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					Mechanisms of Disease
Session 1 – Cell Injury
Cell injury is part of a continuum. Degree of injury is a function of

    M Injury: type, duration and severity
    M Cell: Type, status, adaptability

Type of insult: Hypoxia, chemical, infections, physical, immune, Nutritional.

Cell damage occurs at plasma membranes, organellar membranes, DNA, structural proteins,
enzymes and can affect oxidative phosphorylation.

Pathogenesis of cell injury – ischemic hypoxia

Reversible: - loss of ATP  Failure of Na/K pump  morphological change = cell cytoplasm and
organelles swell with water.

    -   Anaerobic metabolism  increased lactate and phosphate (low pH)  morphological
        change: chromatin clumps
    -   Reduced protein synthesis  altered metabolism  morphological change: intracellular
        accumulations e.g. proteins and/or lipid.

Irreversible: - Massive intra-cytoplasmic [Ca2+]  activates multiple degradative enzymes  lethal
cell damage.

Non-Ischaemic

Reduced ATP synthesis/mitochondrial damage; loss of Ca homeostasis; disrupted membrane
permeability; free radicals.

Free radicals

Associated with cell injury in many settings... there generation occurs by

    -   Absorption of irradiation: e.g. H2O  OHo and Ho
    -   Endogenous normal metabolic reactions: e.g. O2-•, and H2O2
    -   Transition metals: e.g. Fe3+ (receive an donate electrons freely)
    -   Exogenous toxins: e.g. carbon tetrachloride (highlights key concept: liver metabolism often
        required to generate substance from inert substrate)

Removed by... spontaneous decay, anti-oxidants, storage proteins and enzymes.

Injure cells by... membrane lipid peroxidation, interaction with proteins (fragmentation and cross-
linkage), lastly by DNA damage.
Cytosolic free calcium is a potent destructive agent

Calcium is usually rapidly removed form the cytosol by ATP-dependent calcium pumps. In normal
cells, calcium is bound to buffering proteins, such as calbindin or parvalbumin, and is contained in
the ER, as well as in mitochondria. If there is abnormal permeability of calcium-ion channels, direct
damage to membranes, depletion of ATP, or damage to mitochondria, calcium increases in
concentration. If this happens activation of protein kinases causes phophorylation of protein. And
activation of phopholipases causes membrane damage and activation of proteases causes
cytoskeletal disassembly.

Also cell injury by reactive oxygen metabolites that are extremely harmful to cells and are produced
on reperfusion after ischemia. Also ATP loss causes failure of biosynthesis and membrane pumps.




                                                                  Cell injury morphology

                                                                  Irreversible

                                                                  Nuclear chromatin: shrinkage
                                                                  (pyknosis), break-up (karyorrhexis);
                                                                  dissolution (karolysis)

                                                                  Abnormal accumulations - due to
                                                                  altered metabolism

                                                                  Necrosis

                                                                  It is the death of groups of
                                                                  contiguous cells in tissue or organ.

                                                                  Necrosis is a dynamic process so
not always likely to see the characteristic cell death.

What you see depends on:

       Degree of enzyme release: (more of this favours liquefactive necrosis)
            o From lysosomes in dying cells (autolysis)
            o And/or infiltrating inflammatory cells (heterolysis)
       Degree of protein denaturation (favours coagulative necrosis)
       Extent to which necrotic debris have been cleared away.

Coagulative necrosis

Protein denaturation > enzymatic digestion
Cells dead but basic shape endues

Most common form of necrosis

Affected tissue maintains solid consistency.

Liquefactive necrosis

Enzymatic digestion > protein denaturation

Complete dissolution of necrotic tissue

Typically seen: Massive infiltration by neutrophils and ischaemic
necrosis in the brain

Caseous necrosis

Accumulation of amorphous debris, tissue architecture is abolished

Characteristic in certain infections such as TB



Fat Necrosis

Occurs in adipose tissue – typically following acute pancreatitis or trauma to fatty tissue

Pancreatitis  lipase release  digest adipocyte membranes and fat vacuoles  fat necrosis 
release of fatty acids  react with Ca  chalky calcified deposits.

Gangrene (not a separate kind of necrosis)

Clinical term for necrosis that is advanced and visible grossly

     If mostly coagulative = dry gangrene
     If mostly liquefactive necrosis = wet gangrene.

Infarction

Not a specific pattern of necrosis but it refers to the cause of necrosis therefore infarct = ischaemic
necrosis. It can be coagulative (myocardial and liquefactive (brain).

