INTRODUCTORY

PATHOLOGY

NIGERIA INSTITUTE OF RADIOGRAPHY

POST GRADUATE ULTRASOUND

MODULE 1 LECTURE

EJA-EGWU UCHE N.

B.SC.(RADIOGRAPHY), PGC(CT), M.SC.(MEDICAL IMAGING), PGDIP(MRI),

JUNE, 2023
TOPICS

• CELL INJURY
• CELL DEATH
• CELLULAR ADAPTATION
• INFLAMMATION
• HEALING/REPAIR
• NEOPLASIA
PREAMBLE

• PATHOS (SUFFERING)
• LOGOS (STUDY)
• DEFINITION – INVOLVES STUDY OF
DISEASES -> CELLULAR ABNORMALITIES

• GENERAL
• SYSTEMIC
Four Aspects Of Every Disease:

• AETIOLOGY (CAUSE)
• PATHOGENESIS (INSIDIOUS
DEVELOPMENT)
• MORPHOLOGY (ABNORMAL
ANATOMY)
• CLINICAL EXPRESSION
(CONSEQUENCE)
AETIOLOGY
• MANY CAUSES BUT GROUP INTO GENETIC
(INHERITED) AND ACQUIRED
• CAUSE
VS
• RISK FACTORS – MAJOR OR MINOR
PATHOGENESIS
• SEQUENCE OF EVENTS FROM THE INITIAL
STIMULUS TO THE ULTIMATE EXPRESSION OF THE
DISEASE
• INCLUDE CELLULAR, BIOCHEMICAL AND
MOLECULAR EVENTS THAT FOLLOW EXPOSURE TO
INJURIOUS AGENT
MORPHOLOGY
• REFERS TO STRUCTURAL
ALTERATIONS IN CELLS (XTERISTIC
OF THE DISEASE OR DIAGNOSTIC OF
THE AGENT)
• ABNORMAL ANATOMY
• GROSS
• MICROSCOPIC
• MOLECULAR
• RADIOLOGIC
CLINICAL EXPRESSION
• END RESULTS OF FUNCTIONAL
ABNORMALITIES
• THAT LEAD TO CLINICAL
MANIFESTATION
• AND ITS PROGRESS (CLINICAL
COURSE AND OUTCOME)
• CLINICOPATHOLOGIC CORRELATIONS
ARE IMPORTANT IN THE STUDY OF A
DISEASE
“ALL DISEASES ARE THE RESULTS OF VISIBLE
CELL ABNORMALITIES”
FUNCTIONAL DEFINITION OF DISEASE

HOMEOSTASIS
• NORMAL CELL IS CONFINED TO NARROW RANGE OF
FUNCTION AND STRUCTURE
• DUE TO ITS GENETIC PROGRAMMES, METABOLISM,
DIFFERENTIATION AND SPECIALIZATION
• CONSTRAINTS OF NEIGHBOURING CELLS AND
AVAILABILITY OF METABOLIC SUBSTRATE
• YET ABLE TO HANDLE NORMAL PHYSIOLOGICAL
DEMANDS- MAINTAINING A STEADY STATE OF
HOMEOSTASIS
• REVERSIBLE CELL INJURY,
CELLULAR ADAPTATION AND CELL
DEATH ARE STAGES OF PROGRESSIVE
IMPAIRMENTS OF THE CELL NORMAL
FUNCTION AND STRUCTURE

• PHYSIOLOGICAL STRESS AND

PATHOLOGICAL STIMULI BRING
PHYSIOLOGICAL AND MORPHOLOGICAL
CELLULAR ADAPTATION
 CELL INJURY

• REVERSIBLE & IRREVERSIBLE INJURY

REVERSIBLE CHANGES:
HALLMARKS:
• REDUCED OXIDATION PHOSPHORYLATION
• DEPLETION IN ADENOSINE TRIPHOSPHATE
• CELLULAR SWELLING
IRREVERSIBLE CHANGES:
• DUE TO PERSISTENT DAMAGE
• THE CELL CANNOT RECOVER
• STRUCTURAL CHANGES SUCH AS AMORPHOUS
DENSITIES IN MITOCHONDRIA, LOSS OF
MEMBRANE PERMEABILITY
• IRREVERSIBLY INJURED CELLS UNDERGO
MORPHOLOGICAL CHANGES THAT ARE
RECOGNIZED AS CELL DEATH
MITOCHONDRIAL IRREVERSIBILITY
IRREVERSIBLE MEMBRANE DEFECTS
LYSOSOMAL DIGESTION
CAUSES OF CELL INJURY (REVERSIBLE)

OXYGEN DEPRIVATION:
• HYPOXIA INDUCES INJURY BY REDUCING
AEROBIC OXIDATION RESPIRATION
• ISCHAEMIA  LOSS OF BLOOD SUPPLY OR
REDUCED VENOUS DRAINAGE ON A TISSUE
COMPROMISES SUPPLY OF OXYGEN AND
METABOLISM
• INADEQUATE OXYGENATION DUE TO
CARDIORESPIRATORY FAILURE
• LOSS OF OXYGEN-CARRYING CAPACITY AS IN
ANAEMIA OR CARBON MONOXIDE POISONING
PHYSICAL AGENTS:
• MECHANICAL TRAUMA
• EXTREME TEMPERATURES
• SUDDEN CHANGES IN
ATMOSPHERIC PRESSURE
• RADIATION
• ELECTRIC SHOCK
CHEMICAL AGENTS:
• TOXIC CHEMICALS, E.G. SALT IN
HYPERTONIC CONC, CCL4
• POISONS SUCH AS MERCURIC SALT,
ARSENIC, CYANIDE
• AIR POLLUTANTS, INSECTICIDES,
HERBICIDES
• OCCUPATIONAL AND INDUSTRIAL
HAZARDS SUCH AS ASBESTOS
• DRUGS, E.G. TYLENOL, ALCOHOL,
THERAPEUTIC DRUGS -> DOSE
RELATIONSHIP
INFECTIOUS AGENTS:
• RANGE FROM SUBMICROSCOPIC VIRUSES TO TAPEWORMS
• IN BETWEEN ARE RICKETTSIAE, BACTERIA, FUNGI AND
HIGHER PARASITES
• INFECTIOUS AGENTS CAN ENTER HOST CELLS AND
DIRECTLY CAUSE CELL DEATH (CYTOLYSIS)
• PATHOGENS CAN RELEASE ENDOTOXINS OR EXOTOXINS
THAT KILL CELLS AT A DISTANCE
• RELEASE ENZYMES THAT DEGRADE TISSUE COMPONENTS,
OR DAMAGE BLOOD VESSELS AND CAUSE ISCHEMIC INJURY
• PATHOGENS CAN INDUCE HOST CELL RESPONSES THAT MAY
CAUSE ADDITIONAL TISSUE DAMAGE, USUALLY BY
IMMUNE-MEDIATED MECHANISMS
IMMUNOLOGICAL REACTIONS:
• ALTHOUGH THE IMMUNE SYSTEM SERVES
AS ESSENTIAL FUNCTION IN DEFENSE
AGAINST INFECTIONS, IMMUNE
REACTIONS CAUSE CELL INJURY
• E.G. ANAPHYLACTIC REACTION TO DRUG
OR FOREIGN PROTEIN
• REACTIONS TO ENDOGENOUS SELF
ANTIGENS IS BASIS OF AUTOIMMUNE
DISEASES
-LIKE SLE, HASHIMOTO THYROIDITIS,
TYPE I DM
GENETIC DERANGEMENTS:
• GENETIC ABNORMALITIES SUCH AS: EXTRA-
XSOMES AS IN DOWN SYNDROME (TRISOMY
21)
• SUBTLE AS A SINGLE BASE PAIR SUBSTITUTION
OF AMINO ACID AS IN SICKLE CELL ANAEMIA
(SUBSTITUTION OF GLUTAMIC ACID BY VALINE
IN Β-GLOBIN CHAIN
• ENZYME DEFECTS IN INBORN ERRORS OF
METABOLISM
• ACCUMULATION OF DAMAGED DNA OR
MISFOLDED PROTEINS
NUTRITIONAL IMBALANCES:
• UNDER NUTRITION SUCH AS PROTEIN-CALORIE
DEFICIENCIES IN UNDERPRIVILEGED
POPULATION, DEFICIENCIES OF VITAMINS
• OVER NUTRITION OR EXCESSES AS WITH
CHOLESTEROL IN ATHEROSCLEROSIS, OBESITY
WITH DIABETES AND CANCER
• COMPOSITION OF DIET
NB: PHYSICAL, CHEMICAL AND INFECTIOUS
AGENTS ARE THE USUAL SUSPECTS IN
CARCINOGENESIS, TERATOGENESIS,
INFLAMMATIONS, ANY DISEASE IN GENERAL
MOLECULAR TARGETS OF CELL INJURY

1. AEROBIC RESPIRATION (MITOCHONDRIA)

2. MAINTENANCE OF THE INTEGRITY OF CELL

MEMBRANES

3. PROTEIN SYNTHESIS (ENDOPLASMIC RETICULUM )

4. THE CYTOSKELETON

5. PRESERVATION OF THE INTEGRITY OF THE

GENETIC APPARATUS
MECHANISMS OF INJURY
(REVERSIBLE)
• MITOCHONDRIAL DAMAGE
• DECREASED ATP
• INCREASED INTRACELLULAR CALCIUM
• INCREASED OXYGEN-DERIVED FREE
RADICALS (OXIDASE STRESS)
• INCREASED CELL MEMBRANE
PERMEABILITY
• DAMAGE TO DNA AND PROTEINS
DECEASED ATP:

• ATP DEPLETION AND DECREASED

SYNTHESIS ASSOCIATED WITH HYPOXIC
AND CHEMICAL INJURY
• ATP IS REQUIRED FOR MEMBRANE
TRANSPORT, PROTEIN SYNTHESIS,
LIPOGENESIS AND DEACYLATION-
REACYLATION REACTIONS NECESSARY FOR
PHOSPHOLIPID TURNOVER
• ATP IS PRODUCED THROUGH OXIDATION
PHOSPHORYLATION AND GLYCOLYTIC
PATHWAY
• DECREASED ATP RESULTS IN
• REDUCE ACTIVITY OF PLASMA MEMBRANE
ENERGY – DEPENDENT SODIUM PUMP
CELL SWELLING AND DILATATION OF
ENDOPLASMIC RETICULUM
• ALTERED CELLULAR ENERGY METABOLISM
RELAYS ON GLYCOLYTIC PATHWAY
INCREASE IN ANAEROBIC GLYCOLYSIS
DECREASE GLYCOGEN STORE
INCREASE LACTIC ACID RESULTING IN
DECREASE INTRACELLULAR PH
DECREASE ACTIVITY OF MANY
CELLULAR ENZYMES
• FAILURE OF CA 2+
PUMP
LEADS TO INFLUX OF CA2+
WITH DAMAGING EFFECT

• LEAD TO DISRUPTION IN
PROTEIN SYNTHESIS
MITOCHONDRIAL
DAMAGE  CELL DEATH
 MITOCHONDRIAL DAMAGE:

• MITOCHONDRIA ARE IMPORTANT TARGETS OF

INJURIOUS STIMULI
• MITOCHONDRIAL DAMAGE IS DUE TO
INCREASE OF CYTOSOLIC CA2+, OXIDATIVE
STRESS, BREAKDOWN OF PHOSPHOLIPIDS
THROUGH PHOSPHOLIPASE A2
• MITOCHONDRIAL PERMEABILITY TRANSITION
• LEAKAGE OF CYTOCHROME C INTO THE
CYTOSOL CAN TRIGGER APOPTOSIS
ACCUMULATION OF OXYGEN-
DERIVED FREE RADICALS:
• REACTIVE OXYGEN SPECIES ARE FORMED
AS BY-PRODUCTS OF MITOCHONDRIAL
RESPIRATION
• BUT HAVE EFFECTS OF DAMAGING LIPIDS,
PROTEINS AND NUCLEIC ACIDS
• AN IMBALANCE BETWEEN FREE RADICAL
SCAVENGING SYSTEMS RESULTS IN
OXIDATIVE STRESS ASSOCIATED WITH
CELL INJURY
• CHEMICAL SPECIES WITH SINGLE
• FREE RADICALS INITIATED WITHIN
CELLS IN MANY WAYS
• ABSORPTION OF RADIANT ENERGY
E.G. HYDROXYL AND HYDROGEN
• ENZYMATIC METABOLISM OF
EXOGENOUS CHEMICALS OR DRUGS
E.G. CARBON TETRACHLORIDE
• REDUCTION-OXIDATION REACTIONS
THAT OCCUR DURING NORMAL
METABOLIC PROCESSES. E.G.
SUPEROXIDE ANION, HYDROGEN
 • TRANSITION METALS SUCH AS IRON
AND COPPER (DONATE OR ACCEPT
FREE ELECTRONS) – FENTON
REACTION (H2O + FE2+ FE3+ + OH + OH­­-­)
• NITRIC OXIDE (NO) – CAN ACT AS
FREE RADICAL OR CONVERSION TO
REACTIVE PEROXYNITRITE ANION
(ONOO-)
EFFECTS OF FREE RADICAL IN CELL INJURY INCLUDE:
• LIPID PEROXIDATION OF MEMBRANES
• OXIDATIVE MODIFICATION OF PROTEINS
• LESIONS ON DNA
CELLULAR MECHANISMS TO REMOVE FREE
RADICALS INCLUDE:
• DISMUTATION (SPONTANEOUS DECAY)
BECAUSE OF INSTABILITY
• ANTIOXIDANTS SUCH AS VITAMIN E, VITAMIN
A, VITAMIN C AND GLUTATHIONE
• BINDING OF IONS TO STORAGE AND
TRANSPORT PROTEIN E.G. TRANSFERRIN,
FERRITIN, LACTOFERRIN AND CERULOPLASMIN
• ENZYMATIC REACTIONS
E.G. CATALASE DECOMPOSES H2O2
SUPEROXIDE DISMUTASE -> CONVERTS
SUPEROXIDE TO H2O2
GLUTATHIONE PEROXIDASE ->H2O2 + 2GSH –>
GSSH (GLUTATHIONE HOMODIMER)
DEFECTS IN MEMBRANE
•PERMEABILITY:
EARLY LOSS OF MEMBRANE
PERMEABILITY WITH DAMAGE IS
A CONSISTENT FEATURE OF CELL
INJURY
• RESULTS FROM ATP DEPLETION,
ACTIVATION OF
PHOSPHOLIPASES
• ALSO DIRECT DAMAGE BY
BACTERIAL TOXINS, VIRAL
PROCESSES:
• MITOCHONDRIAL DYSFUNCTION
PHOSPHOLIPID REACYLATION/SYNTHESIS 
PHOSPHOLIPID LOSS  MEMBRANE DAMAGE
• LOSS OF MEMBRANE PHOSPHOLIPIDS
• CYTOSKELETAL ABNORMALITIES
• REACTIVE OXYGEN SPECIES
• LIPID BREAKDOWN PRODUCTS SUCH AS
UNESTERIFIED FREE FATTY ACIDS, ACYL
CARNITINE, LYSOPHOSPHOLIPIDS
QUESTIONS/COMMENTS
IRREVERSIBLE CELL DEATH (NECROSIS)

OCCURS DUE TO DENATURATION OF

INTRACELLULAR PROTEIN AND ENZYMATIC
DIGESTION OF LETHALLY INJURED CELL
TYPES:
• COAGULATIVE WHERE THE ARCHITECTURE IS
PRESERVED (DENATURATION OF PROTEIN),
LOCALIZED AREA OF COAGULATIVE NECROSIS IS
CALLED AN INFARCT
• LIQUEFACTIVE IS DUE DIGESTION OF THE DEAD
CELLS (BRAIN)
OTHER DESCRIPTIVE TYPES OF NECROSIS
• GANGRENOUS (EXTREMITIES, BOWEL,) DUE
TO LOST OF BLOOD SUPPLY (WET->WHEN
THERE IS SUPERIMPOSED BACTERIAL
INFECTION AND DRY)
• FIBRINOID (RHEUMATOID, NON-SPECIFIC) –
SEEN IN IMMUNE REACTION INVOLVING
BLOOD VESSELS WHERE COMPLEXES OF
ANTIGENS AND ANTIBODIES ARE DEPOSITED
• CASEOUS (CHEESE) (TUBERCULOSIS)
• FAT (BREAST, ANY FAT) – WHERE THERE IS
FAT DESTRUCTION DUE TO RELEASE OF
ACTIVATED LIPASES
• ISCHEMIC (NON-SPECIFIC)
 APOPTOSIS

• APOPTOSIS COME FROM THE GREEK WORD

“FALLING OFF”
• NORMAL (PREPROGRAMMED)
• PATHOLOGIC (ASSOCIATED WITH NECROSIS)
• CELLS WHICH HAVE SHORTER LIFE SPANS ARE
SUBJECT TO APOPTOSIS
• PATHWAY OF CELL DEATH INDUCED BY
PROGRAMMED EVENT IN CELL DESTINED TO DIE
• BREAKDOWN TO FORM APOPTOTIC BODIES
NORMAL (PHYSIOLOGICAL)
APOPTOSIS

• EMBRYOGENESIS - IMPLANTATION, ORGANOGENESIS,

DEVELOPMENTAL INVOLUTION AND METAMORPHOSIS,
HENCE THE NAME PROGRAMMED CELL DEATH
• HORMONAL “INVOLUTION” IN HORMONE DEPENDENT
TISSUE SUCH AS:
- ENDOMETRIUM SHEDDING DURING MENSES
- OVARIAN FOLLICLE ATRESIA IN MENOPAUSE
- REGRESSION OF LACTATING BREAST AFTER WEANING
- PROSTATE ATROPHY FOLLOWING CASTRATION
• CELL POPULATION CONTROL DURING
PROLIFERATION E.G. EPITHELIAL CELL
IN INTESTINAL CRYPTS, IMMATURE
LYMPHOCYTES IN THE BONE MARROW
AND THYMUS
• POST INFLAMMATORY “CLEAN-UP”
• ELIMINATION OF POTENTIALLY
“HARMFUL” SELF-REACTIVE
LYMPHOCYTES
• CYTOTOXIC T-CELLS CLEANING UP
PATHOLOGIC APOPTOSIS

• DNA DAMAGE WITH TOXIC EFFECT ON CELLS, E.G.,

CHEMICALS, CYTOTOXIC ANTICANCER, RADIATION
• ACCUMULATION OF MISFOLDED PROTEIN DUE TO
GENE MUTATION
• DUCT OBSTRUCTION IN PARENCHYMAL ORGANS
FOLLOWING ATROPHY
• CELL DEATH IN CERTAIN INFECTION SUCH AS VIRUSES
• TUMOR CELLS (RESPONSIBLE FOR SPONTANEOUS
TUMOUR REGRESSION)
MORPHOLOGY

• DECREASE IN CELL SIZE – CELL SHRINKAGE

• CHROMATIN CONDENSATION – HYPERCHROMASIA, PYKNOSIS,
KARYORHEXIS AND KARYOLYSIS
• FORMATION OF CYTOPLASMIC BLEBS AND APOPTOTIC
BODIES
• PHAGOCYTOSIS OF APOPTOTIC CELLS BY MACROPHAGES
MECHANISM OF APOPTOSIS

• RESULTS FROM ACTIVATION OF

ENZYMES CALLED CASPASES
(CYSTEINE PROTEASES THAT CLEAVE
PROTEINS AFTER ASPARTIC RESIDUES)
• THRO TWO PATHWAYS:
• INTRINSIC (MITONCHONDRIAL)
PATHWAY
• EXTRINSIC (DEATH RECEPTOR)
PATHWAY
• INVOLVES INITIATION AND EXECUTION PHASES
• INTRINSIC PATHWAY RESULT FROM INCREASED
PERMEABILITY OF THE MITOCHONDRIAL OUTER
MEMBRANE -> RELEASE OF DEATH-INDUCING
(PRO-APOPTOTIC) MOLECULES
• THE EXTRINSIC PATHWAY ENGAGES THE PLASMA
MEMBRANE DEATH RECEPTOR ON NUMBER OF
CELLS
• BOTH PATHWAYS CONVERGE TO A CASCADE OF
CASPASES ACTIVITY
• THAT MEDIATE FINAL PHASE WITH INTRINSIC
PATHWAY ACTIVATING THE INITIATED CASPASE
9 WHILE THE EXTRINSIC PATHWAY TO
CASPASES 8 AND 10
NECROPTOSIS

• CELL DEATH WHICH IS A HYBRID THAT SHARES

ASPECTS OF BOTH NECROSIS AND APOPTOSIS
• MORPHOLOGICALLY IT RESEMBLES NECROSIS
– LOSS OF ATP, SWELLING OF CELLS,
GENERATION OF REACTIVE OXYGEN SPECIES,
RELEASES OF LYSOSOMAL ENZYMES
• MECHANICALLY IT IS TRIGGERED BY
GENETICALLY PROGRAMMED SIGNAL
TRANSDUCTION EVENTS – RESEMBLES
PROGRAMMED CELL DEATH
• SOMETIMES CALLED PROGRAMMED
NECROSIS
• THERE IS NO CASPASE ACTIVATION –>
CASPASE-INDEPENDENT PROGRAMMED
CELL DEATH
• TRIGGERED BY LIGATION OF TNFR1 AND
VIRAL PROTEINS OF RNA AND DNA
VIRUSES
PYROPTOSIS

