normal regulatory genes- 1 .the growth-promoting protooncogenes,

2. the growth-inhibiting tumor suppressor genes, 3. genes that regulate
programmed cell death (apoptosis), and 4. genes involved in DNA repair- are the
principal targets of genetic damage.

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. A
disability in the DNA repair genes can predispose to mutations in the genome and
hence to neoplastic transformation. Such propensity to mutations is called a mutator
phenotype .

341.
o

Carcinogenesis is a multistep process at both the phenotypic and the genetic levels.
It has several phenotypic attributes, such as excessive growth, local invasiveness,
and the ability to form distant metastases. These characteristics are acquired in a

stepwise fashion, a phenomenon called tumor progression . At the molecular level,

progression results from accumulation of genetic lesions that in some instances are
favored by defects in DNA repair.
342.

THE NORMAL CELL CYCLE

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The orderly progression of cells through the various phases of cell cycle is
orchestrated by cyclins and cyclin-dependent kinases (CDKs), and by their inhibitors

cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or
more CDKs.

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Figure 7-28 Expression of cyclin-cyclin-dependent kinase (CDK) complexes during

the cell cycle. The phases of the cycle are indicated inside the arrows. (Modified
from Pollard TD, Earnshaw WC: Cell Biology. Philadelphia, WB Saunders, 2002.)

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Cyclin D and RB Phosphorylation.

Cyclin D, the first cyclin to increase in the cell cycle, appears in mid G1 but is no
longer detectable in the S phase

During the G1 phase of the cell cycle, cyclin D binds to and activates CDK4, forming
a cyclin D-CDK4 complex ( Fig. 7-29 )- has a critical role in the cell cycle by
phosphorylating the retinoblastoma susceptibility protein (RB)- is a molecular ONOFF switch for the cell cycle-eliminates the main barrier to cell-cycle progression
and promotes cell replication

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Figure 7-29 Schematic illustration of the role of cyclins, CDKs, and cyclin-dependent
kinase inhibitors in regulating the G1/S cell-cycle transition. External signals activate
multiple signal transduction pathways, including those involving the MYC and RAS
genes, which lead to synthesis and stabilization of cyclin D. Cyclin D binds to CDK4,
forming a complex with enzymatic activity. The cyclin D-CDK4 complex
phosphorylates RB, located in the E2F/DP1/RB complex in the nucleus, activating the
transcriptional activity of E2F, which leads to transcription of cyclin E, cyclin A and
other proteins needed for the cell to go through the late G1 restriction point. The cell
cycle can be blocked by the Cip/Kip inhibitors p21 and p27 ( red boxes ) and the
INK4A/ARF inhibitors p16INK4A and p14ARF ( green boxes ). Cell-cycle arrest in
response to DNA damage and other cellular stresses is mediated through p53. The
levels of p53 are under negative regulation by MDM2, through a feedback loop that
is inhibited by p14ARF.

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activation of cyclin D-CDK4 and cyclin E-CDK2 at the G1/S restriction point and
causing phosphorylation of RB. Hyperphosphorylated RB dissociates from the
complex, activating the transcription of E2F target genes that are essential for
progression through the S phase.

M phase- the phosphate groups are removed from RB by cellular phosphatases, thus
regenerating the hypophosphorylated form of RB.

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Cell-Cycle Progression Beyond the G1/S Restriction Point. Further progression

through the S phase and the initiation of DNA replication involve the formation of an
active complex between cyclin E and CDK2 (see Fig. 7-29 ).

Activated E2F increases the transcription of cyclin E and of polymerases needed for
DNA replication, thus stimulating DNA synthesis.

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The next decision point in the cell cycle is the G2/M transition- initiated by the E2Fmediated transcription of cyclin A, which forms the cyclin A-CDK2 complex that
regulates events at the mitotic prophase.

cyclin B-CDK1 complex- the main mediator that propels the cell beyond prophase
which is activated by a protein phosphatase (Cdc 25)

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Cyclin B-CDK1 activation causes the breakdown of the nuclear envelope and
initiates mitosis.

Exit from mitosis requires the inactivation of cyclin B-CDK1.

Newly divided cells can then return to G1 and initiate a new replicative cycle or go
into quiescence.

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Cell-Cycle Inhibitors. The activity of cyclin-CDK complexes is tightly regulated by

inhibitors, called CDK inhibitors

There are two main classes of CDK inhibitors: the Cip/Kip and the INK4/ARF families
(see Fig. 7-29 and Table 7-7 )

function as tumor suppressors and are frequently altered in tumors

The Cip/Kip family has three components, p21, p27, and p57 , which bind to and

351.
inactivate the complexes formed between cyclins and CDKs
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Transcriptional activation of p21 is under the control of p53 - a tumor suppressor

gene that is mutated in a large proportion of human cancers (main role is
surveillance, triggering checkpoint controls that slow down or stop cell-cycle
progression of damaged cells, or causes apoptosis)

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The human INK4a/ARF locus (a notation for " in hibitor of k inase 4 / a

lternative r eading f rame") encodes two proteins, p16INK4a and p14ARF,
which block the cell cycle and act as tumor suppressors.

p16INK4a competes with cyclin D for binding to CDK4 and inhibits the ability of the
cyclin D-CDK4 complex to phosphorylate RB, thus causing cell-cycle arrest at late
G1.

It is frequently mutated or inactivated by hypermethylation in human cancers.

both p16INK4a and p14ARF block the cell cycle, but their targets are different;

-p16INK4a acts on cyclin D-CDK4

-p14ARF prevents p53 degradation.

Figure 7-29 Schematic illustration of the role of cyclins, CDKs, and cyclin-dependent

353.

354.
kinase inhibitors in regulating the G1/S cell-cycle transition.
355.

356.