Description:

White: occlusion of end artery

Red: venous occlusion, dual blood supply, loose tissues, previously congested tissues.

Apoptosis Vs Necrosis

                                 Apoptosis                              Necrosis
Patterns of death                Single cells                           Groups
Cell size                        Shrinkage; fragmentation               Swelling
Plasma membrane                  Preserved continuity                  Early lysis
Mitochondria                     Increased membrane permeability       Swelling; disordered structure
                                 cytochrome c release
Organelle shape                  Contracted                            Swelling; disruption
Nuclei                           Chromatin: clumped &                  Pyknosis; karryhexis; karyolysis
                                 fragmented
DNA degradation                  Internucleosomal cleavage             Diffuse & random
Cell degradation                 Phagocytosis; no inflammation         Inflammation; macrophage
                                                                       invasion
Physiological or pathological  Both                                    Always pathological
Active or passive              Active – cells expend energy in         Passive.
                               order to die
Physiological apoptosis – some examples

     Involution during embryonic development e.g. interdigital space in humans
     Hormone withdrawal e.g. endometrial cells at end of menstrual cycle.
     Removal of auto-reactive immune cells

Pathological apoptosis – some examples

     Removal of cells with DNA damage (mediated by p53)
     Removal of virus-infected cells
     Graft versus host disease.

Apoptosis – triggers

Intrinsic: mitochondria activate apoptosis

     Release cytochrome c
     Cytochrome c + APAF1 – apoptosome  activates procaspase 9
     Caspase 9 activates downstream caspases e.g. caspase 3

Extrinsic – Death ligands and receptors activate apoptosis

     Bind respective TRAIL or FAS receptors  activate procaspase 8
     Caspase 8 activates downstream caspases

Detecting Apoptosis

     DNA ladder on a gel: due to DNA cleavage between nucleosomes
     Altered membrane structure: phosphatidylserine on outside of cell membrane
     Abnormal permeability: e.g. to dyes such as propidium iodide.

Chronic, excessive alcohol intake:

Alcohol is a hepatoxin and live damage is related to its intake. Toxicity is probably due to generation
of acetaldehyde in breakdown. Alcohol causes fatty liver, acute hepatitis and cirrhosis.

Acute hepatitis: ingestion of large amounts of alcohol causes a true hepatitis, with focal necrosis of
liver cells. Function tests show raised levels of transaminases.
With abstinence the inflammation resolves without harm. But with continues ingestion of alcohol,
fibrosis develops around the central veins, and in response to continues heptocyte necrosis. The
end-result is hepatic fibrosis that may progress to cirrhosis. Cirrhosis is characterized by the
replacement of normal tissue with fibrous tissue and the loss of functional liver cells.

A reduction in the capacity of liver cells to take up and conjugate bilirubin leads to
hyperbilirubinaemia that may produce jaundice. A reduction in the capacity to produce urea may
lead to hyperammonaemia. Reduction in protein synthesis so decreased levels of albumin,
lipoproteins and clotting factors these lead to oedema, fatty liver and decreased blood clotting
action respectively.

Acute Hepatic necrosis – Paracetamol

Acute hepatic necrosis is characterized by a markedly raised plasma levels of alanine transaminase
and aspartate transaminase, which are released from damaged hepatocytes.

In cases of paracetamol toxicity, the sulphate and glucuronide pathways become saturated, and
more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result,
hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular
membrane molecules, resulting in widespread hepatocyte damage and death, leading to acute
hepatic necrosis.

Key Facts

Sublethal damage:

       The earliest visible sign of Sublethal damage is ultrastructual damage to mitochondria
       Later damage can be seen as swelling to cellular organelles
       Fatty change is a manifestation of Sublethal impairment of metabolism and is common in
        the liver

Necrosis:

       Intense eosinophilia of the dead cell is due to loss of RNA and coagulation of proteins
       Nuclei undergo phases of pyknosis, karyorrhexis and karyolysis, leaving a shrunken cell
        devoid of nucleus.’
       Proteins may be liberated from the dead cells and be detected in the blood in diagnosis.
Session 2 - Acute Inflammation
Acute: describing a disease of rapid onset, severe symptoms and brief duration. “Response of living
tissue to injury”

It is innate, immediate and early and has a short duration.

    1. Vascular reaction – accumulation of fluid exudates and neutrophils in tissues
    2. Controlled by a variety of chemical mediators derived from plasma cells
    3. Protective, but can lead to local complication and systemic effects.