• FORM OF PROGRAMMED CELL DEATH THAT

INHERENTLY INDUCES AN IMMUNE RESPONSE
• MORPHOLOGICALLY DISTINCT FROM OTHER TYPES
OF CELL DEATH
• CELLS SWELL UP, RUPTURE AND RELEASE PRO-
INFLAMM CELLULAR CONTENTS
• DUE TO RESPONSE TO A RANGE OF STIMULI
INCLUDING MICROBIAL INFECTION AS WELL AS
HEART ATTACKS (MYOCARDIAL INFARCTION)
• CAPSASES 1,4, 5 PLAY IMPORTANT ROLE IN
INDUCING CELL DEATH BY PYROPTOSIS
• LIMITS THE LIFE AND PROLIFERATION OF TIME OF
INTRACELLULAR AND EXTRACELLULAR
INTRACELLULAR ACCUMULATIONS

• ONE OF THE MANIFESTATIONS OF METABOLIC DERANGEMENTS IS

INTRACELLULAR ACCUMULATION OF ABNORMAL SUBSTANCES
• 3 CATEGORIES

• NORMAL CELLULAR COMPONENTS IN

EXCESS E.G. WATER, LIPIDS, PROTEIN,
CARBOHYDRATE
• ABNORMAL SUBSTANCES EITHER
EXOGENOUS (MINERALS OR PRODUCTS OF
INFECTIONS) OR ENDOGENOUS (PRODUCTS OF
ABNORMAL SYNTHESIS OR METABOLISM)
• PIGMENTS
PROCESSES OF ACCUMULATION:
• A NORMAL ENDOGENOUS SUBSTANCE IS
PRODUCED AT A NORMAL OR
INCREASED RATE BUT RATE OF
METABOLISM IS INADEQUATE TO
REMOVE IT
E.G. -FATTY CHANGE IN LIVER
-APPEARANCE OF REABSORPTION
PROTEIN DROPLETS IN RENAL TUBULES
DUE TO INCREASED LEAKAGE
COMMON CAUSES INCLUDE DIABETES,
OBESITY AND ALCOHOL
FATTY LIVER
FATTY LIVER - HISTOLOGY
• A NORMAL OR ABNORMAL ENDOGENOUS
SUBSTANCE ACCUMULATING
• BECAUSE OF GENETIC OR ACQUIRED DEFECTS
IN THE
-METABOLISM
-PACKAGING
-TRANSPORT
-SECRETION OF THESE SUBSTANCES
• AN ABNORMAL EXOGENOUS
SUBSTANCE IS DEPOSITED AND
ACCUMULATES
• BECAUSE THE CELL HAS NEITHER
THE ENZYMATIC MACHINERY TO
DESTRUCT NOR THE ABILITY TO
TRANSPORT TO OTHER SITES
E.G. ACCUMULATION OF CARBON
PARTICLES – ANTHRACOSIS
ANTHRACOSIS
• INVOLVE ALL CLASSES OF LIPIDS
• TRIGLYCERIDES, CHOLESTEROL/CHOLESTEROL
ESTERS AND PHOSPHOLIPIDS
• COMPLEXES WITH CHO AS IN LYSOSOME
STORAGE DISEASE
E.G. FATTY CHANGE (STEATOSIS) IN LIVER AND
HEART
CHOLESTEROL/CHOLESTEROL ESTERS IN
ATHEROSCLEROSIS, XANTHOMAS,
INFLAMMATION AND NECROSIS
CHOLESTEROLOSIS (LAMINA PROPRIA OF GALL
BLADDER)
SPECIAL STAINS FOR LIPIDS/FAT: OIL RED O AND
SUDAN BLACK B
CHOLESTEROL CLEFTS IN
ATHEROSCLEROSIS
PROTEINS
• USUALLY APPEAR AS ROUNDED EOSINOPHILIC
DROPLETS, VACUOLES OR AGGREGATES
• E/M CAN BE AMORPHOUS, FIBRILLAR,
CRYSTALLINE IN APPEARANCE.
• EXTRACELLULAR DEPOSIT IN AMYLOIDOSIS
E.G. REABSORPTION DROPLETS IN PROXIMAL
TUBULES AS IN RENAL DISEASES ASSOCIATED
WITH PROTEIN LOSS
SPECIAL STAIN FOR AMYLOID: CONGO RED
WITH POLARIZED LIGHT (GREEN
BIREFRINGENCE) AND TOLUIDINE BLUE
• SYNTHESIS OF EXCESSIVE
AMOUNTS OF NORMAL
SECRETORY PROTEINS IN PLASMA
CELLS ASSOCIATED WITH
SECRETION OF IMMUNOGLOBULIN
(RUSSELL BODIES)
• DEFECTS IN PROTEINS FOLDING
E.G. CYSTIC FIBROSIS, AIAT
DEFICIENCY AND FAMILIAL
HYPERCHOLESTEROLEMIA
HYALINE CHANGE
• REFERS TO AN ALTERATION WITHIN CELLS
OR IN THE EXTRACELLULAR SPACE
HOMOGENOUS GLASSY PINK APPEARANCE
• DESCRIPTIVE HISTOLOGICAL TERM
• PRODUCED BY A VARIETY OF ALTERATIONS
E.G. INTRACELLULAR ACCUMULATION OF
PROTEIN IN RENAL TUBULES, RUSSELL
BODIES, MALLORY BODIES
• EXTRACELLULAR HYALINE AS IN OLD
SCARS, WALLS OF ARTERIOLES IN
HYPERTENSION AND DIABETES
GLYCOGEN
• EXCESSIVE ACCUMULATIONS ARE SEEN IN
PATIENTS WITH ABNORMALITY IN EITHER
• GLUCOSE OR GLYCOGEN METABOLISM
• APPEAR AS CLEAR VACUOLES WITHIN THE
CYTOPLASM (STAINED WITH BEST
CARMINE OR PAS)
E.G. IN DM, GLYCOGEN IS FOUND IN
EPITHELIAL CELLS OF DISTAL PORTION OF
PROXIMAL CONVOLUTED TUBULES, LIVER
CELLS, HEART MUSCLE AND B-CELLS OF
ISLETS OF LANGERHANS
• IN GLYCOGEN STORAGE DISEASES
(GROUP OF CLOSELY RELATED
GENETIC DISORDERS) GLYCOGEN
ACCUMULATES WITHIN CELLS
• RESULT FROM ENZYME DEFECTS IN
SYNTHESIS OR BREAKDOWN OF
GLYCOGEN  MASSIVE
ACCUMULATION
• COLOURED SUBSTANCES EITHER NORMAL
CONSTITUENTS OF CELLS OR ABNORMAL
• CAN BE EXOGENOUS OR ENDOGENOUS
• EXOGENOUS ONES INCLUDE:
• CARBON OR COAL DUST  ALVEOLI 
REGIONAL LYMPH NODE. IN LUNGS
ANTHRACOSIS
• IN COLD MINES  FIBROBLASTIC
REACTION OR EMPHYSEMA COAL
WORKERS’ PNEUMOCONIOSIS
• TATTOOING - LOCALIZED TO SKIN 
LIFELONG (NO INFLAMMATORY
ENDOGENOUS INCLUDE:
LIPOFUSCIN (LIPOCHROME, WEAR AND
TEAR PIGMENT OR AGING PIGMENT)
• COMPOSED OF POLYMERS OF LIPIDS AND
PHOSPHOLIPIDS COMPLEXED WITH
PROTEIN
• DERIVED THROUGH LIPID PEROXIDATION
OF POLYUNSATURATED LIPIDS
• TELLTALE SIGN OF FREE RADICAL INJURY
PEROXIDATION
• APPEAR AS YELLOW-BROWN (BROWN
LIPID)
• SEEN IN CELLS UNDERGOING SLOW
REGRESSIVE CHANGES (LIVER AND
HEART)
• E/M  GRANULES OF HIGHLY
ELECTRON DENSE, WITH
MEMBRANOUS STRUCTURE AND IN A
PERINUCLEAR LOCATION
MELANIN
• BROWN-BLACK ENDOGENOUS, NON-
HAEMOGLOBIN DERIVED PIGMENT
• FORMED WHEN TYROSINASE CATALYSES
THE OXIDATION OF TYROSINE TO
DIHYDROXYPHENYLALAMINE IN
MELANOCYTES
• ANOTHER BROWN-BLACK PIGMENT IS
HOMOGENTISIC ACID (OCCURS IN
PATIENTS WITH ALKAPTONURIA) DEPOSIT
IN SMALL CONNECTIVE TISSUE, CARTILAGE
KNOWN AS OCHRONOSIS
• SPECIAL STAIN IS MASON-FONTANA
(BLACK)
HAEMOSIDERIN
• HAEMOGLOBIN-DERIVED, GOLDEN-
YELLOW TO BROWN GRANULAR OR
CRYSTALLINE
• TRANSPORTED WITH TRANSFERRINS
• STORED IN ASSOCIATION WITH
APOFERRITIN  FERRITIN MICELLES
• FERRITIN FORMS HEMOSIDERIN GRANULES
WHEN EXCESS
• FOUND IN SMALL AMOUNTS IN CELLS
ENGAGED WITH RED CELL BREAKDOWN
(BONE MARROW, SPLEEN AND LIVER)
• SYSTEMIC OVERLOAD 
HAEMOSIDEROSIS
• SEEN IN INCREASED ABSORPTION OF
DIETARY IRON, IMPAIRED USE,
HAEMOLYTIC ANAEMIA AND
TRANSFUSION
• APPEAR IN LIVER, PANCREAS AND KIDNEY
• STAINED BY PERL’S PRUSSIAN BLUE
BLUE COLOUR
• IMPAIR ORGAN FUNCTION IS SEEN WITH
HAEMACHROMATOSIS  ORGAN
DAMAGE
HAEMOSIDERIN/MELANIN
PATHOLOGICAL CALCIFICATION
• ABNORMAL TISSUE DEPOSITION OF
CALCIUM SALTS ALONG WITH SMALL
AMOUNTS OF IRON, MAGNESIUM AND
OTHER MINERAL SALTS
• SPECIAL STAINS FOR CALCIUM ARE
ALIZERIN’S RED AND VON KOSSA
(RED AND BLACK RESPECTIVELY)
• TWO FORMS: DYSTROPHIC AND
METASTATIC
DYSTROPHIC CALCIFICATION:
• ENCOUNTERED IN AREAS OF NECROSIS,
ATHEROMAS, AGING OR DAMAGED
HEART VALVES, TUBERCULOUS LYMPH
NODE
• APPEARS AS FINE WHITE GRANULES OR
CLUMPS, FELT AS GRITTY DEPOSIT
• SERUM CALCIUM IS NORMAL
• PROCESSES INVOLVE FORMATION OF
CRYSTALLINE CALCIUM PHOSPHATE
MINERAL IN THE FORM OF APATITE
• INVOLVED INITIATION (NUCLEATION) AND
PROPAGATION
METASTATIC CALCIFICATION:
• OCCURS IN NORMAL TISSUE WHENEVER THERE IS
HYPERCALCAEMIA
• FOUR CATEGORIES OF CAUSES
• INCREASED SECRETION OF PTH BONE RESORPTION
(HYPERPARATHYROIDISM)
• DESTRUCTION OF BONE TISSUE AS IN PRIMARY BONE
TUMOUR (MULTIPLE MYELOMA) OR DIFFUSE SKELETAL
METASTASIS (BREAST CANCER)
• VITAMIN D-RELATED DISORDERS (INTOXICATION,
SARCOIDOSIS)
• RENAL FAILURE LEADING TO SECONDARY
HYPERPARATHYROIDISM
• PRINCIPALLY AFFECTS INTERSTITIAL TISSUES OF GASTRIC
MUCOSA, KIDNEYS, LUNGS AND SYSTEMIC ARTERIES
• MASSIVE KIDNEY DEPOSITS NEPHROCALCINOSIS
CELLULAR AGING
• IS THE RESULT OF PROGRESSIVE
DECLINE IN CELLULAR FUNCTION AND
VIABILITY
• CAUSED BY GENETIC ABNORMALITIES
AND THE ACCUMULATION OF
CELLULAR AND MOLECULAR DAMAGE
• DUE TO THE EFFECTS OF EXOGENOUS
INFLUENCES
• PROGRAMMED THEORY (80%)
• WEAR AND TEAR THEORY (20%)
MECHANISM
• DNA DAMAGE FROM EXTERNAL
(PHYSICAL, CHEMICAL, INFECTIOUS
• ENDOGENOUS FROM ROS (REACTIVE
OXIDATIVE SPECIES)
• CELLULAR SENESCENCE – ALL NORMAL
CELLS HAVE A LIMITED CAPACITY FOR
REPLICATION
• AFTER A FIXED NUMBER OF DIVISIONS,
CELL BECOME TERMINALLY NON-
DIVIDING (REPLICATIVE SENESCENCE)
• THREE PROCESSES INVOLVE IN
REPLICATIVE SENESCENCE
• TOLEMERE ATTRITION
• ACTIVATION OF TUMOUR
SUPPRESSION GENES (P16)
• DEFECTIVE PROTEIN HOMEOSTASIS
– WHERE THERE IS DEREGULATED
NUTRIENT SENSING -> ALTERED
TRANSCRIPTION
• QUESTIONS/COMMENT
CELLULAR ADAPTATION
CELLULAR ADAPTATION RESULTS FROM
• INCREASED DEMAND
• EXTERNAL STIMULATION
• REDUCED SUPPLY OF NUTRIENTS/GROWTH
FACTORS
• FOUR ARE KNOWN
ATROPHY
HYPERTROPHY
HYPERPLASIA
METAPLASIA
ATROPHY
• SHRINKAGE IN THE SIZE OF THE CELL BY LOSS
OF CELL SUBSTANCE
• MAY CULMINATE IN CELL DEATH
• ORGAN REDUCES IN SIZE IF SUFFICIENT CELLS
ARE INVOLVED
PHYSIOLOGICAL
• DURING EARLY DEVELOPMENT E.G. NOTOCHORD,
THYROGLOSSAL DUCT UNDERGO ATROPHY
DURING FOETAL DEVELOPMENT
• UTERUS DECREASES IN SIZE AFTER PARTURITION
PATHOLOGICAL ATROPHY
• DEPENDS ON CAUSE, CAN BE LOCAL OR
GENERALIZED.
• DECREASED WORKLOAD (ATROPHY OF
DISUSE) E.G. BROKEN LIMB IMMOBILIZED
IN A POP OR PATIENT RESTRICTED TO LONG
TIME BED  SKELETAL ATROPHY.
• LOSS OF INNERVATION (DENERVATION
ATROPHY) DAMAGE TO THE NERVE SUPPLY
TO MUSCLE (ATROPHY AS IN
POLIOMYELITIS)
• NEUROGENIC ATROPHY OF MUSCLE WHERE
ANTERIOR HORN CELLS OR AXON OF PERIPHERAL
NERVOUS SYSTEM IS AFFECTED AS IN:
INFANTILE MOTOR NEURON DISEASE
DUCHENNE MUSCULAR DYSTROPHY
BECKER MUSCULAR DYSTROPHY
• DIMINISHED BLOOD SUPPLY (ISCHAEMIA)
E.G. IN ARTERIAL OCCLUSIVE DISEASE TISSUE
ATROPHY DUE TO PROGRESSIVE CELL LOSS,
CEREBRAL ATROPHY DUE TO ATHEROSCLEROSIS
• INADEQUATE NUTRITION
PROFOND PROTEIN CALORIE
MALNUTRITION (MARASMUS)
ASSOCIATED WITH SKELETAL
MUSCLE WASTING (CACHEXIA).
• IN CASES OF CHRONIC
INFLAMMATORY DISEASES (TB) AND
CANCER PATIENTS  DUE TO OVER
PRODUCTION OF TNF
• LOSS OF ENDOCRINE STIMULATION
ENDOCRINE GLANDS LIKE THE BREAST AND
REPRODUCTIVE ORGANS DEPEND ON HORMONE
FOR NORMAL METABOLISM AND FUNCTION
E.G. LOSS OF OESTROGEN IN MENOPAUSE 
ATROPHY OF ENDOMETRIUM, VAGINAL
EPITHELIUM AND BREAST
• AGING (SENILE ATROPHY), E.G. BRAIN AND
HEART
COMMON IN ORGANS WITH PERMANENT CELLS
• PRESSURE TISSUE COMPRESSION FOR LONG TIME
 PRESSURE ATROPHY
MECHANISM: BALANCE BETWEEN PROTEIN
SYNTHESIS AND DEGRADATION
HYPERTROPHY
• INCREASE IN THE SIZE OF CELLS,
RESULTING IN INCREASE IN THE SIZE OF
THE ORGAN
• NO NEW CELLS, NO CELLULAR
SWELLING
• DUE TO SYNTHESIS OF MORE
STRUCTURAL COMPONENTS
• OCCURS IN NON-DIVING CELLS LIKE
MYOCYTES AND SKELETAL MUSCLE
PHYSIOLOGICAL
• DUE TO INCREASED WORK LOAD
E.G. BULGING MUSCLES OF BODY
BUILDERS
• HORMONAL INDUCED UTERUS DURING
PREGNANCY.
PATHOLOGICAL
• HAEMODYNAMIC OVERLOAD 
CARDIAC HYPERTROPHY FROM
HYPERTENSION OR FAULTY VALVES
HYPERTROPHY

• INCREASE IN SIZE OF CELLS

HYPERPLASIA
• INCREASE IN THE NUMBER OF CELLS IN AN
ORGAN OR TISSUE USUALLY RESULTING IN
INCREASED VOLUME OF THE ORGAN OR
TISSUE
• OCCURS WHEN CELLULAR POPULATION IS
CAPABLE OF SYNTHESIZING DNA (MITOTIC
DIVISION)
• CAN OCCUR ALONG WITH HYPERTROPHY IN
THE SAME ORGAN
• CAN BE PHYSIOLOGICAL OR
PATHOLOGICAL
PHYSIOLOGICAL HYPERPLASIA
• HORMONAL INDUCED
E.G. PROLIFERATION OF GLANDULAR
EPITHELIUM OF FEMALE BREAST AT PUBERTY
AND DURING PREGNANCY
GROWTH OF UTERUS DURING PREGNANCY
• COMPENSATORY- INCREASES TISSUE MASS
AFTER DAMAGE OR PARTIAL REDUCTION
E.G. REGENERATION OF LIVER FOLLOWING
PARTIAL HEPATECTOMY
INCREASE IN KIDNEY SIZE IN UNILATERAL
NEPHRECTOMY
PATHOLOGICAL HYPERPLASIA
• MAINLY CAUSED BY EXCESSIVE HORMONAL
STIMULATION OR GROWTH FACTORS ACTING ON
TARGET CELLS
E.G. ENDOMETRIAL HYPERPLASIA IN
DYSFUNCTIONAL UTERINE BLEEDING
BENIGN PROSTATE HYPERPLASIA INDUCED BY
ANDROGENS
• NB: FERTILE SOIL FOR DEVELOPMENT OF
CANCER.
• CT HYPERPLASIA IN WOUND HEALING
PROLIFERATING FIBROBLASTS AND BVS AID IN
REPAIR
• HYPERPLASIA SEEN IN HPV VIRAL WARTS
METAPLASIA
• REVERSIBLE CHANGE IN WHICH ONE ADULT
CELL TYPE IS REPLACED BY ANOTHER
• USUALLY CROSSING NO HISTOGENIC
BOUNDARY I.E. EPITHELIAL TO EPITHELIAL OR
CONNECTIVE TISSUE TO CONNECTIVE TISSUE
• ADAPTATIVE SUBSTITUTION OF CELLS
SENSITIVE TO STRESS
EPITHELIAL METAPLASIA OCCURS IN:
COLUMNAR TO SQUAMOUS IN
• RESPIRATORY TRACT IN SMOKERS
• STONES IN SALIVARY GLANDS, PANCREAS OR
BILE DUCT
• DEFICIENCY OF VITAMIN A INDUCES SQUAMOUS
METAPLASIA IN RESPIRATORY TRACT
TRANSITIONAL TO SQUAMOUS IN
• URINARY BLADDER IN SCHISTOSOMIASIS
SQUAMOUS TO COLUMNAR IN
• BARRETT OESOPHAGUS DUE TO ACID REFLUX
• CAN TRANSFORM TO CANCER IF
STIMULUS PERSISTS
• CONNECTIVE TISSUE METAPLASIA
OCCURS WHEN CARTILAGE, BONE OR
ADIPOSE TISSUE (MESENCHYMAL
TISSUES) ARE FOUND IN TISSUES THAT
DO NOT CONTAIN THESE ELEMENTS
E.G. BONE FORMATION IN MUSCLE
(MYOSITIS OSSIFICANS) AFTER BONE
FRACTURE
MECHANISM:

