Histopathology

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CHAPTER TWO
RESPONCE OF THE BODY TO INJRIOUS AGENTS

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2.1 RESPONSE OF THE BODY TO
INJURIOUS AGENTS
 Since pathology deals with disease, it is
appropriate to consider some of the ways
in which the body responds to injurious
agents (bacteria, viruses, trauma, etc.).
 Initially, the body employs one or more
of its natural defense mechanisms.

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These defenses include
Physical barriers (skin, mucous membranes,
etc.)
Detoxification (neutralization of toxin by
liver enzymes, etc.)
Adaptive compensation (increase in heart
size when it is overloaded, etc.)
Immunologic response (reaction of
antibodies with antigens, etc.)
Cellular response (movement of neutrophils
toward an injured site, etc.) and others.

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 The natural bodies defenses may completely
neutralize or destroy the injurious agent before
lesions and/or disease develop.
 However, once lesions and/or disease are
detected, it can be assumed that natural body
defenses were inadequate or at least delayed in
their response.
 As a result, an inflammatory response may
develop.

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 Mild injury causes stress on the cell but not cell
death.
 Such injury is known as reversible injury, such
cells develop structural or functional changes to
overcome injury known as adaptation.
 When injury is severe enough it causes death of
cell termed irreversible injury.
 Changes occurring in dead cells are known as
necrosis.

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 The term “Necrosis” is used to describe structural changes
occurring in dead cells within living tissue.
 For example when blood supply to heart is reduced heart
muscle suffer damage called "Ischemia" and presents as
severe pain and it recovers when blood supply is restored.
 But when blood is blocked for more than 10 min, then cells
in that part of heart die.
 When we start physical exercise our muscles sense the
excess workload and increase their size to avoid trauma this
is called "hypertrophy".
 When we stop using a muscle (e.g. after fracture) the muscle
cells become thin (atrophy).

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Cellular Adaptations
 Cells are the structural and functional units of
tissues and organs.
 They are capable of adjusting their structure
and functions in response to various
physiological and pathological conditions.
 This capability is called cellular adaptation

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Various Types of Adaptations
 Cells may undergo various adaptations in physiological
and pathological conditions.
 These are controlled by complex molecular mechanisms.
 The following are common types of cellular adaptation:
Atrophy
Hypertrophy
Hyperplasia
Metaplasia

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Atrophy
 Shrinkage of cells.
Classified as:
 Physiologic--due to decreased work load
(e.g., decreased size of uterus following
child birth).
 Pathologic--primarily due to denervation
of muscle, diminished blood supply,
nutritional deficiency, Aging, Pressure,etc.

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Hypertrophy
 Increase in the size of cells which results in
enlargement of the organs.
 It is mostly seen in cells that cannot divide,
such as skeletal muscle , and cardiac muscle
(hypertension).
 These changes usually revert to normal if the
cause is removed.

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Hyperplasia
 Increased number of cells in an organ or
tissue.
 Hyperplasia may sometimes co-exist with
hypertrophy.
Hyperplasia can be classified as:
 Physiologic--hormonal (e.g., breast and
uterus during pregnancy)
 Compensatory--regeneration of liver
following partial hepatectomy.
 Pathologic--excessive hormonal
stimulation in response to viral infection
(papilloma viruses); neoplasms

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.
Simple illustration to show the difference between hyperplasia and hypertrophy.

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Metaplasia
 Transformation or replacement of one adult
cell type to another adult cell type. E.g. the
change from columnar to squamous cells in
respiratory tract.
 Metaplastic changes usually result from
chronic irritation.
 Metaplastic changes seem to precede the
development of cancer, in some instances.