Causes: Microbial infections, hypersensitivity reaction (acute phase), physical agents, chemical,
tissue necrosis.

Clinical signs: Rubor, tumor, calor, dolor which is redness, swelling, heat, pain (& loss of function)

Changes in vascular flow and calibre

    1. Transient vasoconstriction of arterioles (few secs)
    2. Vasodilatation of arterioles and then capillaries  increase in blood flow (Histamine,
       prostaglandins, nitric oxide)
    3. Increased permeability of blood vessels. This causes exudation of protein, and slowing of
       circulation. (Histamine, bradykinin,
       leukotreines)
    4. [RBCs] increases in small vessels and
       increases viscosity of blood (stasis).

Migration of neutrophils

    5. Stasis causes neutrophils to line up
       at the edge of blood vessels along
       the endothelium called margination.
    6. Neutrophils then roll along
       endothelium, sticking to it
       intermittently called rolling.
    7. Then stick more avidly called
       adhesion.
    8. Followed by emigration of
       neutrophils through blood vessel
       wall. (C5a, leukotriene B4, bacterial
       products)

Neutrophils chemotaxis and phagocytosis

    9. Neutrophils migrate to site of injury
        down a concentration gradient of
        chemotactic agents.
    10. Neutrophils phagocytose
        microorganisms
    11. Activated neutrophils may release toxic metabolites and enzymes causing damage to the
        host tissue.

Histamine - vascular dilatation and the immediate transient phase of increased vascular permeability

Prostaglandins - potentiate the increase in vascular permeability caused by other mediators, some
cause platelet aggregation

Leukotrienes – has vasoactive properties

Cytokines (interleukins ie.IL-1, IL-6, IL-8; TNF-α, type 1 interferons, chemokines, TGF- α, TGF-β) -
Cytokines that affect the inflammatory response generally up-regulate innate immunity.

Starling’s law

Fluid flow across vessel walls is determined by the balance of hydrostatic pressure within the vessel
and the difference in colloid osmotic pressure between the plasma and interstitial fluid:-

       Increased hydrostatic pressure  increase fluid flow out of vessel
       Increase colloid osmotic pressure of interstitium  increase fluid flow out of vessel

There is a net flow of fluid out of vessel.

Exudate – is fluid loss in inflammation which has a high protein content, specific gravity above 1.02

Transudate – Fluid loss due to hydrostatic pressure imbalance only, low protein content, specific
gravity less than 1.012 (e.g. venous outflow obstruction)

Oedema – excess of fluid in interstitium, can be Transudate or exudate

Pus – a purulent exudate, rich in neutrophils and cell debris.

How does it all work

     Exudation of fluid – Delivers plasma proteins to area of injury, such as immunoglobulins,
      inflammatory mediators and fibrinogen. It also dilutes toxins and increases lymphatic
      drainage. This works to deliver microorganisms to phagocytes and antigens to immune
      system.
     Infiltration of cells – removes pathogenic organisms and necrotic debris
     Vasodilatation – increases delivery and temperature
     Pain and loss of function – this enforces rest, reduces chance of further traumatic damage.

Mechanisms – chemical mediators of each step, these incite complex inter-reactions

Examples:

Proteases – kinins, coagulation/fibrinolytic system

Prostaglandins/Leukotrienes – metabolites of arachidonic acid, synthesis blocked by NSAIDS

Cytokines/chemokines (produced by wbc’s) – many but some are PAF, TNF alpha, PDGF, TGF beta.
From platelets: 5-HT, Histamine, ADP

From neutrophils: Lysosomal constituents

Products released on neutrophil death

From endothelium: Prostacyclin, Nitric oxide

Plasminogen activators / inhibitors

Chemical Mediators

Three phases:

    1. Immediate early response (1/2 hour):
           a. Histamine is released from masts cells, basophils and platelets. These in response to
              many stimuli: physical damage, immunologic reactions C3a, C5a, IL1, factors from
              neutrophils and platelets.
           b. Results in vascular dilatation, transient increase in vascular permeability, pain but
              not chemotactic.
    2. Immediate sustained response – not always seen. Due to direct damage to endothelial cells.
    3. Delayed response: (peaks about 3 hours)
           a. Many and varied chemical mediators, interlinked and of varying importance.
              Important because of possibility of therapeutic intervention.