• RESULTS OF REPROGRAMMING OF STEM

CELLS THAT EXIST IN NORMAL TISSUE OR
DIFFERENTIATED MESENCHYMAL CELLS
PRESENT IN CONNECTIVE TISSUE
• THE PRECURSOR CELLS DIFFERENTIATE
ALONG A NEW PATHWAY
• SIGNALS FROM CYTOKINES, GROWTH
FACTORS AND EXTRACELLULAR MATRIX
COMPONENTS
NOT CELLULAR ADAPTATION
• HYPOTROPHY = ATROPHY
• DYSTROPHY – DIFFICULT CELL GROWTH
• HYPOPLASIA/APLASIA – LACK OF CELL
GROWTH
• DYSPLASIA – ABNORMAL CELL GROWTH
-> PRECANCEROUS
• ANAPLASIA – VERY UNDIFFERENTIATED
CELL GROWTH
• NOT ALL THE –TROPHYS AND –PLASIAS
ARE CELLULAR ADAPTATIONS
• QUESTIONS/COMMENT
INFLAMMMATION

• INFLAMMATION IS A RESPONSE OF
VASCULARIZED TISSUES TO INFECTIONS AND
DAMAGED TISSUES.
• BRINGS CELLS AND MOLECULES OF HOST
DEFENSE FROM THE CIRCULATION TO THE
SITES WHERE THEY ARE NEEDED
• ELIMINATE THE OFFENDING AGENTS
• CAN BE ACUTE OR CHRONIC
WITHOUT INFLAMMATION
- INFECTIONS WOULD GO UNCHECKED
- WOUNDS WOULD NEVER HEAL
- AND INJURED TISSUES MIGHT
REMAIN PERMANENT FESTERING
SORES
THE TYPICAL INFLAMMATORY
REACTION DEVELOPS THROUGH A
SERIES OF SEQUENTIAL STEPS:
STEPS IN INFLAMMATION

- THE OFFENDING AGENT IS RECOGNIZED BY HOST

CELLS
- LEUKOCYTES AND PLASMA PROTEINS ARE
RECRUITED FROM THE CIRCULATION TO THE SITE
WHERE THE OFFENDING AGENT IS LOCATED
- THE LEUKOCYTES AND PROTEINS ARE ACTIVATED
AND WORK TOGETHER TO DESTROY AND
ELIMINATE THE OFFENDING SUBSTANCE
- THE REACTION IS CONTROLLED AND TERMINATED
- THE DAMAGED TISSUE IS REPAIRED
HISTORY
3000 BC –EGYPTIAN PAPYRUS CONTAINED
CLINICAL FEATURES OF INFLAMMATION
 1ST CENTURY AD – ROMAN WRITER, CELSUS,
LISTED THE FOUR CARDINAL SIGNS OF
INFLAMMATION OF RUBOR (REDNESS),
TUMOR (SWELLING), CALOR (HEAT) AND
DOLOR (PAIN)
19TH CENTURY – RUDOLF VIRCHOW ADDED A
FIFTH CLINICAL SIGN OF FUNCTIO LASEA
(LOSS OF FUNCTION)
1973 – JOHN HUNTER NOTED THAT
INFLAMMATION IS NOT A DISEASE BUT A
STEREOTYPIC RESPONSE THAT HAS A
SALUTARY EFFECT ON ITS HOST
1880 – ELLIE METCHNIKOFF DISCOVERED THE
PROCESS OF PHAGOCYTOSIS
SIR THOMAS LEWIS ESTABLISHED THE
CONCEPTS THAT CHEMICAL SUBSTANCES
MEDIATE THE VASCULAR CHANGES OF
INFLAMMATION
ACUTE INFLAMMATION
ACUTE INFLAMMATION HAS THREE MAJOR
COMPONENTS:
DILATION OF SMALL VESSELS LEADING TO AN
INCREASE IN BLOOD FLOW
INCREASED PERMEABILITY OF THE
MICROVASCULATURE ENABLING PLASMA
PROTEINS AND LEUKOCYTES TO LEAVE THE
CIRCULATION
EMIGRATION OF THE LEUKOCYTES FROM THE
MICROCIRCULATION, THEIR ACCUMULATION
AND THEIR ACTIVATION TO ELIMINATE THE
OFFENDING AGENT
VASCULAR RESPONSE

• TRANSIENT VASOCONSTRICTION
• VASODILATATION
• INCREASE IN BLOOD FLOW
• INCREASE VASCULAR PERMEABILITY
• SLOWING OR STASIS
• THE LAST EVENT INITIATE THE
CELLULAR EVENT OF INFLAMMATION
VASODILATION
INDUCED BY THE ACTION OF SEVERAL
MEDIATORS ON VASCULAR SMOOTH
MUSCLE
- IT INVOLVES THE ARTERIOLES AND THEN
LEADS TO OPENING OF NEW CAPILLARY
BEDS IN THE AREA
- THE RESULTS IS INCREASED BLOOD
FLOW, WHICH IS THE CAUSE OF HEAT AND
REDNESS
INCREASED VASCULAR
PERMEABILITY
IVP IS A HALLMARK OF ACUTE
INFLAMMATION, DUE TO:
CONTRACTION OF ENDOTHELIAL CELLS
ELICITED BY HISTAMINE, BRADYKININ,
LEUKOTRIENES, RESULTING IN INCREASED
INTERENDOTHELIAL SPACES
ENDOTHELIAL INJURY, RESULTING IN
ENDOTHELIAL CELL NECROSIS AND
DETACHMENT
INCREASED TRANSPORT OF FLUIDS AND
PROTEINS, (TRANSCYTOSIS) STIMULATED BY
VEGF
 STASIS
• THE LOSS OF FLUID AND INCREASED
VESSEL DIAMETER LEAD TO SLOWER
BLOOD FLOW
• CONCENTRATION OF RED CELLS IN SMALL
VESSELS
• ANDINCREASED VISCOSITY OF THE
BLOOD
CELLULAR RESPONSE

• THE MOVEMENT OF THE CELLULAR

COMPONENT OF INFLAMMATION TO THE SITE
OF INJURY FROM THE VASCULAR SPACES
• THE CELLS ARE:
NEUTROPHIL
MACROPHAGE
LYMPHOCYTE
 EOSINOPHIL
PLASMA CELL
FIBROBLAST
CELLULAR EVENTS INVOLVE:

 STASIS DISTURB THE AXIAL FLOW OF THE BLOOD

CELLULAR ELEMENTS IN THE MIDLINE AND
PLASMATIC FLUID AT THE PERIPHERY
 MARGINATION
 PAVEMENTING
 EMIGRATION
 CHEMOTAXIS
 PHAGOCYTOSIS
PHAGOCYTOSIS INVOLVES:

a. OPSONIZATION
b. ENDOCYTOSIS
c. FORMATION OF PHAGOSOME
d. FORMATION OF PHAGOLYSOSOME
e. CELLULAR KILLING
MARGINATION
• MOVEMENT OF THE INFLAMMATORY CELLS
TO THE MARGIN OF THE VASCULATURE
• ORCHESTRATED BY DISRUPTION OF THE AXIAL
FLOW
• CELLULAR COMPONENTS ARE SHIELDED FROM
THE THROMBOGENIC ENDOTHELIAL WALL BY
PLASMA FLUID
• INCREASE ENDOTHELIAL PERMEABILITY
LEADS TO LOSS OF THE PLASMA FLUID
• INCREASE IN VISCOSITY AND DISRUPTION OF
THE AXIAL FLOW
• THIS CULMINATES IN MIGRATION TO THE
PAVEMENTING
• PROCESS WHEREBY THE INFLAMMATORY
CELL LINED THE ENDOTHELIA CELLS
AVIDLY

• THIS IS A S A RESULT OF ROLLING

MEDIATED BY INTERACTION BETWEEN L-
SELECTIN AND E-SELECTIN

• FIRM ADHESION OF THE LEUCOCYTE TO

ENDOTHELIUM VIA ICAM-1 AND INTEGRIN
ON THE NEUTROPHIL
DIAPEDESIS
• AFTER THIS THE LEUCOCYTE EXTEND THEIR
PSEUDOPOD TO NEGOTIATE FOR A PASSAGE
THRU THE INTER-ENDOTHELIAL JUNCTION
• THIS EVENT IS MEDIATED THROUGH CELL TO
CELL ADHESION MOLECULE CALLED
CD31/PECAM
THE PROCESS IS CALLED DIAPEDESIS (PASSIVE
MOVEMENT)
CHEMOTAXIS
• THE MOVEMENT OF THE LEUKOCYTE
TOWARD THE INJURIOUS AGENT
ALONG CHEMICAL GRADIENT
• THIS MOVEMENT IS INITIATED BY
CHEMOATTRACTANT
• MAJOR ONES ARE LEUKOTRINE B4
AND COMPLEMENT C5
• THE LEUKOCYTE HAS RECEPTOR FOR
CHEMOATTRACTANT
• THE BINDING OF THE CHEMOATTRACTANT TO
THE RECEPTOR INITIATE THE FOLLOWING
EVENTS:
• CHEMOATTRACTANT BIND TO G-PROTEIN
COUPLED RECEPTOR
• ACTIVATION OF PHOSPHOLIPASE C
• HYDROLYSIS OF MEMBRANE PHOSPHOLIPID
• RELEASE OF DAG AND IP3
• THIS ACTIVATION OF GTPASES INCREASE
CYTOSOLIC CALCIUM
• ASSEMBLY AND POLYMERIZATION OF
CONTRACTILE PROTEIN
THE CELL MOVES BY EXTENDING
FILOPODIA
- THAT PULL THE BACK OF THE CELL IN
THE DIRECTION OF THE EXTENSION JUST
AS AUTOMOBILE WITH FRONT WHEEL
DRIVE
- ASSEMBLY AND DISASSEMBLY OF THE
CONTRACTILE PROTEIN IS REGULATED
BY ACTIN REGULATING PROTEIN
(GELSOLIN CALMODULIN, FILAMIN AND
PROFILIN)
PHAGOCYTOSIS
• PROCESS OF AND RELEASE OF ENZYME
FOR ELIMINATION OF INJURIOUS AGENT
• CONSIST OF THREE DISTINCT BUT
INTERRELATED STEPS
1. RECOGNITION AND ATTACHMENT
2. ENGULFMENT
3. KILLING AND DEGRADATION
RECOGNITION AND ATTACHMENT
• PHAGOCYTOSIS IS INITIATED BY RECOGNITION OF
THE INJURIOUS AGENT BY THE PHAGOCYTE
• THIS IS FACILITATED BY THE OPSONIN, C3B AND FC
FRAGMENT OF IGG
• THE LEUKOCYTE HAS A RECEPTOR FOR THE
OPSONIN ON THE MEMBRANE
• THE OPSONIN COAT THE MICROBE
• THE INTERACTION BETWEEN THE RECEPTOR ON
THE LEUKOCYTE AND THE OPSONIN TRIGGER THE
NEXT STEP OF PHAGOCYTOSIS
• OPSONIZATION TRIGGER THIS ACTIVE PROCESS OF
PHAGOCYTOSIS
• FORMATION OF PSUEDOPOD ROUND THE
PARTICLE TO BE ENGULFED, PHAGOSOME
AND PHAGOCYTIC VACUOLE
• FUSION OF PHAGOSOME WITH
LYSOSOME, PHAGOLYSOSOME
• RELEASE OF THE LYSOSOMAL GRANULE
INTO THE VACUOLE
CELLULAR KILLING AND
DEGRADATION
• THE ULTIMATE STEP IN PHAGOCYTOSIS
• MICROBIAL KILLING IS ACCOMPLISHED BY
OXYGEN DEPENDENT MECHANISM
• PHAGOCYTOSIS STIMULATE BURST IN
OXYGEN CONSUMPTION, GLYCOGENOLYSIS,
GLUCOSE OXIDATION VIA HMP SHUNT
• INCREASE IN PRODUCTION OF REACTIVE
OXYGEN SPECIES
REACTIVE OXYGEN SPECIES

• THESE ARE GENERATED BY ACTIVATION OF NADPH

OXIDASE WHICH OXIDIZES NADPH TO NADP, AND IN
THE PROCESS REDUCES OXYGEN TO SUPEROXIDE
ANION
• SUPEROXIDE ANION IS CONVERTED TO HYDROGEN
PEROXIDE (H2O2)
• H2O2 IS NOT ABLE TO EFFICIENTLY KILL MICROBES
BY ITSELF
• MPO-HALIDE SYSTEM HELP IN THE GENERATION OF
HYPOCHLORIDE ANION HOC), A POTENT
ANTIMICROBIAL AGENT
NON OXYGEN DEPENDENT CELLULAR KILLING
• BACTERIAL PERMEABILITY INCREASING PROTEIN
BPI
• LYSOZYMES HYDROLYZE BACTERIAL
GLYCOPROTEIN COAT
• LACTOFERRIN
• MAJOR BASIC PROTEIN OF EOSINOPHIL
CYTOTOXIC TO PARASITE
• DEFENSIN CATIONIC ARGININE RICH GRANULE
PEPTIDE CYTOTOXIC TO MICROBE
• ELASTASE PRESENT IN NEUTROPHIL GRANULE HAS
MICROCIDAL EFFECT
• ACID HYDROLASE IN LYSOSOMES HELP IN
DEGRADING THE MICROBE AFTER KILLING
CHEMICAL MEDIATORS OF ACUTE
INFLAMMATION

• SUBSTANCES THAT INITIATE AND REGULATE

INFLAMMATORY REACTIONS
• HAVE BEEN IDENTIFIED AND ARE BEING TARGETED
THERAPEUTICALLY TO LIMIT INFLAMMATION
• EITHER SECRETED BY CELLS OR GENERATED FROM
PLASMA CELLS
• CELL-DERIVED ONES ARE NORMALLY
SEQUESTERED BY EXOCYTOSIS (HISTAMINE IN
MAST CELL GRANULES) OR SYNTHESIZED DE
NOVO (PGS, LTS, CYTOKINES)
• PLASMA-DERIVED ONES ARE
PRODUCED MAINLY IN THE LIVER AS
INACTIVE FORMS AND MUST BE
ACTIVATED THRU SERIES OF
PROTEOLYTIC CLEAVAGES IN
PRESENCE OF STIMULI
• MOST OF THE MEDIATORS ARE SHORT-
LIVED
• ONE MEDIATORS CAN STIMULATE THE
RELEASE OF THE MEDIATORS
TYPES INCLUDE:
• VASOACTIVE AMINES (HISTAMINE, SEROTONIN)
• PRODUCTS ARACHIDONIC ACID METABOLISM (PGS,
LEUKOTRIENES)
• CYTOKINES AND CHEMOKINES
• PRODUCTS OF COMPLEMENT ACTIVATION (C3A, C5A)
• PRODUCTS OF COAGULATION
• PLATELET ACTIVATING
FACTORS
• KININ
• LYSOSOMAL CONSTITUENTS
• FREE RADICALS
• NITRIC OXIDE
• NEUROPEPTIDES
VASOACTIVE AMINES (HISTAMINE & SEROTONIN)
- HAVE POTENT ACTION ON BLOOD VESSELS
- FIRST MEDIATORS TO BE IDENTIFIED
- STORED IN CELLS AS PREFORMED MOLECULES
- SOURCES INCLUDE MAST CELLS, BASOPHILS AND
PLATELETS
- CAUSES DILATATION OF ARTERIOLES AND
INCREASED VASCULAR PERMEABILITY
- CONTRACTION OF SMOOTH MUSCLE,
ENDOTHELIUM ACTIVATION
ARACHIDONIC ACID METABOLITES
• PROSTAGLANDINS,THROMOXANES,
LEUCOTRIENES AND LIPOXIN ARE PRODUCTS
OF AA
• PRESENT, ESTERIFIED IN MEMBRANE
PHOSPHOLIPIDS
• STIMULATE VASCULAR AND CELLULAR RXNS
• AA IS DERIVED FROM DIETARY SOURCES OR BY
CONVERSION OF ESSENTIAL FATTY ACID,
LINOLEIC ACID
• RELEASED IS STIMULATED BY MECHANICAL,
CHEMICAL OR OTHER MEDIATORS (C5A) THRU
PHOSPHOLIPASE A2
• DERIVED PRODUCTS ALSO KNOWN AS
EICOSANOIDS BCOS DERIVED FROM 20-CARBON
FATTY ACID ARE SYNTHESIZED BY TWO MAIN
PATHWAYS:
• CYCLOOXYGENASE => PGS (PGI2, PGD2, PGE2,
THROMBOXANE A2
• LIPOXYGENASE => LTS (LTA4, LTB4, LTC4 LTD4,
LTE4) -> (LTC4 LTD4, LTE4 CAUSE BRONCHOSPASM
AND INCREASED VP)
• PGI2 -> VD, INHIBIT PLATELET AGGREGATION
• PGD2, PGE2 -> VD, INCREASED VP
• TXA2 -> VC, PROMOTE PLATELET AGGREGATION
• LIPOXINS, ONE OF THE NEW MEDIATOR
FROM AA METABOLISM
• INHIBIT CHEMOTAXIS
• VASODILATATION
• COUNTERACT ACTIONS OF
LEUKOTRIENES
NB
• IMPORTANCE IN INFLAM HAS GIVEN ATTEMPT TO
DEVELOP DRUGS THAT INHIBIT THESE PRODUCTS OR
ACTION -> THUS SUPPRESS INFLAM (ASPIRIN,
NSAIDS)
• CORTICOSTEROIDS ARE BROAD-SPECTRUM ANTI-
INFLAM AGENTS -> REDUCE THE TRANSCRIPTION OF
GENES THAT ENCODE COXYGENASE-2,
PHOSPHOLIPASE A2
• INCREASING THE CONSUMPTION OF FISH OIL -> POOR
SUBSTRATE FOR CONVERSION TO ACTIVE
METABOLITES BY THE TWO PATHWAYS, BUT BETTER
SUBSTRATE FOR THE PRODUCTION OF ANTI-INFLAM
LIPID PRODUCTS
CYTOKINES AND CHEMOKINES
• CYTOKINES ARE PROTEINS PRODUCED BY MANY CELLS
• BUT USUALLY BY LYMPHOCYTES AND MACROPHAGES
• THE TWO MOST CLASSICAL AND FAMOUS ONES ARE TNF-Α AND
INTERLEUKIN-1
• TNF-Α (TUMOR NECROSIS FACTOR, OR CACHECTIN), IS A
SUBSTANCE THAT IS DESTRUCTIVE OF HUMAN TISSUES, AND IS
A KEY PLAYER IN “CACHEXIA”
• TNF AND IL-1 SERVE IN LEUCOCYTE RECRUITMENT BY
PROMOTING ADHESION OF THE CELLS TO ENDOTHELIUM AND
THEIR MIGRATION THRU THE VESSELS
• PRODUCED BY MACROPHAGES, DENDRITIC CELLS, T-
LYMPHOCYTES AND MAST CELLS
• IL-1 IS ALSO PRODUCED BY EPITHELIAL CELLS
• INTERLEUKIN-1 WAS THE FIRST OF MANY INTERLEUKINS
DISCOVERED
• GENERALLY PROPAGATES THE INFLAMMATORY RESPONSE AT
MANY LEVELS
• ALSO HAS A SIGNIFICANT EFFECT ON T-CELLS
THEIR COMBINED ACTIONS INCLUDE:
• LEUCOCYTE ACTIVATION
• ENDOTHELIAL ACTIVATION
• SYSTEMIC ACUTE-PHASE RESPONSE OF FEVER, SEPSIS,
CACHEXIA
• TNF ANTAGONISTS ARE EFFECTIVE IN THE TREATMENT OF
CHRONIC INFLAM DS LIKE RA, PSORIASIS
• CHEMOKINES ARE SMALL PROTEINS WHICH ARE
ATTRACTANTS FOR PMN
• ABOUT 40 IDENTIFIED WITH 20 DIFF RECEPTORS
• CLASSIFIED INTO 4 GROUPS ACCORDING TO THE POSITION OF
CYSTEINE RESIDUES
• C-X-C (IL-8), ACTS ON PMN (ACTIVATION AND CHEMOTAXIS)
• C-C INCLUDES MONOCYTE CHEMOTACTIC PROTEIN 1 (MCP-1),
EOTAXIN, MACROPHAGE INFLAM PROTEIN-1Α (MIP-1Α ) AND
RANTES (REGULATED AND NORMAL T-CELL EXPRESSED AND
SECRETED)
• ATTRACT MONOCYTES, OESINOPHILS, BASOPHILS AND
LYMPHOCYTES
• THOUGH HAVE OVERLAPPING ACTIONS BUT ->
• EOTAXINS SELECTIVELY RECRUIT OESINOPHILS
• C CHEMOKINES (LYMPHOTACTINS) ARE RELATIVELY SPECIFIC
FOR LYMPHOCYTES
• CX3C (FRACTALKINE) ARE SURFACE BOUND PROTEINS
• INDUCE ENDOTHELIAL CELLS AND PROMOTE STRONG
ADHESION OF MONOCYTE AND T-CELLS
• ALL ACT BY BINDING TO SEVEN- TRANSMEMBRANE G
PROTEIN-COUPLED RECEPTORS
• THESE ARE CALLED CXCR OR CCR FOR C-X-C OR C-C
CHEMOKINE RECEPTORS
• NB: CERTAIN RECEPTORS (CXCR-4, CCR-5) ACT AS
CORECEPTORS FOR A VIRAL ENVELOPE GLYCOPROTEIN OF
HIV, HENCE THEIR ABSENCE IS PROTECTIVE AGAINST HIV
INFECTION
• FUNCTIONS OF CHEMOKINES INCLUDE:
• STIMULATE LEUCOCYTE ATTACHMENT TO ENDOTHELIUM AND
MIGRATION TO THE SITE
• MAINTENANCE OF TISSUE ARCHITECTURE BY HOMEOSTATIC
CHEMOKINES
• OTHER CYTOKINES IN INFLAMMATION:
• IL-17 – PRODUCE BY T-LYMPHOCYTES, PROMOTE PMN
RECRUITMENT
• TYPE 1 INTERFERON (INHIBIT VIRAL REPLICATION),
CONTRIBUTE TO SYSTEMIC MANIFESTATIONS OF INFLAM
COMPLEMENT SYSTEM
• CONSISTS OF MORE THAN 20 PROTEINS NUMBERED C1 TO C9
• FUNCTION BOTH IN INNATE AND ADAPTIVE IMMUNITY
• WHEN ACTIVATED, SEVERAL CLEAVAGE PRODUCTS ARE
ELABORATED -> IVP, CHEMOTAXIS AND OPSONIZATION
• CRITICAL STEP IS THE PROTEOLYSIS OF THE THIRD
COMPLEMENT, C3
• ACTIVATION OCCURS IN 3 WAYS:
• THE CLASSICAL PATHWAYS- TRIGGERED BY FIXATION OF C1
TO AB (IGM OR IGG) THAT HAS COMBINED WITH AG
• THE ALTERNATE PATHWAY, TRIGGERED BY MICROBIAL
SURFACE MOLECULES, COMPLEX POLYSACCHARIDES, COBRA
VENOM
• NO AB. IS INVOLVED
• THE LECITHIN PATHWAY IN WHICH PLASMA MANNOSE-
BINDING LECTIN BINDS TO CARBOHYDRATE ON MICROBES AND
DIRECTLY ACTIVATE C1
• ALL PATHWAYS LEAD TO FORMATION OF AN ACTIVE ENZYME
(C3A CONVERTASE) THAT SPLITS C3 INTO C3A AND C3B
• C3A IS RELEASED, WHILE C3B BIND TO CELL WHEN
COMPLEMENT IS BEING ACTIVATED TO FORM C5 CONVERTASE -
> CLEAVES C5 TO RELEASE C5A AND LEAVE C5B TO ATTACH TO
THE CELL SURFACE
• C5B BIND TO LATE COMPLEMENTS (C6-C9) TO FORM
MEMBRANE ATTACK COMPLEX (MAC)
MAIN EFFECTS INCLUDE:
• INFLAMMATION - C3A AND C5A STIMULATE HISTAMINE
RELEASED FROM MAST CELLS -> IVP AND VD
(ANAPHYLACTOXIN)
• C5A IS CHEMOTACTIC AGENT FOR PMN, MONOCYTES,
OESINOPHILS AND BASOPHILS
• ALSO ACTIVATES LIPOXYGENASE PATHWAY OF AA METABOLISM
• OPSONIZATION AND PHAGOCYTOSIS – C3B AND ITS CLEAVAGE
PRODUCT, IC3B ACT AS OPSONINS AND PROMOTE
PHAGOCYTOSIS BY PMN AND MACROPHAGES
• CELL LYSIS – THE DEPOSITION OF MAC ON
CELLS MAKE THEM PERMEABLE TO WATER
AND IONS -> RESULTS IN THE DEATH OR
LYSIS.
• IMPORTANT FOR THE KILLING OF
MICROBES WITH THIN CELL WALL
• THE ACTIVATION OF COMPLEMENT IS
CONTROLLED BY CELL-ASSOCIATED AND
CIRCULATING REGULATORY PROTEINS
SUCH AS C1 INHIBITORS (C1-INH), DECAY
ACCELERATING FACTOR (DAF) AND ID59
• IS A PHOSPHOLIPID –DERIVED MEDIATOR THAT WAS
PLATELET ACTIVATING FACTOR

