General

Pathology

Samuel Essien-Baidoo, PhD.

Course Objectives

By the end of the course, students should be able to:

1. explain the concept of pathology, the history and role of the discipline

2. describe the cellular basis of disease, cell adaptation, injury, and death

3. describe acute and chronic inflammatory processes

4. describe healing of wounds, fractures, and special tissues

5. explain the basic concept of immunology

6. state pathological processes in shock, embolism, infarction, and neoplasm

7. describe pathological processes in cardiac, renal, and liver failure

 Unit 1:

Introduction to
Pathology
What is Pathology?

• Pathology is the scientific study

(logos) of disease (pathos).

• It mainly focuses on the study

of the structural, biochemical
and functional changes in cells,
tissues and organs in disease.

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 FIELDS OF
PATHOLOGY
• General Pathology:
• This deals with all changes that occur in tissue. It
deals with the study of mechanism, basic reactions
of cells and tissues to abnormal stimuli and to
inherited defects.

• Systemic pathology:
• Deals with the pathologic manifestations in
various organs. This deals with the changes in
specific diseases/responses of specialized organs
and tissues.

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 • Forensic Pathology: This deals with medical-legal
autopsies and determine cause and manner of death
when an obvious medical cause is not evident,
particularly for deaths outside the hospital.

• Cellular pathology, includes histopathology (the study

of tissues) and cytopathology (study of separated cells).

Branches of • Chemical pathology or clinical biochemistry is the study

pathology of body chemistry, usually by assaying the level of
substances – electrolytes, enzymes, lipids, trace
elements – in the blood or urine.

• Anatomic Pathology: This deals with evaluation of

tissue, either as specimen taken at surgery or biopsy, or
autopsy due to medical deaths usually in a hospital and
with cytology specimens (PAP smears, or smears from
other procedures.
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 • An abnormal alteration in
structure or function of any
part of the body

DISEASE • A state in which an individual

exhibits an anatomical
physiological or biochemical
deviation from the normal

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 Disease process can be studied under following
aspects:

• Etiology
• The etiology of a disease is its cause. The causative factors of a disease can be
divided into two major categories: Genetic and acquired (e.g. infectious,
chemical, hypoxia, nutritional, physical). Most common diseases are
multifactorial due to combination of causes.

• Pathogenesis
• It refers to the sequence by which the causative factor(s) produces cellular,
biochemical and molecular abnormalities following the exposure of cells or
tissues to an injurious agent. Pathogenesis deals with sequence of events that
occur in the cells or tissues from the beginning of any disease process.

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 Disease study includes

MOLECULAR CELLULAR LEVEL TISSUE LEVEL ORGAN AND

LEVEL SYSTEM LEVEL

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 Gross examination

Light microscopy
Methods of
studying Immunohistochemistry
pathology
Electron microscopy

Molecular biology

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 • Signs: These are objective as perceived by the examiner.

MANIFESTATION OF • Symptoms: These are functional manifestations or

DISEASE evidences of disease processes

• Lesions: These are visible changes produced by a disease

in tissues or organs.

• Exacerbation: Increase in the severity of signs or

symptoms of a disease

• Remission: Decrease in intensity of the disease

• Complications: Unfavorable outcomes of a disease.

• Sequelae: These are remote consequences of a disease.

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 Causes and
classification of
Disease

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 • These are the sequence of events when the
limits of adaptive capability are exceeded,
or no adaptive response is possible.

• Depending on the nature of stimulus/injury,

the cellular responses can be mainly divided
Cell into four types:

Injury 1. Cellular adaptations

2. Cell injury
• Reversible cell injury
• Irreversible cell injury.
3. Intracellular accumulations
4. Pathologic calcification.

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 • Oxygen deprivation (hypoxia or ischemia)
• Physical Agents (trauma)
• Chemical agents and Drugs
Causes of • Infectious Agents
Cell Injury • Immunologic Reactions
• Genetic Derangements
• Nutritional Imbalances
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 Cellular response to injury depends on

• Nature of the injury

Mechanisms
of Cell Injury • Duration of the injury

• Severity of the injury.

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 The outcome of injury depend on
• Type of cell
Mechanisms • State of the cell
of Cell • Adaptability of the injured cell.
Injury • Cell injury results from different
biochemical mechanisms acting on
essential cellular components.