Mechanisms of vascular leakage

Endothelial contraction -->gaps –histamine, leukotrienes

Cytoskeletal reorganisation --> gaps –Cytokines IL-1 and TNF, hypoxia

Direct injury -toxic burns, chemicals

Leukocyte dependent injury –toxic oxygen species and enzymes from leucocytes (pulmonary and
glomerular capillaries)

Increased transcytosis -channels across endothelial cytoplasm–VEGF

Neutrophils

They phagocytose, recognition is facilitated by opsonins. Phagosomes fuse with lysosomes to
produce secondary lysosomes.

Mechanisms of neutrophil migration

Neutrophil adhesion and emigration is due to binding of complementary adhesion molecules on
endothelial and neutrophil surfaces. Chemical mediators change surface expression or avidity of
adhesion molecules. Selectins, immunoglobulins and integrins.

They can escape from vessels because of the relaxation of inter-endothelial cell junctions, the
digestion of vascular basement membrane and of course movement.
Movement is due to chemotaxis – movement along concentration gradients of chemoattractants –
involving receptor-ligand binding, rearrangement of cytoskeleton and production of pseudopod.

Killing mechanisms

O2 dependent

     Produces superoxide and H2O2.
     H2O2-Myeloperodidase-halide system – produces HOCl-
     Myeloperoxidase independent killing is less efficient.

O2 independent

        Lysozyme & hydrolases
        Bactericidal permeability increasing protein (BPI
        Cationic proteins
        Major basic protein (MBP, Eosinophils)

Complication of acute inflammation

Swelling causes blockage of tubes e.g. bile duct, intestine

Exudate causes compression e.g. cardiac tamponade and serositis which is inflammation of a serous
membrane, such as the lining of the thoracic cavity.

Systemic effects

Fever –‘endogenous pyrogens’ produced: IL1 and TNF alpha. Prostaglandins, therefore NSAIDS
reduce fever

Leukocytosis – IL1 and TNF alpha produce an accelerated release from marrow. Macrophages, T
lymphocytes produce colon-stimulating factors. Bacterial infections – neutrophils, viral –
lymphocytes

Acute phase response – decreased appetite, altered sleep pattern and changes in plasma
concentrations of acute phase proteins such as C-reactive protein

Spread of microorganisms and toxins

SHOCK

Sequelae

What happens after...

    1.   Complete resolution
    2.   Continued acute inflammation with chronic inflammation; chronic suppuration
    3.   Chronic inflammation and fibrous repair, probably with tissue regeneration
    4.   Death

Resolution – changes gradually reverse, vascular changes stop:
     Neutrophils no longer marginate
     Vessel permeability returns to normal
     Vessel calibre returns to normal

This results in exudate drainage into lymphatics, fibrin is degraded by plasmin and other proteases,
neutrophils die, break up and are carried away or are phagoctosed. Lastly damaged tissue might be
able to regenerate.

If tissue architecture has been destroyed, complete resolution is not possible.

Mechanisms of resolution

All mediators of acute inflammation have short half lives. So they may be inactivated by degradation,
inhibitors may bind, they may be unstable, they may be diluted in the exudate and lastly specific
inhibitors of acute inflammatory changes.

Clinical example

Lobar pneumonia – caused by streptococcus pneumoniae which mainly infects young adults in
confined conditions such as alcoholics. Its clinical course is worsening fever, prostration,
hypoxaemia over. Fairly sudden improvement when antibodies appear.

Skin blister – caused by heat, sunlight or chemicals. Its predominant features are pain and exudate
which collects as fluid strips in the overlying epithelium.

Abscess – are solid tissues, inflammatory exudate forces the tissue apart. Liquefactive necrosis
occurs in the centre, this may cause high pressure therefore pain, may cause tissue damage and may
squash adjacent structures.

Inherited disorder Hereditary Angio-oedema  bradykinin formation is caused by continuous
activation of the complement system due to a deficiency in one of its prime inhibitors, C1-esterase
inhibitor (C1INH). So bradykinin (peptide) is made in excess leading to excessive inflammation.


Session 3 – Chronic Inflammation
Chronic – a disease of long duration involving very slow change.

May take over from acute inflammation if damage is too severe to be resolved within a few days

May arise de novo from some autoimmune conditions (e.g. rheumatoid arthritis) some chronic
infections (viral hepatitis). Chronic low-level irritation.

May develop alongside acute inflammation in some severe persistent or repeated irritation.

It is characterised by the microscopic appearances.