DISCOVERED TO CAUSE PLATELET AGGREGATION

• ALSO KNOWN AS A PAF, PAF ACETHER OR AGEPC
(ACETYL-GLYCERYL-ETHER-PHOSPHORYLCHOLINE)
• ELABORATE FROM PLATELETS, BASOPHILS, MAST
CELLS, PMN, MACROPHAGES AND ENDOTHELIAL
CELLS
• MEDIATOR OF MANY LEUKOCYTE FUNCTIONS,
INCLUDING PLATELET AGGREGATION AND
DEGRANULATION, INFLAMMATION, AND
ANAPHYLAXIS
• ALSO INVOLVED IN CHANGES TO VASCULAR
PERMEABILITY, THE OXIDATIVE BURST,
CHEMOTAXIS OF LEUKOCYTES, AND STIMULATE
ARACHIDONIC ACID METABOLISM
• TRIALS OF PAF ANTAGONIST IN VARIOUS INFLAM DS
PRODUCTS OF COAGULATION
• MAINLY INVOLVED IN CLOTTING
PROCESS
• INHIBITION OF COAGULATION
REDUCES INFLAMMATORY RXN
• PROTEASE(THROMBIN) CLEAVES
FIBRINOGEN TO PRODUCE FIBRIN
• ALL FORMS OF TISSUE INJURY
THAT LEAD TO CLOTTING ALSO
INDUCE INFLAMMATION
KININS

• ARE VASOACTIVE PEPTIDES DERIVED FROM

PLASMA PROTEINS (KININOGEN) BY THE
ACTION OF KALLIKREINS
• KALLIKREIN CLEAVES HMW KININOGEN TO
PRODUCE BRADYKININ -> IVP AND
CONTRACTION OF SMOOTH MUSCLE,
DILATATION OF BVS AND INDUCE PAIN
• ACTION IS SHORT-LIVED BCOS INACTIVATED
BY KININASE
• IMPORTANT MEDIATOR IN ALLERGIC RXN
(ANAPHYLAXIS)
NEUROPEPTIDES
• ARE SECRETED BY SENSORY NERVES AND
LEUCOCYTES
• PLAY A ROLE IN INITIATION AND
REGULATION OF INFLAMMATION RESPONSES
• EXAMPLES ARE SUBSTANCE P AND
NEUROKININ A
• PRODUCED IN CNS AND PNS
• SUBSTANCE P HAS FUNCTIONS AS
TRANSMISSION OF PAIN SIGNALS,
REGULATION OF BP, STIMULATION OF
HORMONE SECRETION BY ENDOCRINE CELLS
AND IVP
FREE RADICALS
•THESE ARE GENERATED THROUGH A
VARIETY OF ENZYMATIC PATHWAYS
•ONE OF THE MAIN KILLING MECHANISMS OF
MICROBES
•THEY ALL AFFECT THE NADPH SYSTEM
THREE TYPES:
•O2 – (SUPEROXIDE)
•H2O2 (PEROXIDE)
•OH- (HYDROXYL RADICAL)
LYSOSOMAL CONSTITUENTS
• MYELOPEROXIDASE (MPO) PRODUCES
HYPOCHLORIC ACID AND TYROSYL RADICAL
THAT ARE CYTOTOXIC, SO THEY ARE USED BY
THE NEUTROPHIL TO KILL BACTERIA AND
OTHER PATHOGENS
• IT IS WHAT MAKES PUS LOOK GREENISH YELLOW
• LACTOFERRIN (LF), ALSO KNOWN
AS LACTOTRANSFERRIN (LTF), IS
A GLOBULAR MULTIFUNCTIONAL PROTEIN WITH
ANTIMICROBIAL ACTIVITY (BACTERIOCIDE,
FUNGICIDE)
• LYSOZYMES, ALSO KNOWN AS MURAMIDASE
OR N-ACETYLMURAMIDE GLYCANHYDROLASE,
ARE A FAMILY OF ENZYMES (EC 3.2.1.17) WHICH
DAMAGE BACTERIAL CELL WALLS BY
CAUSING HYDROLYSIS
NITRIC OXIDE
• POTENT VASODILATOR
• PRODUCED FROM THE ACTION
OF NITRIC OXIDE SYNTHETASE
FROM ARGININE
ROLE OF MEDIATORS IN DIFFERENT REACTIONS
OF INFLAMMATION

REACTIONS PRINCIPAL MEDIATORS

• VD HISTAMINE, PGS
• IVP HISTAMINE, SEROTONIN, C3A, C5A,
LTC4 D4 E4
• CHEMOTAXIS
• RECRUITMENT
• ADHESION TNF, IL-1, CHEMOKINES, C3A,
C5A, LTB4
• FEVER IL-4, TNF PGS
• PAIN PGS, BRADYKININ
• TISSUE DAMAGE LYSOSOMAL ENZYMES, ROS
MORPHOLOGY PATTERNS (EXUDATES)

• IMPORTANCE OF RECOGNIZING THE GROSS AND

MICROSCOPIC PATTERN IS THAT THEY OFTEN
PROVIDE VALUABLE CLUES ABOUT THE
UNDERLYING CAUSE
SEROUS (WATERY)
• MARKED BY EXUDATION OF CELL-POOR FLUID
INTO SPACES CREATED BY CELLS OR INTO BODY
CAVITIES
• IS NOT INFECTED AND DOES NOT CONTAIN
LARGE NUMBERS OF LEUKOCYTES
• ACCUMULATION IN BODY CAVITIES IS EFFUSION
FIBRINOUS (HEMORRHAGIC, RICH IN FIBRIN)
• CONTAIN LARGE MOLECULES OF FIBRINOGEN PASS
OUT AND FORM FIBRIN
• DEPOSITED AT EXTRACELLULAR SPACE
• COMMONLY SEEN IN THE LINING OF BODY CAVITIES
SUCH AS MENINGES, PERICARDIUM AND PLEURAL
• APPEARS AS OESINOPHILIC, MESH WORK OF THREADS
OR AMORPHOUS COAGULUM
• MAY BE DISSOLVED BY FIBRINOLYSIS, CLEANED UP BY
MACROPHAGES OR FIBROBLASTS AND BVS GROW
INWARD ->SCARRING
SUPPURATIVE (PURULENT)
• XTERISED BY PRODUCTION OF PUS
• AN EXUDATE CONSISTING OF
NEUTROPHILS, LIQUEFIED DEBRIS OF
NECROTIC CELLS AND OEDEMA FLUID
• CAUSE BY PYOGENIC BACTERIA, E.G.
ACUTE APPENDICITIS
• ABSCESS IS A LOCALIZED COLLECTION
OF PURULENT INFLAM TISSUE BURIED
IN A TISSUE OR ORGAN OR A
CONFIRMED SPACE
ULCERATIVE
• AN ULCER IS A LOCAL DEFECT OR EXCAVATION
OF THE SURFACE OF AN ORGAN OR TISSUE
• PRODUCED BY THE SLOUGHING OR SHEDDING
OF INFLAMMED NECROTIC TISSUE
• CAN OCCUR ONLY WHEN TISSUE NECROSIS
AND RESULTANT INFLAM EXIST ON OR NEAR A
SURFACE
• ENCOUNTERED IN THE MUCOSA OF GIT
• BEST EXAMPLE IS PEPTIC ULCER (GASTRIC OR
DUODENAL)
OUTCOMES OF ACUTE INFLAMMATION
ALL ACUTE INFLAMMATORY REACTIONS
TYPICALLY HAVE ONE OF THREE
OUTCOMES:
COMPLETE RESOLUTION TO NORMAL
TISSUE
HEALING BY CONNECTIVE TISSUE
REPLACEMENT/SCAR
PROGRESSION TO CHRONIC
INFLAMMATION DUE TO: ACUTE INFLAM
CANNOT BE RESOLVED OR PERSISTENCE
OF INJURIOUS AGENT OR SOME
INTERFERENCE WITH NORMAL PROCESS
CHRONIC INFLAMMATION
• IS A RESPONSE OF PROLONGED DURATION (WEEKS OR
MONTHS) IN WHICH INFLAM, TISSUE INJURY AND
ATTEMPT AT REPAIR COEXIST
• MAY FOLLOW ACUTE INFLAM OR BEGINS INSIDIOUSLY
• CAUSES:
PERSISTENCE OF INFECTION
• MICROORGANISM DIFFICULT TO ERADICATE SUCH AS
MYCO TB, CERTAIN VIRUSES, FUNGI AND PARASITES
• ORGANISMS EVOKE DELAYED TYPE HYPERSENSITIVITY
RXN
• MAY TAKE SPECIFIC PATTERN LIKE GRANULOMATOUS
RXN
PROLONGED EXPOSURE TO INSULT
• FROM AGENTS THAT ARE POTENTIALLY TOXIC, EITHER
EXOGENOUS OR ENDOGENOUS
• EXAMPLES ARE PARTICLES OF SILICA (A NON
DEGRADABLE MATERIAL), WHEN INHALED FOR
PROLONGED PERIOD -> SILICOSIS, ATHEROSCLEROSIS IS
A CHRONIC INFLAM PROCESS OF THE ARTERIAL WALL
AUTO-IMMUNITY
• DUE TO EXCESSIVE AND INAPPROPRIATE ACTIVATION OF
IMMUNE SYSTEM
• MAYBE AGAINST SELF TISSUE (AUTOIMMUNE
DISEASES) OR AS A RESULT OF UNREGULATED IMMUNE
RESPONSE AGAINST MICROBES AS IN (INFLAM BOWEL
DISEASE)
MORPHOLOGY
• XTERISED BY INFILTRATION WITH
MONONUCLEAR CELLS (MACROPHAGES,
LYMPHOCYTES AND PLASMA CELLS)
• TISSUE DESTRUCTION EITHER BY PERSISTENT
OF INJURIOUS AGENT OR INFLAMMED CELLS
• ATTEMPTS AT HEALING BY CONNECTIVE TISSUE
REPLACEMENT OF DAMAGED TISSUE
ACCOMPANIED BY ANGIOGENESIS AND FIBROSIS
CELLS AND MEDIATORS OF CHRONIC
INFLAMMATION
MACROPHAGES – ARE PROFESSIONAL
PHAGOCYTES THAT ACT AS FILTERS FOR
PARTICULAR MATTER, MICROBES AND SENESCENT
CELLS
• DERIVED FROM HAEMOPOIETIC STEM CELLS IN
BONE MARROW AND FROM PROGENITORS IN THE
EMBRYONIC YOLK SAC
• CIRCULATING CELLS OF THIS LINEAGE ARE
KNOWN AS MONOCYTES
• FOUND IN SPECIFIC ORGANS
• TISSUE -> HISTIOCYTES
• LIVER -> KUPFFER CELLS
• SPLEEN/LN -> SINUS HISTIOCYTES
• CNS -> MICROGLIAL CELLS
• LUNGS -> ALVEOLAR MACROPHAGES
• SKIN -> LANGERHAN CELLS
• FORM THE MONOCYTE PHAGOCYTIC SYSTEM OR
RETICULOENDOTHELIAL SYSTEM
• WHEN ACTIVATED, THEIR PRODUCTS ELIMINATE
INJURIOUS AGENTS AND INITIATE THE PROCESS OF
REPAIR.
LYMPHOCYTES – MICROBES AND OTHER
ENVIRONMENTAL AGENTS ACTIVATE T AND B
LYMPHOCYTES WHICH AMPLIFY AND
PROPAGATE CHRONIC INFLAMMATION
• ABILITY TO SECRETE CYTOKINES ENABLE CD4+
T-LYMPHOCYTES TO PROMOTE INFLAMMATION
• ACTIVATED B-LYMPHOCYTES AND AB-
PRODUCING PLASMA CELLS ARE OFTEN
PRESENT AT SITES OF CHRONIC INFLAMMATION
OESINOPHILS – ARE ABUNDANT IN IMMUNE RXNS
MEDIATED BY IGE AND IN PARASITIC INFECTIONS
• RECRUITMENT IS DRIVEN BY ADHESION
MOLECULES AND SPECIFIC CHEMOKINE
(EOTAXIN)
• HAVE GRANULES THAT CONTAIN MAJOR BASIC
PROTEIN, A HIGHLY CATIONIC PROTEIN THAT IS
TOXIC TO PARASITES, HENCE THEIR NUMBERS IN
PARASITIC MANIFESTATION
MAST CELLS – WIDELY DISTRIBUTED IN CONNECTIVE
TISSUE
• PARTICIPATE IN BOTH ACUTE AND CHRONIC
INFLAMMATORY RXNS
• EXPRESSED ON THEIR SURFACES THE RECEPTORS THAT
BIND THE FC PORTION OF IGE AB -> IMMEDIATE
HYPERSENSITIVITY RXNS
• FOODS, INSECT VENOM, DRUGS CAN TRIGGER THIS
WITH CATASTROPHIC RESULTS (ANAPHYLACTIC
SHOCK)
NEUTROPHILS – ALTHOUGH XTERISTIC OF
ACUTE INFLAM, MAY FORMS OF CHRONIC
INFLAM
• SHOW LARGE NUMBERS OF NEUTROPHILS,
INDUCED EITHER BY PERSISTENT MICROBES
OR BY MEDIATORS PRODUCED BY
ACTIVATED MACROPHAGES AND T
LYMPHOCYTES
• EXAMPLES: CHRONIC BACTERIA INFECTION
OF BONE (OSTEOMYELITIS), IN LUNGS BY
SMOKING AND OTHER IRRITANT STIMULI
• ALSO KNOWN AS ACUTE ON CHRONIC
INFLAMMATION
GRANULOMATOUS INFLAMMATION
• IS A FORM OF CHRONIC INFLAMMATION
XTERISED BY COLLECTIONS OF ACTIVATED
MACROPHAGES OFTEN WITH T
LYMPHOCYTES AND SOMETIMES
ASSOCIATED WITH CENTRAL NECROSIS
• ACTIVATED MACROPHAGES MAY DEVELOP
ABUNDANT CYTOPLASM THAT RESEMBLE
EPITHELIAL CELLS (EPITHELIOID CELLS)
• SOME MAY FUSE TO FORM
MULTINUCLEATED GIANT CELLS
• FOREIGN BODY GRANULOMAS ARE FORMED
AROUND FOREIGN MATERIAL LIKE TALC,
SUTURES
• EPITHELIOID CELLS
AND GIANT CELLS ARE
APPOSED TO THE SURFACE OF THE FB WHICH
OFTEN CAN BE SEEN WITH POLARIZED LIGHT
• IMMUNE GRANULOMAS CAUSED BY A VARIETY
OF AGENTS THAT ARE CAPABLE OF INDUCING A
PERSISTENT T- CELL MEDIATED IMMUNE
RESPONSE
GRANULOMA
 SYSTEMIC EFFECTS OF INFLAMMATION
• INFLAM IS ASSOCIATED WITH CYTOKINE-INDUCED
SYSTEMIC RXNS CALLED ACUTE PHASE RESPONSE
• THE CYTOKINES INVOLVED ARE TNF, IL-1, IL-6, TYPE 1
INTERFERON
• FEVER – INDUCED BY PYROGENS DUE TO PGS, LPS
(EXOGENOUS) AND INDUCE CYTOKINES TO RELEASE IL-
1 AND TNF (ENDOGENOUS)
• ACUTE PHASE PROTEINS – ARE PLASMA PROTEINS
MOSTLY SYNTHESIZED IN THE LIVER WHICH INCREASE
SEVERAL FOLDS IN INFLAMMATION
• THEY ARE C-REACTIVE PROTEIN, FIBROGEN AND
SERUM AMYLOID A (SAA)
• LEUKOCYTOSIS – COMMON FEATURES OF
INFLAM RXN ESPECIALLY THOSE INDUCED
BY BACTERIAL INFECTION
• THE COUNT RANGES FROM 15,000- 20,000
CELLS/ML
• SOMETIMES MAY BE UP TO 40,000-100,000
CELLS/ML (LEUKAEMOID REACTION)
• ASSOCIATED WITH MORE IMMATURE
NEUTROPHILS IN THE BLOOD -> LEFT
SHIFT
• IF BACTERIA INFLAM -> NEUTROPHILIA
• IF VIRAL -> LYMPHOCYTOSIS
• ALLERGIC OR PARASITIC ->
OESINOPHILIA
• IN SOME LIKE TYPHOID, RICKETTSIA,
CERTAIN PROTOZOA -> LEUKOPENIA
OTHER MANIFESTATIONS
• INCREASE PULSE RATE AND BLOOD PRESSURE
• DECREASED SWEATING
• RIGORS (SHIVERING)AND CHILLS
• ANOREXIA
• SOMNOLENCE AND MALAISE
• IN SEVERE BACTERIAL INFECTION
(SEPTICAEMIA) -> DIC, HYPOTENSIVE SHOCK
AND METABOLIC DISTURBANCES (INSULIN
RESISTANCE AND HYPERGLYCAEMIA) -> SEPTIC
SHOCK
• QUESTIONS/COMMENT
 HEALING AND REPAIR