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 • Adaptations are reversible changes in the
number, size, phenotype, metabolic activity,
or functions of cells in response to changes
in their environment.
• Under normal conditions, cells must
constantly adapt to changes in their
CELLULAR environment (physiological, pathological).
ADAPTATION
1. Increase in the number of cells
(Hyperplasia).
2. Alterations in the size of cells
(Hypertrophy and atrophy).
3. Alteration in cellular differentiation
(metaplasia).
Hyperplasia
• Increase in the number of cells in an organ or tissue. (increase
rate of cellular division/ DNA synthesis)
• Hypertrophy and hyperplasia are closely related (exp : gravid
uterus)
• Physiologic or pathologic
• Physiologic – Two types
• Compensatory hyperplasia (exp: liver),
• Hormonal hyperplasia (exp: uterus, breast)
• Pathological – excessive and persistent hormonal or growth
factor stimulation
(exp: endometrial hyperplasia/BPH)
• Hyperplasia is important in wound healing (fibroblast and
blood vessels)
• Benign may lead to malignancy when it persist

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 Hypertrophy
• Increase the size of the cells and
consequently the size of the organs

• Increased the synthesis of structural

protein and organelles

• Can be physiologic (ex; increase workload

during exercise, uterine myometrium
during pregnancy)

• Pathologic (hypertrophy of myocardium –

hypertension/aortic valve disease)
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Uterine
hypertrophy
 Muscular
hypertrophy
 Atrophy
• Shrinkage of the size of the cells by the lost
of the cell's substance.
• Decrease proteins synthesis and increase
degradation
1. Decrease metabolic activity
2. Ubiquitin-proteasome pathway
• The entire tissue or organs diminishes in size
and function
• Atrophy also may be physiologic or
pathologic.
• Physiologic- Regression of embryonic
structures - notochord, loss of hormone
stimulation in menopause.
• Pathologic- denervation 24
 • Decreased workload e.g., atrophy of skeletal
muscle after immobilisation in POP

• Loss of innervation e.g., flaccid paralysis.

• Diminished blood supply e.g., cerebral atrophy
Causes in the elderly as a result of atherosclerotic
narrowing of cerebral vessels. (senile atrophy)

of • Inadequate nutrition e.g., chronic malnutrition

(marasmus).

atrophy • Loss of endocrine stimulation e.g., atrophy of

the breast and endometrium after menopause.

• Pressure atrophy. Compression of an organ by a

mass can lead to atrophy of that organ, probably
due to ischemia.
Metaplasia

• Is a reversible change in which one adult cell

type is replaced by another cell type.
• Adaptation of cells that sensitive to particular
stress to cell types better able to withstand
the adverse of environment
• Columnar to squamous metaplasia is
commonly seen and its as a result of chronic
irritation (e.g., pseudo stratified ciliated
columnar to squamous in chronic smoker)
• Persistent metaplasia may lead to malignancy
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27
The relationship
among normal,
adapted,
reversibly injured,
and dead
myocardial cells
Cell Injury.
• If the cells fail to adapt under
stress, they undergo certain
changes called cell injury.

• Injury may progress through a

reversible stage and culminate
in cell death
 Reversible and
irreversible cell injury
• The affected cells may recover
from the injury (reversible) or may
die (irreversible).

• Reversibility depends on the type,

severity and duration of injury.

• Cell death is the result of

irreversible injury
The hallmarks of reversible
injury are:
1. Reduced oxidative
phosphorylation

2. Adenosine triphosphate (ATP)

depletion
Reversible cell
3. Cellular swelling (hydropic injury
degeneration) caused by
changes in ion concentrations
and water influx.

4. Fatty change (Steatosis)-Excess

fat in a form of small or large
droplet
Reversible Injury -- Morphology

Light microscopic changes Ultrastructural changes

•Cell swelling (aka hydropic •Alterations of cell membrane

change) •Swelling of and small
•Increase in weight of the amorphous deposits in
organ mitochondria
•Pale appearance •Swelling of RER and
detachment of ribosomes
•Nuclear change
Irreversible cell injury

• “point of no return”
• Irreversible responses of cell injury refer to changes that lead to a new equilibrium
in the cellular environment.