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Cell injury
 If the cells fail to adapt under stress, they
undergo certain changes called cell injury.
 Cell injury may be divided to
Reversible cell injury
Irreversible cell injury
 The affected cells may recover from the injury
(reversible) or may die (irreversible)

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Causes of Cell Injury
 Hypoxia(oxygen deprivation)
 Physical agents
 Chemical agents
 Biological /infections agents
 Immunologic reactions
 Genetic defects
 Nutritional imbalances

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1. HYPOXIA:
 Hypoxia refers to a lack of oxygen which is
probably the most common cause of cell
injury and disease.
 It may be the ultimate mechanism of
damage initiated by a variety of physical,
chemical and biological agents.

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HYPOXIA…cont’d
 (1) Loss of their blood supply (e.g.
ischemia subsequent to the presence of a
thrombus in the lumen of a vessel),
 (2) Depletion of the oxygen-carrying
capacity of the blood (e.g. carbon
monoxide poisoning)
 (3) Poisoning of the oxidative enzymes
within cells (e.g. cyanide poisoning in
which cytochrome oxidase is inactivated).

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2 PHYSICAL INJURIES:
 Physical agents responsible for cell/tissue
damage include trauma, pressure,
obstructions of hollow organs, malpositions,
thermal factors, changes in atmospheric
pressure, light, electricity and radiation.
2.1 MECHANICAL TRAUMA:
 Is usually an injury caused by sudden
violent physical forces in which cells/tissues
are torn or crushed.

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The types of trauma include:
 Contusion (bruise) refers to an injury in which
the covering skin is intact, but the underlying
tissues are damaged.
 Abrasion refers to an injury similar to a
contusion, but one in which the skin is broken.
 Incision refers to an injury produced by a
sharp object, resulting in little tissue damage.
 Laceration refers to an injury resulting from
the tearing of tissues with a blunt object.

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The types of trauma…cont’d
 Perforation refers to a wound in which the
point of entry of the mechanical force is small.
 Rupture refers to an injury in which tissues are
stretched until the fibers are disrupted (rupture
occurs in hollow organs or in the capsule of
such organs as the kidneys, liver and spleen or
in muscles and tendons).
 Fracture refers to a break in a hard substance
such as bone or cartilage.
 Luxation (dislocation) refers to an injury of an
articulation in which there is displacement of
bone making up the articulation.

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2.2 PRESSURE:
 Results in mild or less violent injuries which usually
take place over a prolonged period of time.
ulcers which occur over bony prominences of the
body (tuber coxae, zygomatic arch, etc.) of an
animal recumbent for several days is a classical
example of pressure injury.
 Also, pressure injury occurs when casts or bandages
are applied too tightly or when neoplasms,
abscesses, etc. encroach upon parenchymal organs.

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2.3 OBSTRUCTION OF HOLLOW ORGANS:
 Hollow organs may be obstructed and
subsequently injured by changes within the lumen
(rubber ball, etc.), pressure from outside the organ
(neoplasm, etc.) or by changes within the wall of
the organ (abscesses, neoplasm, etc.)
 The term "stenosis" refers to any narrowing of the
lumen of a hollow organ; whereas the term
"stricture" is reserved for a form of stenosis
caused by contraction of fibrous connective tissue
(scar tissue) in the wall of an organ.

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2.4 MALPOSITION:
 Refers to the displacement of an organ or part that results in
cell and/or tissue injury. The types of malpositions include
 Volvulus refers to the rotation of an organ or part around its
mesenteric base of attachment. Loops of intestine are
usually involved and the twist is usually more than 180
degrees.
 Torsion refers to the rotation of an organ or part along its
own long axis. The intestine, uterus, lung lobes, etc. may be
involved.
 Intussusception refers to the telescoping of one portion of a
hollow organ into another portion (e.g., a portion of the
intestine is forced inside the segment just posterior to it).
 Prolapse is the appearance of an organ or portion of an
organ at a natural or artificial body opening.