• REGENERATION: GROWTH OF CELLS TO

REPLACE LOST TISSUES (NORMAL PROCESS)
• HEALING: A REPARATIVE TISSUE RESPONSE TO
A WOUND, INFLAMMATION OR NECROSIS,
OFTEN LEADS TO FIBROSIS (FOLLOWS
DAMAGE)
• GRANULATION TISSUE
REGENERATION

• REPLACEMENT OF LOST STRUCTURES

• IS DEPENDENT ON THE TYPE OF NORMAL
TURNOVER THE ORIGINAL TISSUE HAS
• CAN BE DIFFERENTIATED FROM
“COMPENSATORY” GROWTH
• AN EXAMPLE OF COMPENSATORY GROWTH IS
WHEN ONE KIDNEY BECOMES LARGER AFTER A
NEPHRECTOMY, OR THE LEFT PORTION ON THE
RIGHT LOBE OF THE LIVER “ENLARGES” AFTER
A LEFT LOBECTOMY
HEALING (REPAIR)
• NEEDS A WOUND, INFLAMMATORY PROCESS OR
NECROSIS
• MANY DISEASE APPEARANCES ANATOMICALLY
ARE THE RESULT OF “HEALING” SUCH AS
ATHEROSCLEROSIS
• OFTEN ENDS WITH A SCAR
• FIBROSIS, AS ONE OF THE 3 POSSIBLE
OUTCOMES OF INFLAMMATION, FOLLOWS
“HEALING”
• REQUIRES A CONNECTIVE TISSUE “SCAFFOLD”
• FIBROSIS OCCURS IN PROPORTION TO THE
DAMAGE OF THE ECM
• STEM CELL
• CELLS DERIVED FROM STEM CELLS
CAN DO ONLY THREE THINGS
1) MULTIPLY
2) DIFFERENTIATE
3) DIE (APOPTOSIS)
FATE OF CELL POPULATION

• PROLIFERATION

• HORMONAL, ESPECIALLY STEROID

HORMONES
• E.G. ERYTHROPOIETIN, COLONY
STIMULATING FACTOR
• DIFFERENTIATION (KEY IN NEOPLASIA)

• UNIDIRECTIONAL, GAIN (SPECIALIZATION)

AND LOSS (VERSATILITY)
• APOPTOSIS
CELL CYCLE

• G0 - QUIESCENT (NOT A VERY LONG OR

DOMINANT PHASE)
• G1 - PRE-SYNTHETIC, BUT CELL GROWTH
TAKING PLACE
• S - CELLS WHICH HAVE CONTINUOUS
“TURNOVER” HAVE LONGER, OR LARGER S-
PHASES, I.E., DNA SYNTHESIS, S-PHASE OF
TUMOR CELLS CAN BE PROGNOSTIC
• G2 - PRE-MITOTIC
• M (MITOTIC:, P,M,A,T, CYTOKINESIS)
 CELL TYPES
• LABILE: MARROW, GI
• QUIESCENT OR STABLE: LIVER,
KIDNEY
• NON-MITOTIC OR PERMANENT:
NEURON, STRIATED MUSCLE
• TOTIPOTENTIAL OR
PLEUPOTENTIAL OR STEM
CELLS: ABILITY TO
DIFFERENTIATE MANY LINES
GROWTH FACTORS (GF)

• POLYPEPTIDES
• CYTOKINES
FUNCTIONS
• LOCOMOTION
• CONTRACTILITY
• DIFFERENTIATION
• ANGIOGENESIS
TYPES

EPIDERMAL (EGF)
• MADE IN PLATELETS, MACROPHAGES
• PRESENT IN SALIVA, MILK, URINE, PLASMA
• ACTS ON KERATINOCYTES TO MIGRATE, DIVIDE
• ACTS ON FIBROBLASTS TO PRODUCE “GRANULATION” TISSUE
TRANSFORMING GF-ALPHA
• MADE IN MACROPHAGES, T-CELLS,
KERATINOCYTES
• SIMILAR TO EGF, ALSO EFFECT ON
HEPATOCYTES
TRANSFORMING GF –BETA
• MADE IN MANY CELLS
• CHEMOTACTIC FOR PMNS AND MANY OTHER
TYPES OF CELLS
• INHIBITS EPITHELIAL CELLS
• FIBROGENIC
• ANTI-INFLAMMATORY
HEPATOCYTE (HGF)
• MADE IN MESENCHYMAL CELLS
• PROLIFERATION OF EPITHELIUM,
ENDOTHELIUM, HEPATOCYTES
• EFFECT ON CELL MOTILITY
VASCULAR ENDOTHELIAL (VEGF)
• MADE IN MESENCHYMAL CELLS
• TRIGGERED BY HYPOXIA
• INCREASES VASCULAR PERMEABILITY
• MITOGENIC FOR ENDOTHELIAL CELLS
• KEY SUBSTANCE IN PROMOTING
GRANULATION TISSUE
PLATELET DERIVED (PDGF)
• MADE IN PLATELETS, BUT ALSO
MANY OTHER CELL TYPES
• CHEMOTACTIC FOR MANY CELLS
• MITOGEN FOR FIBROBLASTS
• ANGIOGENESIS
• ANOTHER KEY PLAYER IN
GRANULATION TISSUE
FIBROBLAST (FGF)
• MADE IN MANY CELLS
• CHEMOTACTIC AND MITOGENIC,
FOR FIBROBLASTS AND
KERATINOCYTES
• RE-EPITHELIALIZATION
• ANGIOGENESIS, WOUND
CONTRACTION
• HAEMATOPOESIS
• CARDIAC/SKELETAL (STRIATED)
MUSCLE
KERATINOCYTE GROWTH
FACTOR (KGF)
• MADE IN FIBROBLASTS
• STIMULATES
KERATINOCYTES:
• MIGRATION
• PROLIFERATION
• DIFFERENTIATION
CYTOKINES (INTERFERONS, IL-1 &
TUMOR NECROSIS FACTOR, TNF)
• MADE IN MACROPHAGES, MAST
CELLS, T-CELLS
• ACTIVATES MACROPHAGES
(CACHEXIN)
• KEY INFLUENCE ON OTHER
CYTOKINES
• THE MAJOR TNF IS TNF-ALPHA
INTERLEUKINS
THERE ARE UP TO 36 INTERLEUKINS
• MADE IN MACROPHAGES, MAST
CELLS, T-CELLS, BUT OTHER CELLS
• MANY FUNCTIONS:
• CHEMOTAXIS
• ANGIOGENESIS
• REGULATION OF OTHER CYTOKINES
INTERFERONS
• MADE BY LYMPHOCYTES,
FIBROBLASTS
• ACTIVATES MACROPHAGES
• INHIBITS FIBROBLASTS
• REGULATES OTHER CYTOKINES
INSULIN-LIKE) GF-1

• MADE IN MACROPHAGES,
FIBROBLASTS
• STIMULATES:
• SULFATED PROTEOGLYCANS
• COLLAGEN
• KERATINOCYTE MIGRATION
• FIBROBLAST PROLIFERATION
• ACTION SIMILAR TO GH (PITUITARY
GROWTH HORMONE)
SIGNALING
• AUTOCRINE (SAME CELL)

• PARACRINE (NEXT DOOR NEIGHBOR) (MANY GFS)

• ENDOCRINE
HORMONES)
(FAR AWAY, DELIVERED BY BLOOD, STEROID
EXTRACELLULAR MATRIX (ECM)

• COLLAGEN(S) I-XXVII
• ELASTIN
• FIBRILLIN
• CAMS (CELL ADHESION
MOLECULES)
•
IMMUNOGLOBULINS, CADHERINS, INTEGRINS, SELECTINS

• PROTEOGLYCANS
• HYALURONIC ACID
FUNCTIONS OF ECM

• MAINTAIN CELL DIFFERENTIATION

• SCAFFOLDING
• ESTABLISH MICROENVIRONMENT
• STORAGE OF GF’S
COLLAGENS –MANY TYPES
• COLLAGEN ONE - B ONE (MAIN COMPONENT OF BONE)
• COLLAGEN TWO - CAR TWOLAGE (MAIN COMPONENT OF
CARTILAGE)

• COLLAGEN THREE - RE THREECULATE (MAIN

COMPONENT OF RETICULAR FIBERS)

• COLLAGEN FOUR - FLOOR - FORMS THE BASEMENT

MEMBRANE
• REGENERATION: GROWTH OF CELLS TO
REPLACE LOST TISSUES

• HEALING: A REPARATIVE TISSUE RESPONSE TO A

WOUND, INFLAMMATION OR NECROSIS
 HEALING
• FOLLOWS INFLAMMATION
• PROLIFERATION AND MIGRATION OF
CONNECTIVE TISSUE CELLS
• ANGIOGENESIS (NEOVASCULARIZATION)
• COLLAGEN, OTHER ECM PROTEIN
SYNTHESIS
• TISSUE REMODELING
• WOUND CONTRACTION
• INCREASE IN WOUND STRENGTH (SCAR =
FIBROSIS)
ANGIOGENESIS (NEOVASCULARIZATION)
• FROM ENDOTHELIAL PRECURSOR
CELLS
• FROM PRE-EXISTING VESSELS
• STIMULATED/REGULATED BY GF’S,
ESPECIALLY VEGF
• ALSO REGULATED BY ECM PROTEINS
• AKA “GRANULATION OR GRANULATION
TISSUE”; “ORGANIZATION OR
ORGANIZING INFLAMMATION”
GRANULATION VS. FIBROSIS
THREE PHASES OF REPAIR
TYPES OF WOUND HEALING

1ST INTENTION OR UNION

• EDGES LINED UP
• CLEAN INCISED WOUND E.G. SURGICAL
INCISION
• LESS LIKELY TO BE INFECTED
• LEAVES A VERY THIN SCAR
2ND INTENTION OR UNION
• EDGES NOT LINED UP E.G. BURNS
• PROCESS START FROM THE BASE
• MORE GRANULATION
• MORE EPITHELIALIZATION
• MORE FIBROSIS
• LEAVES CONTRACTURE
• THE PROCESSES ALSO PARALLEL THE
APPEARANCE AND REGRESSION OF
CELLS

• NAMELY, IN ORDER, NEUTROPHILS,

MACROPHAGES, ENDOTHELIAL
CELLS, FIBROBLASTS
FACTORS RETARDING HEALING

LOCAL:

• DECREASED BLOOD
SUPPLY
• DENERVATION
• LOCAL INFECTION
• FOREIGN BODY
• HEMATOMA
• MECHANICAL STRESS
• NECROTIC TISSUE
SYSTEMIC:
• DECREASED BLOOD SUPPLY
• AGE
• ANEMIA
• MALIGNANCY
• MALNUTRITION
• OBESITY
• INFECTION
• ORGAN FAILURE
COMPLICATIONS OF WOUND
HEALING
• INFECTIONS
• DEHISCENCE
• NON-UNION
• MALUNION WITH SHORTENING
• CONTRACTURE
• HYPERTROPHIED SCAR
• KELOID
• ?MALIGNANT TRANSFORMATION
• QUESTIONS/COMMENT
NEOPLASIA

• DEFINITIONS
• NOMENCLATURE
• BIOLOGY OF TUMOR GROWTH
• EPIDEMIOLOGY
• MOLECULAR BASIS OF CANCER
• MOLECULAR BASIS OF CARCINOGENESIS
• AGENTS (THE USUAL SUSPECTS)
• HOST DEFENSE (TUMOR IMMUNITY)
• CLINICAL FEATURES OF TUMORS
DEFINITION OF NEOPLASM
A NEOPLASM IS AN ABNORMAL MASS OF
TISSUE, THE GROWTH OF WHICH EXCEEDS
AND IS UNCOORDINATED WITH THAT OF THE
NORMAL TISSUES AND PERSISTS IN THE
SAME EXCESSIVE MANNER AFTER
CESSATION OF THE STIMULI WHICH
EVOKED THE CHANGE” - WILLIS
• GENETIC CHANGES
• AUTONOMOUS
• CLONAL
• MODEST DEFINITION “A MASS OF TISSUE
FORMED AS A RESULT OF ABNORMAL,
EXCESSIVE, UNCOORDINATED, AUTONOMOUS
AND PURPOSELESS PROLIFERATION OF CELLS
EVEN AFTER CESSATION OF STIMULUS FOR THE
GROWTH WHICH CAUSED IT”
• ONCOLOGY (ONCOS = TUMOUR, LOGOS =
STUDY) – BRANCH OF SCIENCE DEALING WITH
THE STUDY OF NEOPLASM OR TUMOUR
KEY WORDS
• ABNORMAL TISSUE GROWTH
• CONTINUOUS GROWTH
• EXCEEDING NORMAL TISSUE
• UNCOORDINATED
• PURPOSELESS
• PERSISTENCE AFTER REMOVAL
OF STIMULUS
 TERMINOLOGIES
• CANCER – MALIGNANT TUMOURS OF ALL
TISSUES
• MALIGNANT NEOPLASM – CANCERS OF ALL
TISSUES
• CARCINOMA – CANCERS OF EPITHELIAL TISSUE
ORIGIN
• SARCOMA – CANCERS OF CONNECTIVE TISSUE
ORIGIN
• LYMPHOMA – CANCER OF LYMPHOID TISSUES
• LEUKAEMIA – CANCERS OF BLOOD CELLS
• MELANOMA – CANCERS OF SKIN PIGMENT
• SEMINOMA – CANCERS OF THE TESTIS
CANCER = CRAB
(ABILITY TO STICK)
NOMENCLATURE OF CANCERS

TISSUE OF ORIGIN CANCER

EPITHELIAL

Squamous epithelium Squamous Cell Carcinoma

Transitional epithelium Transitional Cell Carcinoma

Glandular epithelium Adenocarcinoma

Basal cell layer Basal Cell Carcinoma

Neuroectoderm Melanoma

Hepatocyte Hepatocellular Carcinoma

Placenta Choriocarcinoma
NON-EPITHELIAL
(MESENCHYMAL)
Adipose Liposarcoma

Fibrous Fibrosarcoma

Cartilage Chondrosarcoma

Bone Osteosarcoma

Smooth Muscle Leiomyosarcoma

Skeletal Muscle Rhabdomyosarcoma

Blood Vessels Angiosarcoma

Haematopoietic Leukaemia

Lymphoid Tissue Lymphoma

• TUMORS WITH MIXED DIFFERENTIATION

• MIXED TUMORS: E.G. PLEOMORPHIC

ADENOMA OF SALIVARY GLAND
• CARCINOSARCOMA
• TERATOMA

• TUMOR COMPRISED OF CELLS FROM

MORE THAN ONE GERM LAYER
• ARISE FROM TOTIPOTENT CELLS
(USUALLY GONADS)
• BENIGN CYSTIC TERATOMA OF
OVARY IS THE MOST COMMON
TERATOMA
• ABERRANT DIFFERENTIATION (NOT
TRUE NEOPLASMS)
• HAMARTOMA: DISORGANIZED
MASS OF TISSUE WHOSE CELL
TYPES ARE INDIGENOUS TO THE
SITE OF THE LESION, E.G., LUNG
• CHORIOSTOMA: ECTOPIC FOCUS
OF NORMAL TISSUE
(HETEROTOPIA), E.G., PANCREAS,
PERHAPS ENDOMETRIOSIS TOO
• HAEMATOMA: COLLECTION OF
BLOOD IN SOFT TISSUE SPACES
• MISNOMERS
• HEPATOMA: MALIGNANT LIVER
TUMOR
• MELANOMA: MALIGNANT SKIN
TUMOR
• SEMINOMA: MALIGNANT
TESTICULAR TUMOR
• LYMPHOMA: MALIGNANT TUMOR
OF LYMPHOCYTES
NATURAL HISTORY OF MALIGNANT
TUMORS

1. MALIGNANT CHANGE IN THE

TARGET CELL, REFERRED TO AS
TRANSFORMATION
2. GROWTH OF THE TRANSFORMED
CELLS
3. LOCAL INVASION
4. DISTANT METASTASES
DIFFERENTIATION
• WELL DIFFERENTIATED NEOPLASM
• RESEMBLES MATURE CELLS OF TISSUE OF
ORIGIN
• POORLY DIFFERENTIATED NEOPLASM
• COMPOSED OF PRIMITIVE CELLS WITH LITTLE
DIFFERENTIATION
• UNDIFFERENTIATED OR “ANAPLASTIC”
TUMOR
• CORRELATION WITH BIOLOGIC BEHAVIOR
• BENIGN TUMORS ARE WELL DIFFERENTIATED
• POORLY DIFFERENTIATED MALIGNANT
TUMORS USUALLY HAVE WORSE PROGNOSIS
THAN WELL DIFFERENTIATED MALIGNANT
ANAPLASIA
•PLEOMORPHISM
•SIZE
•SHAPE
•ABNORMAL NUCLEAR MORPHOLOGY
•HYPERCHROMASIA
•HIGH NUCLEAR CYTOPLASMIC
RATIO
•CHROMATIN CLUMPING
•PROMINENT NUCLEOLI
• MITOSES
• MITOTIC RATE
• LOCATION OF MITOSES
• LOSS OF POLARITY
•DYSPLASIA (PRE-CANCER)
LITERALLY MEANS ABNORMAL GROWTH
• MALIGNANT TRANSFORMATION IS A MULTISTEP
PROCESS
• IN DYSPLASIA SOME BUT NOT ALL OF THE
FEATURES OF MALIGNANCY ARE PRESENT,
MICROSCOPICALLY
• DYSPLASIA MAY DEVELOP INTO MALIGNANCY
• GRADED AS LOW-GRADE OR HIGH-GRADE,
OFTEN PROMPTING DIFFERENT CLINICAL
DECISIONS
• HIGH GRADE DYSPLASIA OFTEN CLASSIFIED
WITH CIS
FEATURES OF MALIGNANT TUMORS

• CELLULAR FEATURES
• LOCAL INVASION
• CAPSULE
• BASEMENT MEMBRANE
• METASTASIS
• UNEQUIVOCAL SIGN OF MALIGNANCY
• SEEDING OF BODY
CAVITIES/TRANSCAELOMIC
• LYMPHATIC
• HAEMATOGENOUS
BENIGN VS. MALIGNANT FEATURES
ENCAPSULATED TUMOUR -
MACROSCOPY
ENCAPSULATED TUMOUR - MICROSCOPY
MALIGNANT TUMOUR – IRREGULAR
EDGES
MALIGNANT TUMOUR - MICROSCOPY
METASTATIC TUMOUR TO LIVER
METASTATIC TUMOUR TO LYMPH NODE
EPIDEMIOLOGY OF CANCER

• OVERALL INCIDENCE OF CANCER IN A POPULATION OR

COUNTRY IS KNOWN BY REGISTRATION OF ALL
CANCER CASES AND BY DEATH FROM CANCER
• THIS IS DONE THROUGH THE CANCER REGISTRY, EITHER
HOSPITAL BASED OR POPULATION BASED
• IN 2008, IT WAS ESTIMATED THAT THERE ARE 12.7
MILLION NEW CANCER CASES WORLDWIDE LEADING TO
7.6 MILLION DEATHS (21,000 DEATHS PER DAY)
• 70% OF DEATHS OCCURRING IN MIDDLE AND LOW
INCOME COUNTRIES
• DUE TO INCREASING POPULATION SIZE AND AGE, BY 2030,
IT IS PROJECTED THAT THE NUMBER OF CASES AND
DEATHS WILL INCREASE TO 21-4 AND 13.2 MILLION
RESPECTIVELY
• AMONG MEN, CANCERS OF THE PROSTATE,
LUNG AND BRONCHUS, AND COLON AND
RECTUM ACCOUNT FOR MORE THAN 56% OF
ALL NEWLY DIAGNOSED CANCERS
• PROSTATE CANCER ALONE ACCOUNTS FOR
APPROXIMATELY 33% (232,090) OF INCIDENT
CASES IN MEN
• IN FEMALES, IT BREAST AND CERVIX CANCERS
THAT ARE COMMON
FIVE MOST COMMON CANCERS IN THE
WORLD

MEN WOMEN CHILDREN

Lung Breast Acute Leukaemia

Prostate Cervix CNS Tumours

Colorectal Lung Bone Sarcoma

Urinary Bladder Colorectal Endocrine Tumours

Lymphoma Endometrial Soft Tissue Sarcoma

• WHO REPORTED THAT ABOUT 24.6
MILLION PEOPLE LIVE WITH CANCER
WORLDWIDE
• 12.5% OF ALL DEATHS ARE ATTRIBUTABLE
TO CANCER AND IT IS ESTIMATED THAT
BY 2020, 16 MILLION NEW CASES WILL BE
DIAGNOSED PER ANNUM OUT OF WHICH
70% WILL BE IN DEVELOPING
COUNTRIES
• INDIGENOUS AFRICANS, 650,000 PEOPLE
OF ESTIMATED 965MILLION ARE
DIAGNOSED OF CANCER ANNUALLY
• LIFETIME RISK OF DYING FROM CANCER
IN AFRICAN WOMEN IS 2 TIMES HIGHER
THAN IN DEVELOPED COUNTRIES
THE WHO ESTIMATED INCIDENCE OF
CANCER FROM ALL SITES IN 2002 FOR
NIGERIA WAS 90.7 AND 100.9 PER 10,000
FOR MALES AND FEMALES RESPECTIVELY
WHILE MORTALITY RATES WERE 72.2 AND
76 RESPECTIVELY
GENERALLY CANCER INCIDENCE IN
NIGERIA APPEARS LOW COMPARED TO
DEVELOPED COUNTRIES WHICH MAY NOT
TRULY REFLECT THE BURDEN
SIMILAR TO REPORTS FROM OTHER
PARTS OF THE WORLD, IT IS SLIGHTLY
HIGHER IN FEMALE
THE SIX MOST COMMON
CANCERS IN NIGERIA