• Types of irreversible responses include interruption of membrane integrity;

hydrolysis of phospholipids, proteins and nucleic acids; and necrosis, where
organelles undergo a sequence of changes.

• Persistent or excessive injury

• Characterized by:
§ Severe mitochondrial damage and nuclear dissolution
§ Loss of membrane permeability
 • Light microscopic changes
• Increased cytoplasmic eosinophilia (loss of
RNA, which is more basophilic)
• Cytoplasmic vacuolization
• Nuclear chromatin clumping
Irreversible • Ultrastructural changes
• Breaks in cellular and organellar membranes
Injury -- • Larger amorphous densities in mitochondria
• Nuclear changes
Morphology • Pyknosis
• Nuclear shrinkage and increased basophilia
• Karyorrhexis
• Fragmentation of the pyknotic nucleus
• Karyolysis
• Fading of basophilia of chromatin
 • Hypoxia is an extremely important and
common cause of cell injury and cell
death.
• Hypoxia is a deficiency of oxygen, which
causes cell injury by reducing aerobic
CAUSES OF oxidative respiration.
CELL
INJURY Causes of hypoxia
1. Reduced blood flow (called ischemia)
(O2 Deprivation)
2. Hypoxemia (pneumonia)
3. Carbon monoxide poisoning
4. Decreased oxygen-carrying capacity of
the blood (blood loss anemia)
Physical Physical agents capable of
causing cell injury include:
Agents 1. mechanical trauma
2. extremes of
temperature
3. radiation
 Chemical Agents and Drugs

• Poisons, such as arsenic, cyanide, or mercuric salts,

may destroy enough cells within minutes or hours to
cause death.

• Other potentially injurious substances such as air

pollutants, insecticides, and herbicides; industrial and
occupational hazards, such as carbon monoxide and
asbestos.

• Drugs, alcohol and the ever-increasing variety of

therapeutic drugs.
Infectious
Agents

•The viral,
protozoa,
bacteria,
fungi, and
parasites.
Immunologic Reactions

1.Autoimmunity

2.Hypersensitivity
Genetic
Derangements
Disease may result
from:
• abnormal
mutated genes or
• chromosomal
abnormalities.
Nutritional
Imbalances

•Nutritional Deficiencies
•Nutritional excesses
 • Aged cells become larger, less able
to divide and multiply

• Alterations in repair mechanism

AGING
• Less ability to respond to damage
or injury and may lead to death

• Lose their ability to functions, or

function abnormally
 • The cellular response to injurious stimuli
depends on the type of injury, its duration, and
its severity
• The consequences of cell injury depend on the
type, state, and adaptability of the injured cell.

Cell Injury – • Four very interrelated cell systems and

biochemical mechanism are particularly
General vulnerable to injury:
• Aerobic respiration involving
Mechanisms mitochondrial oxidative phosphorylation
and production of ATP and ROS
• The integrity of cell membranes, on which
the ionic and osmotic homeostasis of the
cell and its organelles depends
• Calcium homeostasis
• The integrity of the genetic apparatus of
the cell and protein synthesis.
 • ATP depletion
• Loss of calcium homeostasis
• Defects in membrane permeability
Cell Injury –
• Oxygen and oxygen-derived free
General radicals
Mechanisms • Mitochondrial damage
• Misfolded protein and DNA damage
 ATP DEPLETION

• Mitochondrial oxidative phosphorylation is disrupted first à

Decreased ATP à
• Decreased Na/K ATPase à gain of intracellular Na à cell swelling
• Decreased ATP-dependent Ca pumps à increased cytoplasmic Ca
concentration
• Altered metabolism à depletion of glycogen
• Lactic acid accumulation à decreased pH, chromatin clumping
• Detachment of ribosomes from RER à decreased protein synthesis
• End result is cytoskeletal disruption with loss of microvilli, bleb
formation, etc
 • Mitochondria can be damaged by
increases of cytosolic Ca2+, oxidative
stress, breakdown of phospholipids
through phospholipase A2 and
sphingomyelin pathways, and by lipid
breakdown products such as free fatty
acids and ceramide.
Mitochondrial
damage • There is formation of a high-
conductance channel, the so-called
mitochondrial permeability transition,
in the inner mitochondrial membrane