Cell-Cycle Checkpoints. The cell cycle has its own internal controls.

-two main checkpoints:

1. G1/S transition

2. G2/M.

I. G1/S transition
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S phase is the point of no return in the cell cycle, and before a cell makes the final
commitment to replicate, the G1/S checkpoint checks for DNA damage

If DNA damage is present, the DNA repair machinery and mechanisms that arrest
the cell cycle are put in motion.

if the damage is not repairable, apoptotic pathways are activated to kill the cell.

Thus, the G1/S checkpoint prevents the replication of cells that have defects in

357.
DNA , which would be perpetuated as mutations or chromosomal breaks in the
progeny of the cell.
358.

II. G2/M checkpoint

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The G2/M checkpoint monitors the completion of DNA replication and checks
whether the cell can safely initiate mitosis and separate sister chromatids.

important in cells exposed to ionizing radiation. Why? Cells damaged by ionizing

radiation activate the G2/M checkpoint and arrest in G2; -give rise to chromosomal
abnormalities.

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To function properly, cell-cycle checkpoints require sensors of:

1. DNA damage

2. signal transducers

3. effector molecules

Defect in cell-cycle checkpoint components is a major cause of genetic instability in

cancer cells .

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ESSENTIAL ALTERATIONS FOR MALIGNANT TRANSFORMATION

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seven fundamental changes in cell physiology that together determine malignant

phenotype- hallmarks of malignant cells:

1. Self-sufficiency in growth signals : ONCOGENES

-Tumors have the capacity to proliferate without external stimuli, usually as a

consequence of oncogene activation.

-Genes that promote autonomous cell growth in cancer cells are called oncogenes,
and their normal cellular counterparts are called protooncogenes.

-Protooncogenes are physiologic regulators of cell proliferation and differentiation

-oncogenes are characterized by the ability to promote cell growth in the absence of
normal mitogenic signals. (See Table 7-8)

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2. Insensitivity to growth-inhibitory signals :TUMOR SUPPRESSOR GENES

-The proteins that apply brakes to cell proliferation are the products of tumor
suppressor genes ( Table 7-9 )-physiologic function of these genes is to regulate cell
growth, not to prevent tumor formation.

-The growth of cells has to be controlled by many external signals to maintain a

steady state (homeostasis). Failure of growth inhibition is one of the fundamental
alterations in the process of carcinogenesis

- Tumors may not respond to molecules that are inhibitory to the proliferation of
normal cells such as transforming growth factor- (TGF-), and direct inhibitors of
cyclin-dependent kinases.

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3. Evasion of apoptosis :

-Tumors may be resistant to programmed cell death, as a consequence of

inactivation of p53 or other changes.

-cell survival is conditioned by genes that promote and inhibit apoptosis.

-accumulation of neoplastic cells may occur not only by the activation of oncogenes
or inactivation of tumor suppressor genes, but also by mutations in the genes that
regulate apoptosis

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363.

-ex. BCL-2 gene-protects cells from apoptosis by the mitochondrial pathway

4. Defects in DNA repair :

-Humans literally swim in a sea of environmental carcinogens.

- Although exposure to naturally occurring DNA-damaging agents, such as ionizing

radiation, sunlight, dietary carcinogens, and ROS generated by cell metabolism and
oxidative stress, is common, cancer is a relatively rare outcome. Y?- ability of normal
cells to repair DNA damage.

-Tumors may fail to repair DNA damage caused by carcinogens or unregulated

cellular proliferation.

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5. Limitless replicative potential : TELOMERASE

-Tumor cells have unrestricted proliferative capacity, associated with maintenance of

telomere length and function.

-after a fixed number of divisions, normal cells become arrested in a terminally

nondividing state known as replicative senescence .

-it has been noted that with each cell division there is some shortening of
specialized structures, called telomeres, at the ends of chromosomes.

-Once the telomeres are shortened beyond a certain point, the loss of telomere
function leads to activation of p53 -dependent cell-cycle checkpoints, causing
proliferative arrest or apoptosis

-telomere shortening is prevented by the sustained function of the enzyme

telomerase, thus explaining the ability of these cells to self-replicate extensively.

-telomerase activity has been detected in more than 90% of human tumors

6. Sustained angiogenesis :

-Tumors stimulate the growth of host blood vessels, a process called angiogenesis,

365.

which is essential for supplying nutrients to the tumor.

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-Tumors are not able to grow without formation of a vascular supply, which is
induced by various factors, the two most important: being 1. vascular endothelial
growth factor (VEGF) and 2. basic fibroblast growth factor (bFGF)- tumor-associated
angiogenic factors

-tumors cannot enlarge beyond 1 to 2 mm in diameter or thickness unless they are

vascularized.

-Angiogenesis is a requisite not only for continued tumor growth, but also for
metastasis

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7. Ability to invade and metastasize :

-Invasion and metastasis are biologic hallmarks of malignant tumors

-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.

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Figure 7-42 The metastatic cascade. Schematic illustration of the sequential steps
involved in the hematogenous spread of a tumor. Each step in this sequence is
subject to a multitude of influences; hence, at any point in the sequence the
breakaway cell may not survive

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Mutations in genes that regulate these cellular traits are seen in every cancer.

the precise genetic pathways that give rise to these attributes differ between
cancers, even within the same organ.

the occurrence of mutations in cancer-causing genes is conditioned by the

robustness of the DNA repair machinery of the cell.

When genes that normally sense and repair DNA damage are impaired or lost, the
resultant genomic instability favors mutations in genes that regulate the other
acquired capabilities of cancer cells.

The main principles of the molecular basis of cancer are summarized in simplified
form in Fig. 7-27 .

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Figure 7-27 Flow chart depicting a simplified scheme of the molecular basis of
cancer.

370.

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