• BREAST
• CERVIX
• PROSTATE
• COLORECTAL
• LIVER CANCER AND
• NON HODGKIN LYMPHOMA
 EPIDEMIOLOGICAL FACTORS

• NO SINGLE FACTOR IS RESPONSIBLE FOR

DEVELOPMENT OF CANCER

• THE ROLE OF SOME FACTORS IN CAUSATION OF

CANCER IS WELL ESTABLISHED

• WHILE THAT OF OTHERS IS EPIDEMIOLOGICAL

AND MANY OTHERS ARE STILL UNKNOWN
• THE PATTERN AND INCIDENCE CANCER
DEPENDS UPON THE FOLLOWINGS:

1. PREDISPOSING EPIDEMIOLOGICAL
FACTORS OR COFACTORS
(ENDOGENOUS HOST FACTORS AND
EXOGENOUS ENVIRONMENTAL FACTORS

2. CHRONIC NON-NEOPLASTIC
(PREMALIGNANT) CONDITIONS.

3. ROLE OF HORMONES IN CANCERS

 PREDISPOSING FACTORS FOR CANCER
• AGE
• MOST CANCERS OCCUR IN PERSONS ≥ 55 YEARS
• CHILDHOOD CANCERS
• LEUKEMIAS & CNS NEOPLASMS
• BONE TUMORS
• GENETIC PREDISPOSITION
• FAMILIAL CANCER SYNDROMES
• EARLY AGE AT ONSET
• TWO OR MORE PRIMARY RELATIVES WITH THE
CANCER
• MULTIPLE OR BILATERAL TUMORS
• POLYMORPHISMS THAT METABOLIZE
PROCARCINOGENS, E.G., NITRITES
•
NONHEREDITARY
PREDISPOSING CONDITIONS

• CHRONIC INFLAMMATION
• PRECANCEROUS CONDITIONS
• CHRONIC ULCERATIVE COLITIS
• ATROPHIC GASTRITIS OF
PERNICIOUS ANEMIA
• LEUKOPLAKIA OF MUCOUS
MEMBRANES
• IMMUNE COLLAPSE
• HORMONES AND CANCER
• CANCER IS LIKELY TO DEVELOP IN
ORGANS AND TISSUES WHICH UNDERGO
PROLIFERATION UNDER THE INFLUENCE
OF EXCESSIVE HORMONAL STIMULATION
• ON CESSATION OF HORMONAL STIMULUS,
SUCH TISSUES BECOME ATROPHIC
• HORMONES SENSATION TISSUE
DEVELOPING TUMOURS ARE BREAST,
ENDOMETRIUM, MYOMETRIUM,
VAGINA, THYROID, LIVER, PROSTATE
AND TESTIS
CARCINOGENESIS
• OESTROGEN – INDUCE CANCERS IN BOTH
EXPERIMENTAL ANIMALS AND HUMANS
• IN MICE INDUCTION OF BREAST CANCER BY
ADMINISTRATION OF HIGH DOSE OF
OESTROGEN AND REDUCTION OF THE
TUMOUR FOLLOWING REMOVAL OF
OVARIES
• HAS BEEN KNOWN THAT ASSOCIATED
INFECTION WITH MOUSE MAMMARY
TUMOUR VIRUS (MMTV) OR BITTNER MILK
FACTOR HAS AN ADDED INFLUENCE WITH
DEVELOPMENT OF BREAST CANCER IN
• CONTRACEPTIVE HORMONES – THE
SEQUENTIAL TYPES OF ORAL CONTRACEPTIVES
INCREASE THE RISK OF DEVELOPING BREAST
CANCER
• HAVE TO BE ON IT FOR A LONG PERIOD
• OTHER TUMOURS INCLUDE BENIGN AND
MALIGNANT TUMOURS OF LIVER
• ANABOLIC STEROIDS – CONSUMPTION OF
ANABOLIC STEROIDS BY ATHLETES TO INCREASE
THE MUSCLE MASS IS NOT ONLY UNETHICAL
ATHLETIC PRACTICE
• BUT ALSO INCREASE THE RISK OF DEVELOPING
BENIGN AND MALIGNANT TUMOURS OF THE
LIVER
• HORMONE-DEPENDENT TUMOURS
• HAS BEEN SHOWN IN EXPERIMENTAL
ANIMALS THAT INDUCTION OF
HYPERFUNCTION OF ADENOPHYSIS
(ANTERIOR PITUITARY) IS ASSOCIATED
WITH INCREASED RISK OF DEVELOPING
OF THE TARGET ORGANS FOLLOWING
PRECEDING FUNCTIONAL HYPERPLASIA
• THERE IS TUMOURS REGRESSION ON
REMOVAL OF THE STIMULATION FOR
EXCESSIVE HORMONAL SECRETION
EXAMPLES
• PROSTATIC CANCER THAT IS ANDROGENIC
DEPENDENT USUALLY RESPONDS TO
ADMINISTRATION OF OESTROGEN
• BREAST CANCER MAY REGRESS WITH
OOPHORECTOMY, HYPOPHYSECTOMY OR
ADMINISTRATION OF MALE HORMONE
• THYROID CANCER MAY SLOW DOWN IN
GROWTH WITH ADMINISTRATION OF
THYRONINE THAT SUPPRESS THE SECRETION OF
TSH BY THE PITUITARY
CARCINOGENESIS

• AETIOLOGY & PATHOGENESIS OF CANCER

• CARCINOGENESIS, ONCOGENESIS OR
TUMOURIGENESIS MEANS MECHANISM OF
INDUCTION OF TUMOURS (PATHOGENESIS)
• AGENTS WHICH CAN INDUCE TUMOURS ARE
CALLED CARCINOGENS (AETIOLOGY)
• INCREASING LIST OF AGENTS IMPLICATED IN
THE AETIOLOGY OF CANCERS
• MOLECULAR PATHOGENESIS OF CANCERS

(ONCOGENES)

• CHEMICAL CARCINOGENESIS (CHEMICAL

CARCINOGENS)

• PHYSICAL CARCINOGENESIS (RADIATION

CARCINOGENS)
MOLECULAR PATHOGENESIS OF
CANCER

• NON-LETHAL GENETIC DAMAGE

• A TUMOR IS FORMED BY THE CLONAL EXPANSION
OF A SINGLE PRECURSOR CELL (MONOCLONAL)
• FOUR CLASSES OF NORMAL REGULATORY GENES
• PROTO-ONCOGENES
• ONCOGENES ONCOPROTEINS
• DNA REPAIR GENES
• APOPTOSIS GENES
• CARCINOGENESIS IS A MULTISTEP PROCESS
SCHEMATIC ILLUSTRATION OF MOLECULAR
BASIS OF CANCER
• MOST CANCERS ARISE FROM A SINGLE CLONE OF
CELLS BY GENETIC TRANSFORMATION OR
MUTATION
• E.G. IN MULTIPLE MYELOMA (CANCER OF PLASMA
CELLS), THERE IS PRODUCTION OF A SINGLE TYPE
OF IMMUNOGLOBULIN OR ITS CHAIN AS SEEN BY
MONOCLONAL SPIKE IN SERUM
ELECTROPHORESIS
FIELD THEORY OF CANCER
• IN AN ORGAN, DEVELOPMENT OF CANCER IN THE
BACKGROUND OF NORMAL CELLS, LIMITED
NUMBER OF CELLS ONLY GROW INTO CANCER
AFTER UNDERGOING SEQUENCE OF CHANGES
UNDER THE INFLUENCE OF AETIOLOGIC AGENTS
• FIELD THEORY OR CONCEPT IS FIELD THEORY OF
MULTI-STEP PROCESS OF CANCER GROWTH
AND PROGRESSION
• CARCINOGENESIS IS A GRADUAL MULTI-STEP PROCESS
INVOLVING MANY GENERATIONS OF CELLS
• THE VARIOUS CAUSES MAY ACT ON THE CELL ONE
AFTER ANOTHER (MULTI HIT PROCESS)
• SAME PROCESS IS ALSO INVOLVED IN FURTHER
PROGRESSION OF THE TURNOVER
• ULTIMATELY, THE CELLS SO FORMED ARE
GENETICALLY AND PHENOTYPICALLY TRANSFORMED
CELLS HAVING PHENOTYPE FEATURES OF
MALIGNANCY
• I.E. EXCESSIVE GROWTH, INVASIVENESS AND DISTAL
METASTASES
• CELL GROWTH OF NORMAL AS WELL AS
ABNORMAL TYPES IS UNDER GENETIC
CONTROL
• IN CANCER, THERE ARE EITHER GENETIC
ABNORMALITIES IN THE CELL OR THERE
ARE NORMAL GENETIC ABNORMAL
EXPRESSION
• THE ABNORMALITIES IN GENETIC
COMPOSITION MAY BE FROM INHERITED OR
INDUCED MUTATION (INDUCED BY
AETIOLOGIC CARCINOGEN AGENTS SUCH
AS CHEMICALS, VIRUSES, RADIATION)
• THE MUTATED CELLS TRANSMIT THEIR
GENETIC REGULATORS OF NORMAL AND ABNORMAL
MITOSIS (CELL DIVISION)
• IN NORMAL CELL GROWTH, REGULATOR GENES CONTROL
MITOSIS AS WELL AS CELL AGING, TERMINATING IN CELL
DEATH BY APOPTOSIS
• IN NORMAL CELL GROWTH, THERE ARE FOUR
REGULATORY GENES
• PROTO-ONCOGENES – GROWTH PROMOTING GENE
(ENCODE FOR CELL PROLIFERATION PATHWAY)
• ANTI-ONCOGENES – GROWTH INHIBITING OR GROWTH –
SUPPRESSOR GENES
• APOPTOSIS REGULATING GENES – CONTROL THE
PROGRAMMED CELL DEATH
• DNA REPAIR GENES – THESE ARE NORMAL GENES WHICH
REGULATE THE REPAIR OF DNA DAMAGE THAT HAS
OCCURRED DURING MITOSIS
PATHOGENESIS OF CANCER

1. ACTIVATING OF GROWTH PROMOTING ONCOGENES

• CAUSING TRANSFORMATION OF CELL
• MUTANT FORM OF NORMAL PROTO-ONCOGENES IN
CANCERS IS TERMED ONCOGENES
• MANY WERE DISCOVERED IN VIRUSES AND HENCE
CALLED V-ONC
• GENE PRODUCTS OF ONCOGENES ARE CALLED
ONCOPROTEINS
• ONCOGENES ARE DOMINANT SINCE THEY APPEAR IN
PRESENCE OF PROTO-ONCOGENES
2. INACTIVATION OF CANCER-SUPPRESSOR GENES (I.E.
INACTIVATION OF ANTI-ONCOGENES)
• PERMITTING THE CELLULAR PROLIFERATION OF
TRANSFORMED CELLS
• ANTI-ONCOGENES ARE ACTIVE IN RECESSIVE FORM
I.E. THEY ARE ACTIVE ONLY IF BOTH ALLELES ARE
DAMAGED
3. ABNORMAL APOPTOTIC REGULATORY GENES
• WHICH MAY ACT AS ONCOGENES OR ANTI-
ONCOGENES
• MAY BE ACTIVE IN DOMINANT OR RECESSIVE
4. FAILURE OF DNA REPAIR GENES
• THUS INABILITY TO REPAIR THE DNA DAMAGE
• RESULTING IN MUTATION
CANCER-RELATED GENES AND CELL GROWTH
(HALLMARKS OF CANCER)

• GENES CONTROL THE NORMAL

CELLULAR GROWTH
• IN CANCER, THESE CONTROLLING GENES
ARE ALTERED, TYPICALLY BY MUTATION
• A LARGE NUMBERS OF SUCH CANCER-
ASSOCIATED GENES HAVE BEEN
DESCRIBED, EACH WITH A SPECIFIC
FUNCTION IN CELL GROWTH
MAJOR GENETIC PROPERTIES OR HALLMARK OF
CANCERS INCLUDE:
• 1. EXCESSIVE AND AUTONOMOUS GROWTH – GROWTH
PROMOTING ONCOGENES
• 2. REFRACTORIES TO GROWTH INHIBITION – GROWTH
SUPPRESSING ONCOGENES
• 3. ESCAPING CELL DEATH BY APOPTOSIS
• 4. AVOIDING CELLULAR AGING
• 5. CONTINUED PERFUSION OF CANCER – CANCER
ANGIOGENESIS
• 6. INVASION AND METASTASIS – CANCER DISSEMINATION
• 7. DNA DAMAGE AND REPAIR SYSTEM –
MUTATOR GENES
• 8. CANCER PROGRESSION AND TUMOUR
HETEROGENEITY – CLONAL AGGRESSIVENESS
• 9. CANCER AS A SEQUENTIAL MULTISTEP
MOLECULAR PHENOMENON – MULTISTEP
THEORY
• 10. MICRORNAS IN CANCER - ONCOMIRS
1. EXCESSIVE AND AUTONOMOUS GROWTH –
GROWTH PROMOTING ONCOGENES
• MUTATED FORM OF NORMAL PROTO-ONCOGENES
ARE CALLED ONCOGENES
• BECOME ACTIVATED BY THE FOLLOWING
MECHANISMS:
• BY MUTATION IN THE PROTO-ONCOGENE WHICH
ALTERS ITS STRUCTURE AND FUNCTION
• BY RETROVIRAL INSERTION IN THE HOST CELL
• BY DAMAGE TO THE DNA SEQUENCE
• BY ERRONEOUS FORMATION OF EXTRA COPIES
OF PROTO-ONCOGENE CAUSING GENE
AMPLIFICATION AND OVEREXPRESSION OR
OVERPRODUCTION THAT PROMOTES AUTONOMOUS
AND EXCESSIVE CELLULAR PROLIFERATION
• TRANSFORMATION FROM PROTO-ONCOGENE TO ONCOGENE OCCURS IN THREE
MECHANISMS
• POINT MUTATION – ALTERATION OF A SINGLE BASE IN THE DNA CHAIN (RAS
ONCOGENE IN BLADDER CANCER)
• CHROMOSOMAL TRANSLOCATION – TRANSFER OF A PORTION OF ONE XSOME
AND MATCHING IT INDEPENDENT OF CELL GROWTH CONTROL
• PHILADELPHIA XSOME IN CML WHERE C-ABL PROTO-ONCOGENE IN XSOME 9 IS
TRANS LOCATED TO XSOME 2
• IN BL, TRANSLOCATION OF C-MYC PROTO-ONCOGENE FROM ITS SITE ON XSOME
TO A PORTION OF XSOME 14)
• GENE AMPLIFICATION I.E. INCREASING THE NUMBER OF COPIES OF DNA
SEQUENCE IN PROTO-ONCOGENE LEADING TO INCREASED OR OVEREXPRESSION
GENE PRODUCTS
• NEUROBLASTOMA HAVING N-MYC HSR GENE
• ERB –B1 IN BREAST AND OVARIAN CANCERS
TYPES OF PROTO-ONCOGENES:
• GROWTH FACTORS
• RECEPTORS FOR GROWTH FACTORS
• CYTOPLASMIC SIGNAL TRANSDUCTION PROTEINS
• NUCLEAR TRANSCRIPTION FACTORS
• CELL CYCLE REGULATORY PROTEINS
2. REFRACTORIES TO GROWTH INHIBITION – GROWTH
SUPPRESSING ONCOGENES
• THE MUTATION OF NORMAL GROWTH SUPPRESSOR ANTI-
ONCOGENE RESULTS IN REMOVAL OF THE BRAKES FOR
GROWTH
• I.E. THE INHIBITORY EFFECT TO CELL GROWTH IS REMOVED
AND THE ABNORMAL GROWTH CONTINUES UNCHECKED
• IN OTHER WORDS, MUTATED ANTI-ONCOGENES BEHAVE LIKE
GROWTH PROMOTING ONCOGENES
EXAMPLES
• RB GENE LOCATED ON LONG ARM OF XSOME13
• FIRST TUMOUR SUPPRESSOR GENE IDENTIFIED
• MUTANT FORM IS INVOLVED IN INHERITED/FAMILIAL FORM OF
RETINOBLASTOMA
• P53 GENE(TP53)
• FUNCTIONS ARE BLOCKING MITOTIC ACTIVITY AND
PROMOTING APOPTOSIS
• CALLED PROTECTIVE OF THE GENOME
• FOUND IN CANCERS OF LUNG, HEAD AND NECK, COLON AND
BREAST
• BRCA 1 AND BRCA 2 GENES
• THESE ARE TWO BREAST (BR) CANCER (CA) SUSCEPTIBILITY
GENES
• BRCA 1 IS LOCATED ON XSOME 17Q21 AND BRCA 2 ON XSOME
13Q12-13
• WOMEN WITH INHERITED DEFECT IN BRCA 1 GENE HAVE 85%
RISK OF DEVELOPING BREAST AND OVARIAN CANCERS
• TEND TO OCCUR AT A RELATIVELY YOUNGER AGE AND MOST
OFTEN TENDS TO BE BILATERAL
TUMOUR SUPPRESSOR ANTI-ONCOGENES
3. ESCAPING CELL DEATH BY APOPTOSIS
• ANOTHER MECHANISM OF GROWTH IS BY
ESCAPING CELL DEATH BY APOPTOSIS
• APOPTOSIS IN NORMAL CELL IS GUIDED BY
CELL DEATH RECEPTOR, CD95, RESULTING
IN DNA DAMAGE
• IN CANCER CELLS, THE FUNCTION OF
APOPTOSIS IS INTERFERED DUE TO
MUTATION IN THE GENES WHICH
REGULATE APOPTOSIS IN THE NORMAL
CELL
EXAMPLE
• BCL2 GENE SEEN IN NORMAL LYMPHOCYTES
BUT ITS MUTANT FORM WITH
CHARACTERISTIC TRANSLOCATION [T(14;18)
(22;Q21)] WAS 1ST DESCRIBED IN B-CELL
LYMPHOMA
• ALSO SEEN IN OTHER CANCERS SUCH AS
BREAST, THYROID, PROSTATE
• MUTATION IN BCL2 GENE REVERSES THE
APOPTOSIS INHIBITORY CONTROL ON CANCER
CELLS, THUS MORE LIVE CELLS UNDERGOING
MITOSIS, CONTRIBUTING TO TUMOUR
GROWTH
• AFTER EACH MITOSIS, THERE IS
PROGRESSIVE SHORTENING OF
TELOMERES WHICH ARE THE
TERMINAL TIPS OF XSOME
• TELOMERASE IS THE RNA ENZYME
THAT HELPS IN REPAIR OF SUCH
DAMAGE DNA AND MAINTAIN
NORMAL TELOMERE LENGTH IN
SUCCESSIVE CELL DIVISIONS
• IT HAS BEEN OBSERVED THAT AFTER
REPETITIVE MITOSIS FOR A MAXIMUM
OF 60-70 TIMES, TELOMERES ARE LOST
IN NORMAL CELLS AND THE CELLS
• TELOMERE IS ACTIVE IN NORMAL STEM CELLS BUT NOT IN
NORMAL SOMATIC CELLS
• CANCER CELLS IN MOST MALIGNANCIES HAVE MARKEDLY
UPREGULATED TELOMERASE ENZYME AND HENCE TELOMERE
LENGTH IS MAINTAINED
• THUS CANCER CELLS AVOID AGING, MITOSIS DOES NOT SLOW
DOWN OR CEASE, THEREBY IMMORTALIZING THE CANCER
CELLS
5. CONTINUED PERFUSION OF CANCER – CANCER ANGIOGENESIS
• CANCER CAN ONLY SURVIVE AND THRIVE IF THE CANCER
CELLS ARE ADEQUATELY NOURISHED
• OTHERWISE THEY CAN NOT GROW FURTHER
• NEOVASCULARIZATION IN THE CANCERS CAN NOT ONLY
SUPPLIES THE TUMOUR WITH OXYGEN AND NUTRIENTS BUT
THE NEWLY FORMED ENDOTHELIAL CELLS ALSO ELABORATE A
FEW GROWTH FACTORS FOR PROGRESSION OF PRIMARY AS
WELL AS METASTATIC CANCER
• THE STIMULUS FOR ANGIOGENESIS IS PROVIDED BY:
• PROMOTERS OF TUMOUR ANGIOGENESIS (VEGF, BFGF)
• ANTI-ANGIOGENESIS FACTORS INHIBITING ANGIOGENESIS
INCLUDING THROBOSPONDIN-1, ANGIOSTATIN, ENDOSTATIN
AND VASCULOSTATIN
• MUTATED FORM OF P53 GENE IN BOTH ALLELES IN VARIOUS
CANCERS RESULT IN REMOVAL OF ANTI-ANGIOGENIC ROLE OF
THROMBOSPONDIN-1, THUS FAVOURING CONTINUED
ANGIOGENESIS
6. INVASION AND METASTASIS – CANCER DISSEMINATION
• ONE OF THE MOST IMPORTANT CHARACTERISTICS OF CANCERS
IS INVASION AND METASTASIS
MECHANISMS INCLUDE:
• AGGRESSIVE CLONAL PROLIFERATION ON BASIS OF TUMOUR
HETEROGENEITY ( A SUBPOPULATION OF TUMOUR CELLS IN
THE MONOCLONAL TUMOUR CELLS HAVING THE RIGHT TO
METASTASIS
• TUMOUR CELLS LOOSENING (NORMAL CELLS REMAIN CLUED
TO EACH OTHER DUE TO PRESENCE OF CELL ADHESION
MOLECULES (CAMS) IN CANCER THAT IS EITHER LOSS OF
INACTIVATION OF CAMS -> LOOSENING OF CANCER CELLS)
• TUMOUR CELL-ECM INTERACTION – LOOSENED CANCER
CELLS ARE NOW ATTACHED TO ECM PROTEIN MAINLY LAMININ
OR FIBRONECTIN -> FACILITATED DUE TO PROFOUNDNESS OF
RECEPTORS ON THE CANCER CELLS FOR BOTH THESE PROTEINS
THERE ARE ALSO INTEGRINS, FURTHER FAVOURING INVASION
• DEGRADATION OF ECM BY PROTEINASES AND MATRIX
DEGRADING ENZYMES (METALLOPROTEINASES AND
COLLAGENASES AND GELATINASES) WHILE THE INHIBITORS
OF METALLOPROTEINASES DECREASED
• ALSO PRESENT ARE CATHEPSIN D -> ALL DISSOLVE THE
BASEMENT MEMBRANE OF THE CANCER CELLS AND BLOOD
VESSELS
• ENTRY OF TUMOUR INTO CAPILLARY LUMEN – ENHANCE BY
AUTOCRINE MOTILITY FACTOR AND CLEAVAGE PRODUCT OF MATRIX
COMPONENT
• THROMBUS FORMATION – PROVIDES NOURISHMENT TO THE
TUMOUR CELLS AND ALSO PROTECTS THEM FROM THE IMMUNE
ATTACK BY THE CIRCULATING HOST CELLS
• EXTRAVASATION OF TUMOUR CELLS – ATTACH THEMSELVES TO
VASCULAR ENDOTHELIUM -> EXPOSING BASEMENT MEMBRANE
• SURVIVAL AND GROWTH OF METASTATIC DEPOSIT – THE
EXTRAVASATED MALIGNANT CELLS ON LODGMENT IN THE RIGHT
ENVIRONMENT GROW FURTHER UNDER THE INFLUENCE OF GROWTH
FACTORS
• MAY GROW FURTHER IF THE HOST IMMUNE DEFENSE MECHANISM
FAILS TO ELIMINATE IT
7. DNA DAMAGE AND REPAIR SYSTEM – MUTATOR GENES
• NORMAL CELLS DURING MITOSIS SUFFER FROM MINOR DAMAGE
TO DNA WHICH IS COMPLETED SO THAT THE INTEGRITY OF THE
GENOME IS MAINTAINED
• SIMILARLY SMALL MUTATIONAL DAMAGE TO THE DIVIDING CELL
BY EXOGENOUS FACTORS (E.G. RADIATION, CHEMICALS) IS ALSO
REPAIRED
• P53 IS RESPONSIBLE FOR DETECTION AND REPAIR OF DNA
DAMAGE
• HOWEVER, IF THIS SYSTEM OF DNA REPAIR IS DEFECTIVE AS
HAPPENS IN SOME INHERITED MUTATION (MUTATOR GENES), THE
DEFECT IN UNREPAIRED DNA IS PASSED TO THE NEXT PROGENY
OF CELLS AND CANCER RESULTS
EXAMPLES OF EXISTENCE OF MUTATOR GENES:
• HEREDITARY NON-POLYPOSIS COLON CANCER (LYNCH
SYNDROME) – XTERISED BY HEREDITARY PREDISPOSITION IN
DEVELOPMENT OF COLORECTAL CANCER
• DUE TO DEFECT IN GENE INVOLVED IN DNA MISMATCH REPAIR
WHICH RESULTS IN ACCUMULATION OF ERRORS IN FORM OF
MUTATION IN MANY GENES
• ATAXIA TELANGIECTASIA - HAS ATM GENE
• HAVE MULTIPLE CANCERS IN ADDITION TO CEREBELLAR
DEGENERATION, IMMUNOLOGICAL DERANGEMENTS AND
OCULO-CUTANEOUS MANIFESTATIONS
• XERODERMA PIGMENTOSUM – THERE IS DEFECT IN DNA
REPAIR MECHANISM
• UPON EXPOSURE TO SUNLIGHT, THE UV RADIATION DAMAGED
TO DNA CANNOT BE REPAIRED
• MORE PRONE TO VARIOUS SKIN CANCERS
• BLOOM SYNDROME – DNA IS DAMAGED BY IONIZING
RADIATION WHICH CANNOT BE REPAIRED DUE TO INHERITED
DEFECT
• INCREASED RISK OF DEVELOPING LEUKAEMIAS
8. CANCER PROGRESSION AND TUMOUR HETEROGENEITY –
CLONAL AGGRESSIVENESS
• FEATURE OF CANCER BIOLOGY IS THAT WITH TIME, CANCERS
BECOME MORE AGGRESSIVE
• TERMED TUMOUR PROGRESSION
• CLINICAL PARAMETERS INCLUDE:
• INCREASE IN CANCER SIZE, HIGHER HISTOLOGICAL GRADE,
AREAS OF TUMOUR NECROSIS, INVASIVENESS AND DISTANT
METASTASIS
• DUE TO ACQUISITION OF MORE AND MORE HETEROGENEITY
(HETEROGENEOUS CELLS)
9. CANCER AS A SEQUENTIAL MULTISTEP MOLECULAR
PHENOMENON – MULTISTEP THEORY
• CANCER OCCURS FOLLOWING SEVERAL SEQUENTIAL STEPS OF
ABNORMALITIES IN THE TARGET CELL
• E.G. INITIATION, PROMOTION AND PROGRESSION IN PROPER
SEQUENCE
• MULTIPLE STEPS ARE INVOLVED AT GENETIC LEVELS BY WHICH
CANCER CELLS ARE ACTIVATED BY:
• ACTIVATION OF GROWTH FACTORS
• LOSS OF GROWTH SUPPRESSORS
• INACTIVATION OF INTRINSIC APOPTOTIC MECHANISM OF
ESCAPING CELLULAR AGING
10. MICRORNAS IN CANCER – ONCOMIRS
• THERE ARE EVOLUTIONALLY CONSERVED ENDOGENOUS
NONCODING SINGLE STRANDED RNA MOLECULES WITH A
LENGTH OF 22 NUCLEOTIDES
• NORMALLY FUNCTION AS THE POST TRANSLATIONAL GENE
REGULATORS OF CELL PROLIFERATION, DIFFERENTIATION AND
SURVIVAL
• MORE THAN 500 MIRNAS HAVE BEEN IDENTIFIED
• HAVE ONCOGENIC ROLE IN INHIBITION AND PROGRESSION OF
CANCERS -> ONCOGENIC MIRNAS OR ONCOMIRS
• CAN ALSO PERFORM FUNCTION AS TUMOUR SUPPRESSOR, AS
TUMOUR PROMOTERS AND AS PRO-APOPTOTIC
PROPERTIES OF CANCER
1. CHEMICAL CARCINOGENESIS