Macrophages

They are derived from blood monocytes. Also they accumulate in chronic inflammation due to:

    1. Recruitment from blood
    2. Mitotic division
    3. Immobilisation by cytokines (macrophage inhibitory factor)

May undergo activation once extravasated.

Function phagocytosis of debris & bacteria. This works by recognition, engulfment into a phagosome
and then formation of phagolysosome and killing.

They control other cells by cytokine release: TNF-alpha and IL-1.

They control other leukocytes – which in turn promotes other cytokine secretion, reciprocal
relationship with the lymphocytes. On endothelial cells they promote leukocyte adherence and on
fibroblasts, proliferation and collagen synthesis.

They produce blood clotting factors, growth factors and proteases.

They control processing and presentation of antigen to immune system by T-cell activation.

They secrete growth factors PDGF, EGF, FGF. These stimulate the growth of blood vessels, and
division and migration of fibroblasts.

Lymphocytes – B lymphocytes differentiate to produce antibodies and T lymphocytes are involved in
control & some cytotoxic functions

Plasma cells – differentiated antibody producing B lymphocytes

Eosinophils – allergic reactions, parasite infestations, some tumours

Fibroblasts/myofibroblasts – recruited by macrophages; make collagen

Giant cells – multinucleate cells made by fusion of macrophages. There are several types.

Morphology of most reactions is not specific, but proportions of each cell type may vary in different
conditions.

Effects of Chronic Inflammation

Fibrosis: found in Chronic Cholecystitis

This causes repeated obstruction by gall stones, repeated inflammation leads to chronic, fibrosis of
gall bladder wall then occurs.

Found in gastric ulceration. This is due to imbalance of acid production and mucosal defence.

Impaired function:

Inflammatory bowel disease

Ulcerative colitis is superficial – diarrhoea and bleeding

Crohn’s disease is transmural – strictures, fistulae
Rheumatoid Arthritis – is an autoimmune disease which consists of localised and systemic immune
response and localised chronic inflammation of synovium leads to joint destruction – can also affect
blood vessels, skin and lung.

Atrophy – gastric mucosa and adrenal glands

Stimulation of immune response – macrophage – lymphocyte interactions.

Chronic inflammation and immune responses overlap. This is due to immune diseases causes
pathology by chronic inflammation. Chronic inflammatory processes can stimulate immune
responses.

Granulomatous Inflammation
Is chronic inflammation with granulomas




They occur with persistent, low-grade antigenic stimulation and hypersensitivity.

Causes of granulomatous inflammation:

       Mildly irritant ‘foreign’ material – common materials include keratin, urate crystals (such as
        gout), degenerated altered collagen, and degenerated altered elastin.
       Mycobacteria: TB, leprosy
       Syphilis
       Other rare infections
       Unknown causes such as Sarcoid, Wegener’s granulomatosis and Crohn’s disease

Tuberculosis - Caused by mycobacteria, it produces no toxins or lytic enzymes, causes disease by
persistence and induction of cell-mediated immunity. Destruction of tissues occurs by caseating
granulomas. In TB granulomas, Langhans’ type giant cell, caseous necrosis, epithelioid histocytes and
lymphocytes are all present.
Primary TB – non-sensitized individual

Outcome: usually heals with some scarring & persistent bacteria in lung

Secondary TB – previously exposed individual

Usually starts in apex of lung and the outcome is varied

Arrest, fibrosis scarring erosion into bronchus  tuberculous empyema  Erosion into blood
stream.

Sarcoidosis is a chronic granulomatous disease of unknown cause, in which many tissues are
infiltrated by non-caseating granulomas. Common systems involved ate the lymphoreticular system,
lungs, skin, eyes and brain.

Syphilis the organism gains access to the body and then forms a primary lesion. The organism then
disseminated throughout many organs from this site. An immune response develops and the
primary infection heals but, thereafter, the disease becomes a chronic inflammatory condition,
affecting many organs.


Session 4- Regeneration and Fibrous repair
Regeneration – replacement of functional, differentiated cells

Repair – production of a fibrous scar

Regeneration

Stem cells – capable of indefinite division, though slowly

Labile cells – normal state is active cell division and usually rapid regeneration

Stable cells – Not normally dividing at significant rate, so the speed and regeneration is variable.

Permanent cells – unable to divide or regenerated

This is a discrete series of cell types but in fact it is more of a continuum.

Factors involved

Complex and poorly understood.

Growth factors – GF< PDGF, FGF,
IGF, and hormones ACTH,
oestrogen and growth hormone.