This is initially reversible but may

progress to irreversibility if injury
persist
• Membrane damage and loss of calcium
homeostasis are most crucial

• Gradients are modulated by membrane-

associated, energy-dependent
Ca2+,Mg2+ -ATPases

• Ca accumulation trigger many enzymatic CALCIUM

reaction i.e ATPase, Phospholipase,
endonucleases and proteases, HOMEOSTASIS
• Too much cytoplasmic calcium:
• Denatures proteins
• Poisons mitochondria
• Inhibits cellular enzymes
• Apoptosis is also activated
 DEFECTS IN MEMBRANE PERMEABILITY
• Early loss of selective membrane permeability leading ultimately to overt membrane damage
is a consistent feature of most forms of cell injury

• Ischaemia, ATP depletion, Bacteria toxin, lytic complement pathways, viral proteins and
numerous chemical and physical agent could cause this defect

• Biochemical Pathways that contributes to this damage include:

• Hypoxia - decrease phospholipids synthesis and increase phospholipid breakdown
• Increased Ca level (activates enzymes, mitochondrial permeability)
• Cytoskeletal abnormalities
• Reactive oxygen species
• Three main site:
• Mitochondria membrane damage
• Plasma membrane damage
• Lysosomal membrane damage
• Injured membranes are
leaky

• Enzymes and other Clinical

proteins that escape
through the leaky
Correlation
membranes make their
way to the bloodstream,
where they can be
measured in the serum
 ACCUMULATION OF OXYGEN-DERIVED
FREE RADICALS (REACTIVE OXYGEN SPECIES)
• Reduced reactive oxygen products are generated unavoidably in the process of energy generation when
oxygen is reduced to water
• Free radicals have an unpaired electron in their outer orbit
• Free radicals cause chain reactions
• An imbalance between free radical-generating and radicals scavenging systems results in cell injury seen in
many pathologic conditions.

• Five main causes:

• Absorption of radiant energy (e.g., ultraviolet light, xrays).
• Enzymatic metabolism of exogenous chemicals or drugs
• The reduction-oxidation reactions that occur during normal metabolic processes
• Transition metals such as iron and copper donate or accept free electrons during intracellular reactions
and catalyze free radical formation
• Nitric oxide (NO), an important chemical mediator generated by endothelial cells, macrophages, neurons
and other cell types can act as a free radical
• Inflammation
 Cellular mechanism of
dealing with free radicals
• Antioxidants either block the initiation of free radical formation or
inactivate (e.g., scavenge) free radicals and terminate radical damage
e.g., vit A,C, E and Glutathione

• Binding of Fe and Cu by transferrin, ferritin, lactoferrin, and

ceruloplasmin

• Enzymes which acts as free radical–scavenging systems and break

down hydrogen peroxide and superoxide anion e.g., Catalase,
superoxide dismutase, Glutathione Peroxidase
• Lipid peroxidation à
damage to cellular and
organellar membranes
Mechanism of
• Protein cross-linking and
fragmentation due to Free Radical
oxidative modification of Injury
amino acids and proteins

• DNA damage
• Normal proteins fold into 3
dimensional architecture

• Misfolded proteins get MISFOLDED

injured and die
PROTEIN AND
• DNA mutation due to DNA DAMAGE
exogenous reasons

• Cells die by apoptosis

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Types of Cell Death
• There are two types of cell death, necrosis and apoptosis, which
differ in their morphology, mechanisms, and roles in disease and
physiology

• Apoptosis
• Usually a regulated, controlled process
• Plays a role in embryogenesis
• Necrosis
• Always pathologic – the result of irreversible injury
• Numerous causes
Necrosis
Necrosis = Death / premature death of cells in
living tissue.