• FIRST EVIDENCE OF ANY CAUSE OF CANCER CAME FROM THE

OBSERVATION OF SIR PERCIVAL POTT IN 1775
• THAT THERE WAS HIGHER INCIDENCE OF CANCER OF THE SCROTUM IN
CHIMNEY SWEEPERS IN LONDON THAN THE GENERAL POPULATION
• THIS EVOKED WIDE INTEREST IN SOOT AND COAL TAR AS POSSIBLE
CARCINOGENIC AGENTS AND POSSIBILITY OF OTHER OCCUPATIONAL
CANCERS
• THE FIRST SUCCESSFUL EXPERIMENTAL INDUCTION OF CANCER
WAS PRODUCED BY THE TWO JAPANESE WORKERS (YAMAGIWA
AND ICHIKAWA) IN 1914 IN THE RABBITS SKIN BY REPEATEDLY
INJECTING WITH COAL TAR
• SINCE THEN, THE LIST OF CHEMICAL CARCINOGENS IN INDUCING
CANCERS IS EVER INCREASING
STAGES IN CHEMICAL CARCINOGENESIS
• THE INDUCTION OF CANCER BY CHEMICAL CARCINOGENS
OCCURS AFTER A DELAY -WEEKS TO MONTHS IN
EXPERIMENTAL ANIMALS AND SEVERAL YEARS IN HUMAN
• OTHER FACTORS ARE DOSE AND MODE OF ADMINISTRATION
OF CARCINOGENIC CHEMICALS
• INDIVIDUAL SUSCEPTIBILITY AND VARIOUS PREDISPOSING
FACTORS
• BASIC MECHANISM IS BY INDUCTION OF MUTATION IN THE
PROTO-ONCOGENES AND ANTI-ONCOGENES
EVENTS IN CHEMICAL CARCINOGENESIS
• THREE PROGRESSIVE STAGES OF:
• INITIATION
• PROMOTION
• PROGRESSION
INITIATION
• FIRST STEP IN CARCINOGENESIS, INDUCED BY INITIATOR CHEMICAL
CARCINOGEN
• THE CHANGE CAN BE PRODUCED BY A SINGLE DOSE OF INITIATING
AGENT FOR A SHORT TIME
• LARGE DOSES FOR LONGER DURATION ID MORE EFFECTIVE
• THE CHANGE SO INDUCED IS SUDDEN, IRREVERSIBLE AND
PERMANENT
GROUP IN TWO CATEGORIES:
DIRECT ACTING CARCINOGENS
INDIRECT ACTING CARCINOGENS (PROCARCINIGENS)

• DIRECT ACTING CARCINOGENS INDUCE TRANSFORMATION

WITHOUT UNDERGOING ANY PRIOR METABOLIC
ACTIVATION E.G. ALKYLATING AGENT, ACYLATING AGENTS
• INDIRECT ACTING AGENTS REQUIRE CONVERSION WITHIN
THE BODY E.G. POLYCYCLIC AROMATIC HYDROCARBON,
AROMATIC AMINES, AZO DYES, NATURALLY-OCCURRING
PRODUCTS
• TRANSFORMATION OF TARGET CELLS TO INITIATED CELLS
FOLLOWS CERTAIN STEPS:
• METABOLIC ACTIVATION ESPECIALLY FOR PRO-
CARCINOGENIC CHEMICALS – DONE IN THE LIVER VIA
MONOOXYGENASE OF THE CYTOCHROME P-450 SYSTEM
• REACTIVE ELECTROPHILE – DIRECT ACTIVATING
CARCINOGENS ARE INTRINSICALLY ELECTROPHILIC, WHILE
INDIRECT ACTING ONES BECOME ELECTRON-DEFICIENT AFTER
METABOLIC ACTIVATION I.E. THEY BECOME REACTIVE
ELECTROPHILES
• TARGET MOLECULES – MOSTLY DNA CAUSING MUTAGENESIS -
> LEAD TO INITIATED CELLS
PROMOTION
• PROMOTERS ARE SUBSTANCES SUCH AS PHORBOL ESTERS,
PHENOLS, HORMONES, ARTIFICIAL SWEETENERS AND DRUGS
LIKE PHENOBARBITURATES
• XTERISTICS INCLUDE:
• DO NOT PRODUCE SUDDEN CHANGE
• REQUIRE APPLICATION OR ADMINISTRATION, AS THE CASE MAY
BE, FOLLOWING INITIATOR EXPOSURE BY SUFFICIENT TIME
AND IN SUFFICIENT DOSE
• THE CHANGE INDUCED NAY BE REVERSIBLE
• DO NOT DAMAGE THE DNA PER SE AND ARE THUS NOT
MUTAGENIC BUT INSTEAD ENHANCE THE EFFECT OF DIRECT-
ACTING CARCINOGENS OR PROCARCINOGENS
• ACT BY FURTHER CLONAL PROLIFERATION AND EXPRESSION OF
INITIATED (MUTATOR) CELLS AND HAVE REDUCED
REQUIREMENTS OF GROWTH FACTORS
• PERSISTENCY AND SUSTAINED APPLICATION AND EXPOSURE OF
THE CELL TO INITIATED ALONE UNASSOCIATED WITH
SUBSEQUENT APPLICATION OF PROMOTER MAY ALSO RESULT
IN CANCER BUT THE VICE VERSA DOES NOT HOLD TRUE
PROGRESSION
• PROGRESSION OF CANCER IS THAT THE LAST STAGE WHEN
MUTATED PROLIFERATED CELLS SHOW PHENOTYPIC FEATURES
OF MALIGNANCY
• THESE FEATURES PERTAIN TO MORPHOLOGY, BIOCHEMICAL
COMPOSITION AND MOLECULAR FEATURES OF MALIGNANCY
• THE NEW PROGENY OF CELLS THAT DEVELOP AFTER
REPETITIVE PROLIFERATION INHERITS GENETIC AND
BIOCHEMICAL XTERSTICS OF MALIGNANCY
CARCINOGENIC CHEMICALS

• MOST HAVE SUFFICIENT EPIDEMIOLOGIC EVIDENCE IN HUMANS

• DIVIDED INTO TWO BASED ON MODE OF ACTION
• DIRECT ACTING AND INDIRECT ACTING CARCINOGENS
DIRCT ACTING
• DO NOT REQUIRE METABOLIC ACTIVATION
TWO CLASSES:
• 1. ALKYLATING AGENTS
• MAINLY ANTI-CANCER DRUGS – CYCLOPHOSPHOMIDE,
CHLORAMBUCIL, BUSULPHAN, MEPHALAM, NITROSOUREA
• Β-PROPRIOLACTONE, EPOXIDES
• IMPLICATED IN LYMPHOMA AND LEUKAEMIA
• 2. ACYLATING AGENTS
• ACETYLIMIDAZOLE
• DIMETHYLCARBAMYLCHLORIDE
• INDIRECT ACTING (PROCARCINOGENS)
• REQUIRE PRIOR METABOLIC ACTIVATION
• BEFORE BECOMING ULTIMATE CARCINOGEN
• INCLUDE VAST MAJORITY OF CHEMICALS
• FOUR CATEGORIES:
1. POLYCYCLIC AROMATIC HYDROCARBONS
• COMPRISED THE LARGEST GROUP OF COMMON PROCARCINOGENS
• CAUSE DIFFERENT CANCER BY VARIOUS MODE OF ADMINISTRATION
• E.G. BY TOPICAL APPLICATION (SKIN CANCERS)
• BY SUBCUTANEOUS INJECTIONS (SARCOMAS)
• BY INHALATION (LUNG CANCER)
• BY PARENTERAL/METABOLIZING ROUTES (CANCERS IN THOSE ORGANS)
• MAIN SOURCES ARE COMBUSTION AND CHEMICAL OF
TOBACCO, SMOKE, FOSSIL FUEL (E.G. COAL), SOOT, TAR,
MINERAL OILS, SMOKED ANIMAL FOODS, INDUSTRIAL AND
ATMOSPHERIC POLLUTANTS
• CHEMICALS HERE INCLUDE:
• ANTHRACENES (BENZENE, DIENZA-, DIMETHYL BENZA-),
BENZAPYRENES, METHLCHOLANTHRENE
• EXAMPLES: SMOKING AND LUNG CANCER -> AT LEAST 2 PACKS
(40 CIGARETTES) PER DAY FOR 20 YEARS
• SKIN CANCER AND POLYCYCLIC AROMATIC HYDROCARBON
• TOBACCO AND BETEL NUT CHEWING AND ORAL CAVITY
CANCER
2. AROMATC AMINES AND AZO-DYES
• Β-NAPHTHYLAMINE VS. BLADDER CANCER IN ANILINE DYE
AND RUBBER INDUSTRY WORKERS
• BENZIDINE AND BLADDER CANCER
• AZO-DYES USED IN COLOURING OF FOODS VS LIVER CANCER
3. NATURALLY OCCURRING PRODUCTS
• DERIVED FROM PLANTS AND MICROBIAL AGENTS
• AFLATOXIN B1 DERIVED FROM ASPERGILUS FLAVUS THAT
GROWS IN STORED GRAINS AND PLANTS AND LIVER CANCER
• ACTINOMYCIN D, MITOMYCIN C, SAFROLS, BETEL NUTS
4. MISCELANEOUS
• NITROSAMINES AND NITROSAMIDES INVOLVED IN GASTRIC
CANCER
• VINYLCHLORIDE MONOMER DERIVED FROM
POLYVINYLCHLORIDE (PVC) POLYMER IN
HAEMANGIOSARCOMA OF LIVER
• ASBESTOS IN LUNG CANCER
• METALS LIKE NICKEL, LEAD, COBALT, CHROMIUM IN
INDUSTRIAL WORKERS AND LUNG CANCER
• INSECTICIDES AND FUNGICIDES, SACCHARIN, CYCLOMATES -
CARCINOGENIC IN EXPERIMENTAL ANIMALS
PROMOTER CARCINOGENS

• LACK INTRINSIC CARCINOGENIC POTENTIAL BUT THEIR

APPLICATION SUBSEQUENT TO INITIATOR EXPOSURE HELPS THE
INITIATED CELL TO PROLIFERATE FURTHER
• EXAMPLES:
• PHORBOL ESTERS – TPA (TETRA-DECANOYL PHORBOL
ACETATE) -> ACTS BY SIGNAL INDUCTION PROTEIN ACTIVATION
PATHWAYS
• HORMONES – ENDOGENOUS AND EXOGENOUS OESTROGEN IN
PROMOTION OF CANCER OF BREAST AND ENDOMETRIUM
• PROLONGED ADMINISTRATION OF DIETHYLSTIBOESTEROL IN
POSTMENOPAUSAL ENDOMETRIAL CANCER AND VAGINA
CANCERS IN ADOLESCENT GIRLS BORN TO MOTHER EXPOSED
TO THIS HORMONE DURING PREGNANCY
• MISCELLANEOUS - DIETARY FAT IN CANCER OF COLON,
CIGARETTE SMOKING AND VIRAL INFECTION
2. PHYSICAL CARCINOGENESIS

• DIVIDED INTO TWO GROUPS

• RADIATION (UV AND IONIZING)
• NON-RADIATION (VARIOUS FORMS OF INJURY)
• RADIATION CARCINOGENESIS
• UV LIGHT AND IONIZING RADIATION ARE TWO MAIN FORMS
• INDUCE CANCERS IN EXPERIMENTAL ANIMALS AND
IMPLICATED IN CAUSATION OF SOME FORMS OF CANCERS IN
HUMANS
• COMMON PROPERTY IS THE APPEARANCE OF MUTATIONS
FOLLOWED BY A LONG PERIOD OF LATENCY AFTER INITIAL
EXPOSURE, OFTEN 10-20 YEARS
• ACT TO ENHANCE THE EFFECT OF ANOTHER CARCINOGEN
(COCARCINOGEN)
• HAVE SEQUENTIAL STAGES OF INITIATION, PROMOTION AND
PROGRESSION IN THEIR EVOLUTION
I. UV LIGHT
• MAIN SOURCE IS SUNLIGHT
• OTHERS ARE UV LAMPS, WELDER’S ARCS
• UV LIGHT PENETRATES THE SKIN FOR A FEW MILLIMETRES
ONLY, SO THAT ITS EFFECT IS LIMITED TO THE EPIDERMIS
• EFFICIENCY DEPENDS ON THE EXTENT OF LIGHT ABSORBING
PROTECTIVE MELANIN PIGMENTATION OF THE SKIN
• CAUSES VARIOUS SKIN CANCERS (SSC, BCC AND MELANOMA)
S