Contact with basement
membrane & adjacent cells 
signalling through integrins
Growth factors act differently in different tissues.

Stem cells
Embryonic                                              Adult
Totipotent                                             Multipotent – extent unknown
Only from embryos                                      Available from bone marrow
Hard to obtain                                         Syngenetic source easily available
Syngenetic source required therapeutic cloning         Much studied – bone marrow transplantation
Ethical problems                                       -
Stem cells

        Proliferate locally to replace parenchymal cells
        Respond to local environment and cytokines
        May sometimes colonise tissues from the bloodstream
        The theoretical potential for manipulating regeneration is enormous.

Fibrous Repair

Formation and healing of granulation tissue.

    1.   Blood clot forms (haemorrhage and exudate)
    2.   Acute inflammation around the edges (neutrophils)
    3.   Chronic inflammation: macrophages infiltrate the clot and digest it
    4.   Capillaries and lymphatics sprout and infiltrate
    5.   Myofibroblasts infiltrate and differentiate
    6.   They glycoproteins and collagen are produced
    7.   Cell population falls, vessels differentiate and are reduced in number
    8.   Collagen matures contracts and remodels.

Features of fibrous collagens- triple helical fibrils arrange in ‘quarter stagger’ mode to form insoluble
fibres these are relatively resistant to general proteases; slow remodelling by specific collagenases.

Platelets are activated when brought into contact with collagen (which is exposed when the
endothelial blood vessel lining is damaged), thrombin (primarily through PAR-1), ADP receptors
(P2Y1 and P2Y12) expressed on platelets, a negatively charged surface (e.g. glass), or several other
activating factors. Once activated, they release a number of different coagulation factors and
platelet activating factors.

Extrinsic pathway: coagulation is initiated by a substance generated from damaged tissues called
Tissue Factor by interaction with factor VII

Intrinsic Pathway: coagulation is initiated by contact with surface agents such as collagen or by
proteases such as kallikrein, acting through factor XII

Healing by primary intention

A clean sutured wound

        Epidermis regenerates
       Dermis undergoes fibrous repair
       Sutures out at 5-10 days
       Maturation of scar continues up to 2 years
       Minimal scarring, good strength
       Risk of trapping infection under skin – produces abscess.

Healing by secondary intention

Open wounds

       Initial contraction
       Clot dries to form a scab or eschar
       Epidermis regenerates beneath
       Repair process produces granulation tissue
       It takes longer
       Produces a larger scar; not necessarily weaker.
       Produces more late contraction

Factors influencing wound healing

     Local factors
          o Type, size, location of the wound
          o Apposition lack of movement
          o Infection: suppuration, gangrene, tetanus
          o Blood supply: arterial, venous
          o Foreign material: dirt, glass, sutures, necrotic tissues
          o Radiation damage. (slows healing)
     General factors
          o Age, general state of health
          o Drugs
          o General cardiovascular status
          o Dietary deficiencies e.g. protein, vitamin C, sulphur containing amino acids

Complications of repair

Insufficient fibrosis: wound dehiscence; hernia; ulceration

Excessive fibrosis cosmetic scarring; hypertrophic scars; keloid

Excessive contraction = limitation of joint movement obstruction of tubes & channels.

Healing in tissues

Cardiac muscle - No regeneration just scarring, as myocytes can’t divided they are differentiated to
such a degree they can’t proliferate. Convert contractile muscle into inflexible collagen which affects
the contraction. This results in arrhythmias or cardiac failure which results in fluid accumulation.

Brain - Liquefactive necrosis  left with cystic space – no scarring because wouldn’t have any
connections
Bone - Can repair completely from haematoma  inflammatory reaction  capillary grow  stem
cell develop a callus which supported the framework

Liver - Hepatocytes are very differentiated but can still proliferate. You can remove 70% of the liver
and it can still regenerate.

Peripheral nerves - (wallerian degeneration) where damage is distal, regeneration begins at 3/4
days, regrow down previous channels

Wallerian nerve degeneration - nerves regenerate to previous node of Ranvier and then axon
regrows down the path it took previously, no cell division actually occurs - nerve growth only
requires cytoplasm and membrane.

Cartilage – can regenerate

Kidney – epithelium regenerates, architecture cannot, produces glomerular scarring and loss of
filtration capacity

Muscle – replaced by scar tissue

Voluntary muscle – limited regenerative capacity from satellite cells


Session 5 – Haemostasis, Thrombosis and Embolism

Haemostasis
Haemostasis is the arrest of bleeding, involving the physiological processes of blood coagulation and
the contraction of damaged blood vessels.