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2.5 THERMAL INJURIES
 Extremes of temperature, such as freezing and
burning, cause injury in several ways (direct
damage, vasconstriction, etc.).
 Burns refer to lesions produced directly by heat.
 Heat retention (heatstroke/sunstroke) occurs
when animals are unable to eliminate sufficient
heat to maintain body temperature at a level
compatible with life. Subsequently, cells and
tissues are injured.

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THERMAL INJURIES…cont’d
 Freezing of tissues occurs when the body is
exposed to very low temperatures.
 When tissues freeze, there is damage to blood
vessels, formation of thrombi and subsequent
interference with circulation.
 Thrombi -is the plural of thrombus.
 A thrombus, or blood clot, is the final product
of the blood coagulation step in hemostasis.

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2.6 LIGHT:
 Sunburn or overexposure to light is rare in animals due
to skin pigmentation and protection by the hair coat.
 Photosensitization with damage to the skin occurs as the
result of the action of sunlight on fluorescent pigments
(phylloerythrin, etc.) in the skin.
 Phylloerythrin is photodynamic substance produced in
the body, a derivative of chlorophyll.
 Normally, the phylloerythrin is secreted into the intestine
by the biliary system and get excreted.
 But due to failure or damage to biliary system,
phylloerythrin enters the systemic circulation and is
accumulated under the skin.

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2.7 ELECTRICITY
 Strong electrical currents from artificial sources
or from lightning cause burns or result in somatic
death.
 An animal produces a short circuit with his body
between two conductors.
 The effects of electricity include burning of
tissues, hemorrhages, and/or death due to
interference with cardiac and respiratory
functions.

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2.8 RADIATION:
 Injuries produced by ionizing radiation depend
upon the type of radiation (alpha, beta, gamma,
etc.) and the susceptibility of the cell or tissue
exposed.
 Rapidly growing cells (e.g., lymphoid cells)
are quite susceptible; whereas, more slow
growing cells (e.g., cells of bone) are more
resistant.

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3. CHEMICAL INJURIES:
 The list of chemical that may produce
cell/tissue injury challenge compilation.
 Simple chemicals such as glucose or salt in
hypertonic concentrations may cause cell
injury by deranging the fluid and electrolyte
homeostasis of cells; even oxygen in high
concentrations is severely toxic.

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CHEMICAL INJURIES…cont’d
 On the other hand, the levels of toxicity of certain
substances are so high that they are known as
poisons and trace amounts (arsenic, cyanide,
mercury salts) may destroy a sufficient number of
cells within minutes or hours to cause death.
 Under certain conditions, toxic materials may be
formed within the body and subsequently cause cell
damage.
 Severe burns, uremia, and gangrene may be
associated with endogenous poisons.

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4. BIOLOGICAL AGENTS
 Biological agents are important causes of
cell injury and death.
 They include
Bacteria,
Viruses,
Rickettsiae,
Fungi and
Parasites.

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5 .IMMUNOLOGIC REACTIONS:
 Immunological reactions maybe life-saving or
lethal.
 Some immune reactions may cause cell injury
and death (anaphylactic reaction to a foreign
protein or drug, etc.).
 Also, there is evidence that an immune
reaction against "self-antigens" (autoimmunity)
is the cause of certain diseases in animals.

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6. GENETIC DEFECTS
 Genetic defects are important causes of
cellular injury. E.g. Sickle cell disease
7. NUTRITIONAL IMBALANCES
 There may be deficiencies (e.g., in proteins or
specific vitamins), excesses (e.g., in lipids
causing atherosclerosis) or lack of an
appropriate balance.

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Cell Death-Irreversible injury
 Death of cells occurs in two ways:
 Necrosis--(irreversible injury) changes
produced by enzymatic digestion of dead
cellular elements
 Apoptosis--vital process that helps eliminate
unwanted cells--an internally programmed
series of events effected by dedicated gene
products

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Patterns of Necrosis In Tissues or Organs
 As a result of cell death the tissues or organs
display certain macroscopic changes:
 Coagulative necrosis: the outline of the dead
cells are maintained and the tissue is somewhat
firm. Example: Myocardial infarction.
 Liquifactive necrosis: the dead cells undergo
disintegration and affected tissue is liquified.
Example: cerebral infarction.