• EPIDEMIOLOGICAL EVIDENCE OF HIGH INCIDENCE OF THESE

CANCERS:
• IN FAIR-SKINNED, EUROPEANS
• ALBINOS
• INHABITANTS OF AUSTRALIA AND NEW ZEALAND LIVING
CLOSE TO THE EQUATOR WHO RECEIVE MORE SUNLIGHT
• IN FARMERS AND OUTDOOR WORKERS DUE TO THE EFFECT OF
ACTINIC LIGHT RADIATION
II. IONIZING RADIATION
• IONIZING RADIATION OF ALL KINDS CAN CAUSE CANCER IN
HUMANS
• TYPES ARE X-, Α-, Β-, Γ-RAYS, RADIOACTIVE ISOTOPE,
PROTONS AND NEUTRONS
• CAUSE VARIOUS CANCERS – LEUKAEMIAS, THYROID, SKIN,
BREAST, OVARY UTERUS, LUNG, MYELOMA
IONIZING RADIATION (NEOPLASTIC &
NON-NEOPLASTIC)
• THE RISK OF CANCER IS INCREASED BY HIGHER DOSE AND
WITH HIGH LINEAR ENERGY TRANSFER (LET) SUCH AS
NEUTRONS AND Α-RAYS
• LOW LET IN X-RAYS AND Γ-RAYS
• EXAMPLES:
• HIGHER INCIDENCE OF RADIATION DERMATITIS AND
SUBSEQUENT CANCERS OF THE SKIN IN X-RAYS WORKERS AND
RADIOTHERAPISTS WHO DID INITIAL PIONEERING WORK
BEFORE THE ADVERT OF SAFETY MEASURES
• MINERS IN RADIOACTIVE ELEMENT HAVE HIGHER INCIDENCE
OF CANCERS
• JAPANESE ATOM BOMB SURVIVORS OF THE TWIN CITIES OF
HIROSHIMA AND NAGASAKI AFTER WORLD WAR II HAVE
INCREASED FREQUENCY OF CANCERS (BLOOD, BREAST,
THYROID LUNG)
• ACCIDENTAL LEAKAGE OF NUCLEAR POWER PLANT IN 1985
IN CHERNOBYL (UKRAINE) HAS CAUSED LONG-TERM
HAZARDOUS EFFECTS OF RADIOACTIVE MATERIAL TO THE
POPULATION LIVING IN THE VICINITY
• THERAPEUTIC X-RAY IRRADIATION RESULTS IN INCREASED
FREQUENCY OF CANCERS IN PATIENTS OF ANKYLOSING
SPONDYLITIS IN CHILDREN WITH ENLARGED THYMUS AND IN
CHILDREN IRRADIATED IN UTERO DURING INVESTIGATION ON
THE MOTHERS
• WHAT OF TOXIC WASTE DUMPED IN KOKO TOWN IN DELTA
IN 1988 ????
III. NON-RADIATION PHYSICAL CARCINOGENS
• MECHANICAL INJURY TO TISSUES AS FROM STONES IN GALL
BLADDER AND URINARY TRACT, HEALED SCARS FOLLOWING
BURNS OR TRAUMA -> INCREASED RISK OF CANCERS IN THESE
ORGANS
• ASBESTOSIS AND ASBESTOS ASSOCIATED CANCERS OF LUNG
• IMPLANTS OF INERT MATERIALS SUCH AS PLASTIC, GLASS IN
PROSTHESES
3. BIOLOGIC CARCINOGENESIS

• MOSTLY VIRUSES
• OTHERS ARE:
• PARASITES – SCHISTOSOMA HAEMATOBIUM VS URINARY
TRACT CANCER
• FUNGI – ASPERGILUS FLAVUS VS LIVER CANCER
• BACTERIA – HELICOBACTER PYLORI VS GASTRIC CANCER
VIRAL CARCINOGENESIS

• ABOUT 20% OF ALL CANCERS WORLDWIDE ARE DUE TO

PERSISTENT VIRAL INFECTION
• ASSOCIATED OF ONCOGENIC VIRUSES WITH NEOPLASM WAS
FIRST OBSERVED BY AN ITALIAN PHYSICIAN, SANARELLA IN
1889, WHO NOTED ASSOCIATED BETWEEN MYXOMATOSIS OF
RABBITS WITH POXVIRUS
• COMMON HUMAN VIRAL WART WAS ESTABLISHED IN 1907
• SINCE THEN MANY ONCOGENIC VIRUSES ARE BEING
DISCOVERED
• MOST COMMON THREE ROUTES OF VIRAL TRANSMISSION
• HORIZONTAL TRANSMISSION – FROM ONE TO ANOTHER BY
DIRECT CONTACT, BY INGESTION OF CONTAMINATED WATER OR
FOOD OR BY INHALATION
• FROM EPITHELIAL SURFACE -> DEEPER TISSUES -> BLOOD,
LYMPHATIC OR NEURAL ROUTE DISSEMINATION
• PARENTERAL ROUTE – BY INOCULATION AS HAPPENS IN SOME
VIRUSES BY INTER HUMAN SPREAD AND FROM ANIMALS AND
INSECTS TO HUMAN
• VERTICAL TRANSMISSION – GENETICALLY TRANSMITTED
FROM INFECTED PARENTS TO OFFSPRINGS
• ONCOGENIC VIRUS CAN BE DNA OR RNA (RETROVIRUS)
• BOTH TYPES USUALLY HAS THREE GENES:
• GAG GENE – CODES FOR GROUP ANTIGEN
• POL GENE – CODES FOR POLYMERASE ENZYME
• ENV GENE – CODES FOR ENVELOPE PROTEIN
• MODE OF DNA VIRAL ONCOGENESIS RESULTS IN REPLICATION
AND INTEGRATION
• MODE OF RNA VIRAL ONCOGENESIS USES THE REVERSE
TRANSCRIPTASE ENZYME THAT RESULTS IN SYNTHESIS OF A
SINGLE STRANDED OF MATCHING VIRAL DNA , THE SS OF
VIRAL DNA IS THEN COPIED BY DNA-DEPENDENT DNA
SYNTHETASE TO FORM DOUBLE STRANDED VIRAL DNA OR
PROVIRUS
• THE PROVIRUS IS THEN INTEGRATED IN THE HOST DNA
GENOME AND INDUCE MUTATION AND TRANSFORMED THE
CELL TO CANCER CELLS
REPLICATION AND INTEGRATION
OF ONCOGENIC VIRUSES
DNA ONCOGENIC VIRUSES
• FIVE GROUPS:
• PAPOVAVIRUSES
• HERPESVIRUSES
• ADENOVIRUSES
• POXVIRUSES
• HEPADNA VIRUSES
1. PAPOVAVIRUSES
• INCLUDE HUMAN PAPILLOMA VIRUS (HPV), POLYOMA VIRUS,
SIMIAN VACUOLATING VIRUS (SV-40)
• HUMAN PAPILLOMA VIRUS –FIRST VIRUS TO BE IMPLICATED IN
HUMAN CANCERS
• REPLICATION IN THE LAYERS OF STRATIFIED SQUAMOUS
EPITHELIUM
• MORE THAN 100 HPV TYPES HAVE BEEN IDENTIFIED
• HPV WAS FIRST DETECTED IN COMMON SKIN WARTS OR VERRUCA
VULGARIS IS BY SLOPE IN 1933 -> LOW RISK HPV 1, 2, 4, 7
• LOW-RISK HPV TYPES 6 AND 11 VS GENITAL WARTS (CONDYLOMA
ACUMINATA)
• VIRAL DNA OF HIGH RISK HPV 16, 18, 31, 33. 45 ARE SEEN IN 75-100%
OF INVASIVE CERVICAL CANCER AND PRECANCEROUS LESIONS (CIS
OR CIN)
• HIGH RISK HPV ARE ALSO SEEN IN CANCER OF ANUS, PERIANAL
REGION, VAGINA, VULVA, PENIS AND ORAL CAVITY
• HPV TYPES 5 AND 8 IS THE CAUSE OF EPIDERMAL DYSPLASIA
VERRUCIFORMIS (MULTIPLE SKIN WARTS AND DEFECT IN CELL
MEDIATED IMMUNITY) -> ONE THIRD DEVELOP SCC IN SUN EXPOSED
WARTS
2. HERPESVIRUSES
• PRIMARY INFECTION PERSISTS FOR LIFE IN A LATENT STAGE
WHICH CAN GET ACTIVATED LATER
• MEMBERS OF THIS GROUP ARE EPSTEIN-BARR VIRUS, HERPES
SIMPLEX VIRUS TYPE 2, HHV8 AND CYTOMEGALOVIRUS
• NO KNOWN ONCOGENIC ROLE OF HSV2 AND CMV IN HUMANS
• EB VIRUS – INFECTS B LYMPHOCYTES AND EPITHELIAL CELLS
• LONG TERM INFECTION STIMULATE THEM TO PROLIFERATE
AND DEVELOPMENT OF CANCER
• EB VIRUS IS IMPLICATED IN BURKITT LYMPHOMA,
ANAPLASTIC NASOPHARYNGEAL CARCINOMA, PRIMARY CNS
LYMPHOMA IN AIDS PATIENTS AND HODGKIN LYMPHOMA
• NORMALLY CAUSES INFECTIOUS MONONUCLEOSIS WHICH IS A
SELF-LIMITING DISEASE
• BL WAS INITIALLY NOTICED IN AFRICAN CHILDREN AS JAW
MASSES BY DENNIS BURKITT IN 1958
• BUT NOW OCCUR IN TWO FORMS – AFRICAN ENDEMIC FORM
AND SPORADIC FORM SEEN ELSEWHERE IN THE WORLD
3. HEPDNA VIRUSES
• HBV IS A MEMBER OF HEPDNA VIRUS (HEPA-DNA)
• USUALLY CAUSES ACUTE HEPATITIS -> CARRIER STATE ->
CHRONIC HEPATITIS -> PROGRESSING TO CIRRHOSIS ->
HEPATOCELLULAR CARCINOMA
• EVIDENCES ARE THE GEOGRAPHICAL DIFFERENCES IN THE
INCIDENCE OF HCC CLOSELY MATCH THE VARIATION IN
PREVALENCE OF HBV INFECTION
• AND EPIDEMIOLOGICAL STUDIES IN HIGH INCIDENCE REGIONS
INDICATE ABOUT 200 TIMES HIGHER RISK OF DEVELOPING HCC
IN HBV-INFECTED CASES AS COMPARED TO UNINFECTED POP.
RNA ONCOGENIC VIRUSES

• THESE ARE RETROVIRUSES BECAUSE OF THE ENZYME

REVERSE TRANSCRIPTASE
• BUT NOT ALL RETROVIRUSES ARE ONCOGENIC
• RT IS REQUIRED FOR REVERSE TRANSCRIPTION OF VIRAL RNA
TO SYNTHESIZE VIRAL DNA STANDS
• RT IS A DNA POLYMERASE AND HELP TO FORM
COMPLEMENTARY DNAS (CDNA) THAT MOVES INTO HOST CELL
NUCLEUS AND GETS INCORPORATED INTO IT
• DIVIDED INTO THREE TYPES BASED ON THEIR ACTIVITY TO
TRANSFORM TARGET CELLS INTO NEOPLASTIC CELLS
• ACUTE TRANSFORMING VIRUSES
• SLOW TRANSFORMING VIRUSES
• HUMAN T-CELL LYMPHOTROPIC VIRUS
1. ACUTE TRANSFORMING VIRUS
• TRANSFORM ALL THE CELLS INFECTED BY THEM INTO MALIGNANT CELLS
RAPIDLY
• ALL POSSESS ONE OR MORE VIRAL ONCOGENES (V-ONC)
• THEY ARE DEFECTIVE VIRUSES IN WHICH THE PARTICULAR V-ONC HAS
SUBSTITUTED OTHER ESSENTIAL GENETIC MATERIAL SUCH AS GAG, POL,
ENV
• CANNOT REPLICATE BY THEMSELVES UNLESS THE HOST CELL IS INFECTED
BY ANOTHER HELPER VIRUS

• IDENTIFIED IN TUMOURS IN ANIMALS:

• ROUS SARCOMA VIRUS IN CHICKENS
• LEUKAEMIA-SARCOMA VIRUS IN AVIAN, FELINE, BOVINE OR PRIMATE
2. SLOW TRANSFORMING VIRUS
• CAUSE DEVELOPMENT OF LEUKAEMIA AND LYMPHOMA IN
DIFFERENT SPECIES OF ANIMALS (MICE, CATS AND BOVINE)
• INCLUDE MOUSE MAMMARY TUMOUR VIRUS (MMTV) THAT
CAUSES BREAST CANCER IN THE DAUGHTER MICE SUCKLED BY
THE MMTV-INFECTED MOTHER VIA THE CAUSAL AGENT IN THE
MOTHER’S MILK (BITTNER MILK FACTOR)
• HAVE LONG INCUBATION PERIOD BETWEEN INFECTION AND
DEVELOPMENT OF NEOPLASM (SLOW)
• CAUSE NEOPLASTIC TRANSFORMATION BY INSERTION
MUTAGEN
• I.E. VIRAL DNA SYNTHESIZED BY VIRAL RNA VIA RT IS
INSERTED OR INTEGRATED NEAR THE PROTO-ONCOGENES OF
THE HOST CELL RESULTING IN DAMAGE TO HOST CELL GENOME
• LEADING TO NEOPLASTIC TRANSFORMATION
3. HUMAN T-CELL LYMPHOTROPIC VIRUS (HTLV)
• IS A FORM OF SLOW TRANSFORMING VIRUS
• ONLY SLOW TRANSFORMING VIRUS IMPLICATED IN HUMAN
CANCER
• HAVE DIFFERENT MECHANISM OF NEOPLASTIC TRANSFORMATION
• FOUR TYPES IDENTIFIED – HTLV-I, HTLV-II, HTLV-III AND HLTV-IV
• HTLV-III CAUSES HIV/AIDS
• HLTV-I IS IMPLICATED IN CUTANEOUS ADULT T-CELL LEUKAEMIA-
LYMPHOMA
• HLTV-II IS IMPLICATED I T-CELL VARIANT OF HAIRY CELL
LEUKAEMIA
• HLTV-I IS TRANSMITTED THROUGH SEXUAL CONTACTS, BY
BLOOD OR TO INFANTS DURING BREAST FEEDING
• INITIATION OF NEOPLASTIC PROCESS SIMILAR TO THAT OF BL
EXCEPT THAT THE VIRUS HAS TROPISM FOR CD4+ T-
LYMPHOCYTES AS IN HIV INFECTION
• IMMUNOSUPPRESSION PLAYS A SUPPORTIVE ROLE IN THE
NEOPLASTIC TRANSFORMATION OF HTLV-I
VIRUSES AND HUMAN CANCERS
SUMMARY

• EPIDEMIOLOGICAL AS WELL AS CIRCUMSTANTIAL EVIDENCE

HAS BEEN ACCUMULATING THAT CANCER HAS VIRAL
AETIOLOGY
• ABOUT 20% OF ALL HUMAN CANCERS WORLDWIDE ARE
VIRALLY INDUCED
• THE FOLLOWING VIRUSES ARE IMPLICATED IN HUMAN
CANCERS:
• EPSTEIN-BARR VIRUS IN BURKITT LYMPHOMA AND
NASOPHARYNGEAL CANCER
• HBV & HCV IN HEPATOCELLULAR CARCINOMA
• HIGH RISK HPV TYPES 16 AND 18 IN CERVICAL CANCER
• HHV-8 IN KAPOSI SARCOMA AND PLEURAL EFFUSION B-CELL
LYMPHOMA
• HTLV-I IN ADULT T-CELL LEUKAEMIA/LYMPHOMA
• HTLV-II IN T-CELL VARIANT OF HAIRY CELL LEUKAEMIA
• CURRENT KNOWLEDGE AND UNDERSTANDING OF VIRAL
CARCINOGENESIS HAS PROVIDED AN OPPORTUNISTIC TO
INVERT SPECIFIC VACCINES
• AND SUGGEST APPROPRIATE SPECIFIC THERAPY
• E.G. HBV AND HPV VACCINES TO LOWER OR PREVENT HCC AND
CERVICAL CANCER RESPECTIVELY
EFFECTS OF TUMOR ON THE
HOST

• LOCATION ANATOMIC ENCROACHMENT

• HORMONE PRODUCTION
• BLEEDING, INFECTION
• ACUTE SYMPTOMS, E.G., RUPTURE, INFARCTION
• METASTASES
• CACHEXIA (FAT LOSS AND MUSCLE LOSS)
• DUE TO TNF-Α, IL-(6), PIF (PROTEOLYSIS INDUCING FACTOR)
PARA-NEOPLASTIC SYNDROMES (PNS)

• SIGNS/SYMPTOMS IN CANCER BEARING PATIENTS NOT

EXPLAINED BY ANATOMIC DISTRIBUTION OF TUMOUR
• OR BY ELABORATION OF HORMONES INDIGENOUS TO THE
TISSUE FROM WHICH THE TUMOUR AROSE
• MAY BE THE EARLIEST MANIFESTATION OF THE TUMOUR
• MAY CAUSE SIGNIFICANT CLINICAL PROBLEMS
• MAY MIMIC METASTATIC DISEASE ->CONFOUND TREATMENT
CLASSIFICATION
• ENDOCRINOPATHIES – CUSHING SYNDROME, SIAADHS,
HYPERCALCICAEMIA, HYPOGLYCAEMIA, POLYCYTHAEMIA
• NERVE AND MUSCLE SYNDROME – MYSTHENIA
• DERMATOPATHIC – ACANTHOSIS NIGRICANS,
DERMATOMYOSITIS
• VASCULAR AND HAEMATOLOGIC CHANGES – VENOUS
THROMBOSIS (TROUSSEU PHENOMENON), DIC, NONBACTERIAL
THROMBOTIC ENDOCARDITIS, RED CELL APLASIA
• OSSEOUS, ARTICULAR AND SOFT TISSUE – HYPERTROPHIC
OSTEOARTHROPATHY AND CLUBBING OF THE FINGERS
• RENAL – NEPHROTIC SYNDROME
GRADING/STAGING

GRADING:
• DETERMINED BY CYTOLOGIC APPEARANCE OF BASED ON THE
IDEA THAT BEHAVIOUR AND DIFFERENTIATION ARE RELATED
• HOW “DIFFERENTIATED” ARE THE CELLS? -> WD, MD, PD, UD
• PD TUMOURS HAVING AGGRESSIVE BEHAVOIUR
STAGING:
• BASED ON THE SIZE OF PRIMARY LESION, ITS EXTENT OF
SPREAD TO LN AND PRESENCE OF BLOOD BORNE METASTASES
• HOW MUCH ANATOMIC EXTENSION?
• AJC ->TNM (TUMOUR SIZE, NODE AND METASTASES)
• T0-T4
• N0-N3
• M0-M1
LAB DIAGNOSIS OF CANCERS

• BIOPSY (EXCISIONAL, TRUCUT, INCISIONAL)

• CYTOLOGY - (EXFOLIATIVE, EFFUSION, URINE, CSF)
• CYTOLOGY - (FNA, FINE NEEDLE ASPIRATE)
• IMMUNOHISTOCHEMISTRY*
• FLOW CYTOMETRY – RATE OF TUMOUR TURNOVER
• MOLECULAR & CYTOGENETIC – FOR DIAGNOSIS AND
PREDICTING BEHAVIOUR OF TUMOUR
IMMUNOHISTOCHEMISTRY
(IHC)

• IHC HAS BECOME THE MAGIC BULLET OF DIAGNOSTIC

SURGICAL PATHOLOGY
• BASED ON THE THEORY THAT EVEN IF YOU DO NOT KNOW
WHAT KIND OF TUMOR CELL YOU ARE LOOKING AT, IF YOU CAN
IDENTIFY SPECIFIC ANTIGENS BY STAINING FOR THEM, THEN,
YOU CAN FEEL SURE YOU KNOW THE CELL OF ORIGIN
• IT DOES NOT IDENTIFY ANTIGENS WHICH DIFFERENTIATE
BENIGN FROM MALIGNANT, BUT IDENTIFY ANTIGENS COMMON
TO CERTAIN TYPES OF CELLS
• CATEGORIZATION OF UNDIFFERENTIATED TUMORS
• LEUKAEMIAS/LYMPHOMAS/CARCINOMA/SARCOMA
• SITE OF ORIGIN OF METASTATIC TUMOUR- PSA
• DETECTION OF MOLECULES THAT HAVE PROGNOSTIC AND
THERAPEUTIC SIGNIFICANCE
-RECEPTORS, E.G. ER, PR, HER2
TUMOR MARKERS

• BIOCHEMICAL ASSAYS FOR TUMOUR ASSOCIATED

SUBSTANCES LIKE:
• HORMONES: HCG, CALCITONIN
• ONCOFETAL: AFP, CEA
• ISOENZYMES: PAP, NSE
• PROTEINS: PSA, PSMA
• GLYCOPROTEINS: CA-125, CA-195, CA-153
• MOLECULAR: P53, RAS
• NOTE: THESE SAME SUBSTANCES
WHICH CAN BE MEASURED IN THE
BLOOD, ALSO CAN BE STAINED BY
IMMUNOCHEMICAL METHODS IN TISSUE
• CAN BE USED FOR DIAGNOSIS,
SCREENING, MONITORING AND
PROGNOSIS
FINAL NOTE:
• CANCER IS UBIQUITOUS IN HUMAN POPULATIONS
• WHATEVER WE DO FOR A LIVING, SOCIALIZING
AND EVEN GETTING MEDICATION FOR CANCER
ITSELF IS TO INCUR RISK OF DEVELOPING ONE
• THE ONLY WAY TO AVOID CANCER RISK IS TO NOT
TO BE BORN !!!!!!
• THANK YOU