Successful haemostasis depends on

       Constriction on blood vessels to limit blood loss.
       Platelets to adhere to the damaged vessel wall and each other, to form a plug, and the
        platelet release reaction.
            o ATP  ADP
            o ADP, thromboxane A2 cause platelet aggregation, 5HT also realised.
            o Platelets coalesce after aggregation.
       Coagulation – cascade, series of inactive components converted to active components.
        Prothrombin  thrombin which activates fibrinogen  fibrin.
       Fibrinolysis – plasminogen  plasmin via plasminogen activators

This is aided by endothelium, which is anti-thrombotic. On it there are plasminogen activators,
prostacyclin, nitric oxide and thrombomodulin.

Thrombosis
It is the formation of a solid mass of blood within the circulatory system during life.

It is not a normal physiological process.

Occurrence is due to...
       Abnormalities of the vessel wall such as
           o Atheroma
           o Direct injury
           o Inflammation
       Abnormalities of blood flow
           o Stagnation or turbulence
       Abnormalities of blood components
           o Smokers, post-partum, post-op

Appearance

Arterial – they are pale, granular, lines of Zahn and have lower cell content than venous.

Venous – soft, gelatinous, deep red and have a higher cell content.

Outcomes

       Lysis
            o  Complete dissolution of thrombus, the fibrinolytic system active, blood flow is re-
               established, this is most likely when thrombi are small
       Propagation
           o Progressive spread of thrombosis
           o Distally in arteries and proximally in veins.
       Organisation
           o Reparative process due to ingrowth of fibroblasts and capillaries and lumen remains
               obstructed.
       Recanalisation
           o Blood flow re-established but usually incompletely
           o One or more channels formed through organising thrombus.
           o This is an unlikely outcome
       Embolism
           o Part of thrombus breaks off, travels through bloodstream and lodges at distant site

Effects of thrombosis

Arterial – it causes ischaemia, infarction though this depends on site and collateral circulation – if
other vessels are supplying the same tissue.

Venous – it causes congestion, oedema, ischaemia and infarction.

Embolism
Embolism is the blockage of a blood vessel by solid, liquid or gas at a site distant from its origin.
More than 90% of emboli are thrombo-emboli. Other types include air, amniotic fluid, nitrogen,
medical equipment and tumour cells.

Thrombo-emboli

       From systemic veins pass to the lungs = pulmonary emboli
       From the heart, they pass via the aorta to renal, mesenteric and other arteries
       From atheromatous carotid arteries pass to the brain
       From atheromatous abdominal aorta pass to arteries of the legs

Deep vein thrombosis
Predisposing factors include – immobility, post-op, pregnancy and post-partum, oral contraceptives,
severe burns, cardiac failure and disseminated cancer.

High risk patients must be identified and offered prophylaxis.

       Heparin subcutaneously
       Leg compression during surgery, Thrombo emboli disorder stockings.

Treatment intravenous heparin and oral Warfarin  anticoagulant prevents propagation but does
not dissolve embolism.

Effects of pulmonary embolism
Massive PE > 60% reduction in blood flow rapidly fatal

Major PE – medium sized vessels blocked = shortness of breath +/- cough and blood stained sputum

Minor PE – small peripheral pulmonary arteries blocked. Asymptomatic or minor shortness of breath

Recurrent minor PEs lead to pulmonary hypertension.

Other emboli
Nitrogen embolism required rapid decompression, gaseous nitrogen in blood. This is the bends.

Fat embolism - can occur whenever there is a chance for fat to enter the circulatory system, such as
during surgery. So due to laceration of adipose tissue or fractures of long bones. One of the more
common scenarios is the fatty marrow entering the circulation after a fracture to a large long bone,
such as the femur, or after surgery on this bone, which then lodges in the lung, causing inflammation
of the lung and pulmonary failure.

Disorders of coagulation

Idiopathic Thrombocytopenia –is due to autoimmune destruction of platelets, which are coated
with anti-platelet antibodies. Can be acute of chronic, acute seen in children after viral infection
which generally recovers. Chronic occurs in adults and platelet destruction occurs in the spleen, a
spenectomy is a good treatment as it prolongs survival.