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Patterns of Necrosis…cont’d
 Caseous necrosis: a form of Coagulative
necrosis (cheese-like). Example: Tuberculosis
lesions.
 Fat necrosis: enzymatic digestion of fat.
Example: necrosis of fat by pancreatic
enzymes.
 Gangrenous necrosis: Necrosis (secondary to
ischemia) usually with superimposed infection.
Example: necrosis of distal limbs, usually foot
and toes in diabetes.

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AUTOLYSIS
 Lysis of tissues by their own enzymes, following
the death of the organism.
 Therefore, the key difference is that there is no
vital reaction (i.e., no inflammation).
 Autolysis is essentially rotting of the tissue.
 Early autolysis is indistinguishable from early
coagulative necrosis due to ischemia, unless the
latter is focal.

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APOPTOSIS
 This process helps to eliminate unwanted cells by an
internally programmed series of events effected by
dedicated gene products.
 Morphology of Apoptosis
 Shrinkage of cells
 Condensation of nuclear chormatin peripherally under nuclear
membrane
 Formation of apoptotic bodies by fragmentation of the cells and
nuclei. The fragments remain membrane-bound and contain cell
organelles with or without nuclear fragments.
 Phagocytosis of apoptotic bodies by adjacent healthy cells or
phagocytes.
 Unlike necrosis, apoptosis is not accompanied by inflammatory
reaction

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Mechanisms of Apoptosis
 Apoptosis can be induced by various
factors under both physiological and
pathological conditions.
 It is an energy-dependent cascade of
molecular events which include protein
cleavage by a group of enzymes, protein
cross-linking, DNA breakdown.

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Mechanisms of Apoptosis…cont’d
 Apoptosis goes through several complex
phases.
 To put it simply, abnormal mitochondrial
membrane permeability is a crucial event
which allows escape of cytochrome-c into the
cystosol which, in turn, activates proteolytic
enzymes leading to the execution of the
process.
 The final phase is the removal of dead cell
fragments by phagocytosis without
inflammatory reactions.

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Ageing
Cellular Aging
 Many cell functions decline, and morphologic
changes occur with aging.
 Ageing is thought to be influenced by an intrinsic
molecular program, called the "programmed
ageing hypothesis."
 It states that sequential shortening of telomeres
(the natural ends of chromosomes) may lead to
loss of genes, causing cellular ageing.
 Ageing is also thought to be influenced by
cumulative effects of various extrinsic factors.

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2.2 Inflammation
 Inflammation is "dynamic response of vascularized
tissues to injury".
 It is a complex multi step process of tissue response to
injury.
 The purpose of inflammation is to defend against
injurious agent and start healing & repair of injured tissue.
 Inflammation is an important part of body's defense
mechanisms.
 Inflammation brings together defense forces such as
WBC, antibodies and other chemicals apart from bringing
more nutrients and healing factors to the site of injury.

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An abscess on the skin, showing the redness and swelling
characteristic of inflammation.
Black rings of necrotic tissue surround central areas of pus

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 Inflammation is one of the primary host defense
mechanisms against all forms of tissue damage.
 It can best be defined as the "vascular and cellular
response of living tissue to injury."
 The "vascular response" is reflected by changes in the
size of blood vessels as well as by changes in the flow
rate of blood to the damaged tissue (arterioles and
capillaries dilate resulting in an increased blood
flow).
 The "cellular response" is reflected by the movement
of inflammatory cells (neutrophils, etc.) from the
lumen of blood vessels into the damaged tissue site.
(i.e., neutrophils attracted to the damaged tissue site
will attempt to ingest and destroy the injurious agent.)