It occurs when there is severe damage to the cell

resulting in loss of membrane permeability

Lysosomal enzyme enter the cytoplasm and digest

the cells

There is leakage of cellular content to the

surrounding which result in inflammation
 • Early changes : morphologically normal
• Nuclear changes :
• Pyknosis
• Nuclear shrinkage and increased basophilia
• Karyorrhexis
• Fragmentation of the pyknotic nucleus
• Karyolysis
Morphology • Fading of basophilia of chromatin

of Necrosis
• Cytoplasmic changes :
• Necrotic cells show increased eosinophilia and decrease
basophilia
• Have a glassier homogeneous appearance than do normal
cells, mainly as a result of the loss of glycogen particles.
• The cytoplasm becomes vacuolated and appears moth-
eaten.
• Dead cells may be replaced by large, myelin figures.
• The dead cells may ultimately become calcified.
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Types of Necrosis
• There are four of five major
types:

1. Coagulative (most common)

2. Liquefactive
3. Caseous
4. Fat necrosis
5. Gangrenous necrosis
 Coagulative Necrosis

• Coagulative necrosis is a type of accidental

cell death typically caused by ischemia or
infarction.

• A localized area of coagulative necrosis is

called an infarct.

• E.g. Ischemic injury in any organ ( heart,

kidney, adrenal glands), except the brain

• Denaturation of protein albumin causes

coagulation
• In coagulative necrosis the architecture of
dead tissue is preserved for at least a couple
of days.
Liquefactive
necrosis
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 • Gross: Resembles cheese

• Micro: Amorphous, granular

eosinophilic material surrounded
by a rim of inflammatory cells with
a characteristic of a focus of
Caseous inflammation known as a
granuloma

Necrosis • No visible cell outlines – tissue

architecture is obliterated

• Usually seen in infections (esp.

mycobacterial and fungal
infections)
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 • Results from hydrolytic action of lipases on fat
• Most often seen in and around the pancreas (enzymatic
fat necrosis); can also be seen in other fatty areas of the
body (breast and other abdominal structures), usually due
to trauma(traumatic fat necrosis)

Fat • Lipases enzymes which break down triglycerides (lipid)

into fatty acids

Necrosis • Fatty acids then combine with Ca to form Calcium Soaps

(Saponification-soapy deposits in tissues)

• The necrotic tissue appears opaque and chalk white

• Histologically, one sees shadowy outlines of fat cells (like

coagulative necrosis), but with Ca++ deposits, foam cells,
and a surrounding inflammatory reaction
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 • Usually seen in the walls of blood
vessels (e.g., in vasculitis)

• Complexes of antigens and antibodies

Fibrinoid are deposited in the walls of arteries

Necrosis • Glassy, eosinophilic fibrin-like material

is deposited within the vascular walls

• Complexes together with the fibrin

produces bright pink and amorphous
appearance
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 Gangrenous Necrosis
(gangrene)
• Extensive tissue necrosis. Most often seen on
extremities, usually due to trauma or physical injury

• Divide into two; dry and wet

• Dry – occurs in extremities as a results of ischemic
coagulative necrosis due to arterial obstruction
• Wet – occurs in extremities and internal organ as a
results of liquefactive necrosis due to bacterial infection.
• Gas – necrotic tissue infected by clostridium perfringes
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 • 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 • Autolysis is essentially rotting of
the tissue.

• Early autolysis is indistinguishable

from early coagulative necrosis due
to ischemia, unless the latter is
focal.
Apoptosis
• Four main points
• Cells commit suicide
• Program cell death
• Activates certain enzymes
• Intact membrane
• 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

• Apoptotic cells break up into fragments, called apoptotic

bodies, which contain portions of the cytoplasm and
nucleus
• The plasma membrane of the apoptotic cell and bodies remains
intact, but its structure is altered in such a way that these become
“tasty” targets for phagocytes.

• The dead cell is rapidly cleared, before its contents have leaked
out, and therefore cell death by this pathway does not elicit an
inflammatory reaction in the host nor followed by calcification
 • Apoptosis occurs normally both during
development and throughout adulthood,
and serves to eliminate unwanted, aged
or potentially harmful cells.

CAUSES OF • It is also a pathologic event when diseased

cells become damaged beyond repair and
APOPTOSIS are eliminated.