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Inflammation…cont’d
 Thus, the inflammatory process serves to
dilute, neutralize, destroy or wall-off the
injurious agent as well as damaged
parenchymal cells.
 In other words, a complex series of events are
initiated which, as far as possible, heal and
reconstitute the damaged tissue.
 It should be remembered that inflammation
and repair of tissues occur together.

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Inflammation…cont’d
 Repair is the process by which dead cells are
replaced by viable cells.
 Sometimes repair is accomplished by
regeneration of native parenchymal cells.
 More often, however, it is accomplished by
the replacement of native parenchymal cells
by fibrous connective tissue.

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Inflammation…cont’d
 On the whole, inflammation and repair are
beneficial to the host.
 In their absence, infections would go unchecked,
burns would not heal, and wounds would remain
rotten open sores.
 However, under certain circumstances,
inflammation and repair may be harmful to the
body.
 Also, the inflammatory process and other body
defenses may not be effective in controlling an
infection and somatic death follows.

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Inflammation…cont’d
 Understand that although inflammation is a
protective defence mechanism, inflammation causes
pain and distress to the patient
 Excess inflammation or inflammation due to
abnormal immune reaction such as allergy can be
very destructive. Example Asthma is inflammation
of respiratory mucosa due to hypersensitivity
reaction.
 Inflamed tissue are named by adding suffix-itis to
anatomic site of involvement e.g. Appendicitis,
conjunctivitis, etc.

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Classification of inflammation
Inflammation can be acute or chronic
Acute Chronic
 Less tissue destruction Severe tissue destruction
 Mainly polymorphs Mainly mononuclear cells
 Less than a week or Many weeks, months, years
 Exudative Proliferative
 Self resolving Irreversible

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Inflammation…cont’d
 Traditional signs of acute inflammation (five
signs)
Swelling
Pain
Hotness
Redness and
Functional loss

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Some terms pertinent with inflammation:
 1. Exudates: are fluids, cells, or other cellular
substances that are slowly discharged from
blood vessels usually from inflamed tissues.
Serous exudate- more fluid (water), early or mild
damages
Fibrinous exudates – more protein, sever damage
(high molecular weight protein e.g. fibrinogen)
Purulent – more infiltrates, mainly polymorphs (pus
cells)
Hemorrhagic – severe vascular damages eg. anthrax

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 2. Transudate: are fluids that pass through a
membrane or squeeze through tissue or into the
extracellular space of tissues.
 Transudates are thin and watery and contain few
cells or proteins. [Specific Gravity (SG) < 1.015
transudate and > 1.020 exudate]
3. Abscess: Localized tissue destruction with pus.
Components of pus include: polymorphs (dead and
intact), Tissue debris and macrophages (dead &
intact)
 4. Empyema: Pus in preformed body space eg.
pleura, joints, G. bladder etc
 5. Fibrosis: Fibroblast proliferation depositing
variable amount of collagen and evolves to scar.

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Property
Transudate Exudate
 Appearance Clear Cloudy
 Total Protein (g/dl) < 3 >3
 Specific gravity <1.018 >1.018
 Cell count (/µl) < 10,000 >10,000
 Clot No Yes

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2.3 INTRODUCTION TO NEOPLASIA
 Neoplasm: (Literally: New growth)
 An abnormal tissue mass whose growth
exceeds and is uncoordinated with that of
adjacent normal tissue and persists after
cessation of the stimuli that provoked it.
Colectomy specimen
containing a malignant
neoplasm, namely an
invasive colorectal
carcinoma (reddish,
irregularly-shaped tumor)

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NEOPLASIA
Excessive Growth
Neoplastic Non-Neoplastic
Benign Malignant
(= Cancer)

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NEOPLASIA
 A neoplasm results from the derangement of
normal growth control mechanisms.
 In some manner, the balance between cell
division and cell death is upset.
 Hyperplasia can result as a reaction to
environmental influences such as chronic
inflammation,
 But a neoplasm's growth is partially or totally
independent of such external influences.

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BASIC TERMINOLOGY
 Tumor - A swelling; could be due to any number
of causes
 Neoplasia - A relatively autonomous growth of
tissue; the growth of which exceeds and is
uncoordinated with that of normal tissue and
persists in some manner after cessation of the
inducing stimulus.

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BASIC TERMINOLOGY…cont’d
 Benign Neoplasm
 A neoplasm that grows without invading
adjacent tissue or spreading to distant sites.
 It is usually fairly well-circumscribed due to
the lack of invasion of surrounding tissues.
 Malignant Neoplasm
 A neoplasm that invades the surrounding
normal tissue and usually spreads to distant
sites given sufficient time.

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Differentiation
 Differentiation (of a neoplasm) refers to the
extent to which the cells comprising the neoplasm
resemble comparable normal cells both
morphologically and functionally.
 The tissue type represented by the tumor.
 Well-differentiated tumors resemble the tissue of
origin while poorly differentiated tumors may
only be identifiable by the expression of cell
markers or by extremely focal and subtle
histologic and/or cytologic findings.

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Anaplasia
 Anaplasia Denotes a lack of differentiation
in a malignant neoplasm, making it difficult
to determine the tissue or cell of origin.
 1. Anaplasia is evidenced by wide variety
in size, shape, staining and organization of
malignant cells within a neoplasm
 2. Anaplasia is not a characteristic of
benign neoplasms

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Dysplasia
 The term "plasia" means growth.
 Dysplasia means disordered growth.
 Alterations in size, shape, staining
characteristics of cells and unusual proliferation
of cells characterized by nuclear enlargement
and failure of maturation and differentiation.

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Dysplasia… cont’d
 Dysplasia is recognized by alterations in the
appearance of cells (cytology).
 Dysplastic cells have some of the features of
malignant cells but the changes are less
pronounced.

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Reactive atypia
 State of being not typical.
 An abnormal cellular appearance and an
increased mitotic rate associated with a
reparative state due to environmental
influences such as inflammation.
 Reactive atypias are non-neoplastic.
 Once the environmental influence goes
away, the atypia disappears.

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Reactive atypia
 The atypia general involves enlargement
of both the cytoplasm and nucleus and an
increased prominence of nucleoli.
 These features reflect the increased
metabolic activity of the cells.
 Malignant criteria such as extremely
irregular nuclear membranes are absent.

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Carcinoma in situ (cis)
 Full-thickness dysplasia extending from the
basement membrane to the surface of the
epithelium.
 Applicable only to epithelial neoplasms.
 If the entire lesion is no more advanced than CIS,
then the risk of metastasis is zero.
 This is because there are no blood vessels or
lymphatics within the epithelium above the
basement membrane.

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Carcinoma in situ (cis)…cont’d
 Invasion: Growth into the surrounding
tissue by direct expansion.
 Metastasis: Spread of tumor to distant
sites by lymphatic or hematogenous
routes.

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Tumor Nomenclature
A. Basic Rule #1
1. Carcinoma- from epithelial tissue.
 Eg. Squamous cell carcinoma from skin
 Adenocarcinoma- epith of glands (most colon,
breast, lung tumors)
 common and deadly form of cancer
2. Sarcoma- from mesynchymal cells (bone,
muscle, fibroblasts)

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B. Basic Rule #2
 1.Benign: “-oma” eg. fibroma
 2. Malignant: “-carcinoma” or “-sarcoma”
eg. fibrosarcoma
Exceptions: eg. Lymphoma
(malignant lymphocytes)

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Classification of Tumors

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77. The next chapter 3 and 4 will be
your assignement
 You will prepare hard cope and soft cope for
presentation
 Document sub. Date will be 20/3/14/presentation
date will be 22/3/14
 Your first test will be 29/3/14
1. Histophatological technique
2. Handling of biopsy specimen
3. Compound of fixation
4. microtome
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