• DNA damage
• Lack of hormones, cytokines, growth
factors
• Death receptors like FAS, TNFR1
Apoptosis in Physiologic Situations

• During development for removal of excess cells during

embryogenesis
• To maintain cell population in tissues with high turnover of cells,
such as skin.
• Hormone-dependent involution - Endometrium, prostate, breasts
etc.
• Elimination of potentially harmful self-reactive lymphocytes,
Cytotoxic T lymphocytes
• Elimination of cells that have served their useful purpose, such as
neutrophils
Apoptosis in Pathologic Situations

• To eliminate cells with DNA damage by radiation, cytotoxic agents,

hypoxia etc.
• To remove damaged cells by virus or immune response
• Cell death in tumours
• Accumulation of misfolded proteins
Apoptosis – Morphologic Features

• Cell shrinkage with increased cytoplasmic density

• Chromatin condensation
• Formation of cytoplasmic blebs and apoptotic bodies
• Content will contain cytoplasm, densely packed organelles and with or
without nuclear material
• Phagocytosis of apoptotic cells by adjacent healthy cells (microphages)
 • Three main features
• Protein cleavage
BIOCHEMICAL
FEATURES OF • DNA breakdown
APOPTOSIS
• Phagocytose recognition
 • When a cell is compelled to commit
suicide , proteins called caspases go
into action. They break down the
cellular components needed for survival
MECHANISM
• Two phases:
OF • Initiation
APOPTOSIS • Intrinsic (Mitochondrial)
Pathway
• Extrinsic ( Death Receptor)
Pathway
• Execution
INTRINSIC (MITOCHONDRIAL) PATHWAY
 INTRINSIC
(MITOCHONDRIAL)
PATHWAY
EXTRINSIC (DEATH RECEPTOR) PATHWAY
 Autophagy
• Autophagy is a process in which a cell
eats its own contents.
• It is a survival mechanism in times of
nutrient deprivation.

• In this process intracellular

organelles and portions of cytosol are
first sequestered from the cytoplasm
in an autophagic vacuole, which
subsequently fuses with lysosomes to
form an autophagolysosome, and the
cellular components are digested by
lysosomal enzymes
 Intracellular
Accumulations

Accumulation of abnormal
amounts of various substances
due to manifestations of
metabolic derangements in the
cell.
FOUR MAJOR PATHWAYS
• Inadequate removal of a normal
substance

• Accumulation of an abnormal
endogenous substance

• Failure to degrade a metabolite due

to inherited enzyme deficiencies.

• Deposition and accumulation of an

abnormal exogenous substance
PATHOLOGIC
CALCIFICATION
• Abnormal tissue deposition of calcium salt
together with small amount of iron,
magnesium, mineral salts
• Deposition of calcium salts in tissues other
than osteoid and enamels
• Two types (Type of tissue and serum calcium
level)
• Dystrophic
• Metastatic (Involve in intestitial cell of
gastric mucosa, kidney, systemic arteries,
pilmonary veins, lungs)
Dystrophic Calcification

Dead and degenerative tissues

•Past Injury or organ dysfunction

Typical example: Atheromas (fatty materials forms in

arteries)
•Intimal injury in the aorta and large arteries and characterized by
lipid accumulation
 • Binding of calcium to phospholipids on
vesicle membrane
• Phosphatase in phospholipid produce
PATHOGENESIS phophate
OF • Calcium-phospate binding leads to increase
PATHOLOGICAL concentration of its deposition on the
vesicle membrane
CALCIFICATION • Crystalline calcium phosphate
• Structural changes in calcium and phospate
gives microcrystal –Calcification.
METASTATIC CALCIFICATION

Excessive mobilation of calcium from bone

•Hyper-parathyroidism (Parathyroid adenoma, chronic renal failure,
parathyroid hyperplasia)
•Bony lesion (multiple myeoloma, Leukemia)
•Prolonged bed rest (disuse atrophy of the bone)

Excess absorption of Ca from the Intestine (Gut)

•Excess Vitamin D (Hypervitaminosis D)
•Milk Alkali Syndrome
•Hypercalcemia of infancy
MORPHOLOGY OF CALCIFICATION
• With H&E stains, calcification appears basophilic, amorphous or
granular or sometimes clumpsy
• Either intracellar or extracellular or both
• Psammoma Bodies – Grain of seed (Dystrophic, in certain tumors)
• E.g.
• Papillary carcinoma of the thyroid, papillary serous cyst
adenocarcinoma
• Somatostatinoma
• Meningioma (tumor of the meninges)