Disseminated intravascular coagulation – results from activation of the coagulation system in small
vessels throughout the body. This has several main effects:

       Platelets are consumed, so low count.
       Fibrin thrombi are deposited in small vessels in the brain, kidney, lung and other organs,
        causing ischemic changes.
       Coagulation factors are consumed and there is activation of the fibrinolytic system; fibrin-
        degradation products acting as inhibitors of coagulation are generated.
       Red cells are fragmented by passage through vessels occluded by thrombi, and there is
        destruction of red cells.

Thrombophilia – the term describes an inherited or acquired tendency to make thrombi.

Haemophilia – the level of factor VII is reduced.


Session 6- Atheroma
Atheroma is the accumulation of intracellular and extracellular lipid in the intima and media of large
and medium sized arteries.

Atherosclerosis is the thickening and hardening of arterial wall as a consequence of atheroma.

Arteriosclerosis is the thickening of the walls of arteries and arterioles usually as a result of
hypertension or diabetes mellitus.

Macroscopic features of Atheroma

   Fatty streak
        o Lipid deposits in intima, yellow slightly raised. Relationship to atheroma is debateable.
   The simple plaque
        o Raised yellow/white with an irregular outline widely distributed, enlarged and
             coalesced.
   The complicated plaque
        o Thrombosis
        o Haemorrhage into plaque
        o Calcification
        o Aneurysm formation

Common sites – Aorta – especially abdominal, coronary arteries, carotid arteries, cerebral arteries
and leg arteries.

Microscopic features - Early changes – proliferation of smooth muscle cells, accumulation of foam
cells and extracellular lipid

Later changes – fibrosis, necrosis, cholesterol clefts and maybe inflammatory cells.

Also disruption of internal elastic lamina, damage extends into media, ingrowth of blood vessels and
plaque fissuring.

Clinical effects

     Ischaemic heart disease
          o Sudden death
          o Myocardial infarction
          o Angina pectoris
          o Arrhythmias
          o Cardiac failure
    Cerebral ischaemia
         o Transient ischaemic attack
         o Cerebral infarction
         o Multi-infarct dementia.
    Mesenteric ischaemia
         o Ischaemic colitis
         o Malabsorption
         o Intestinal infarction
    Peripheral vascular disease
         o Intermittent claudication – exercise incapability
         o Leriche syndrome - is atherosclerotic occlusive disease involving the abdominal
            aorta and/or both of the iliac arteries.
         o Ischaemic rest pain
         o Gangrene

Pathogenesis

      Age
           o Slow progressive throughout adult life – risk factors operate over years
      Gender
           o Women protected relatively before menopause – presumed hormonal basis
      Hyperlipidaemia
           o High plasma cholesterol associated with atheroma
           o LDL most significant, adversely HDL protective
      Cigarette smoking
           o Mode of action uncertain but changes coagulation system reduced PG12 and
               increased platelet aggregation.
      Hypertension
           o Strong link between IHD and high blood pressure
           o The mechanism is uncertain but it is suggested that endothelial damage is caused by
               raised pressure.
      Diabetes Mellitus
           o DM doubles IHD risk, and furthers risk of cerebrovascular and peripheral vascular
               disease. The protective effect in premenopausal women is also lost.
      Alcohol consumption
           o >5 units/day increases risk of IHD
           o Smaller amounts of alcohol may be protective
      Infection - such as Chlamydia pneumoniae, helicobacter pylori and cytomegalovirus.
      Lack of exercise, obesity, soft water oral contraceptive and stress.

Lipoprotein Class   Transport Function
Chylomicrons        Dietary Triacylglycerols from the intestine to tissues such as adipose tissue
VLDL                Triacylglycerols synthesised in the liver to adipose for storage
LDL                 Cholesterol synthesised in the liver to tissues
HDL                 Excess tissue cholesterol to the liver for disposal as bile salts
Genetic variations in apolipoprotein E are associated with changes in LDL levels. Polymorphisms
involved lead to at least 6 Apo E phenotypes. Polymorphisms can be used as risk markers for
atheroma.

Familial Hyperlipidaemia –genetically determined abnormalities of lipoproteins lead to earl
development of atheroma. Physical signs arcus, tendon xanthomas, xanthelasma

How it occurs – just a hypothesis

Atheroma involves thrombosis, lipid accumulation, production of intercellular matrix and
interactions between cell types. Cells involved: endothelial, platelets, smooth muscle, macrophages,
lymphocytes, neutrophils.

Endothelial – key to haemostasis, alter permeability to lipoproteins, secretion of collagen,
stimulation of proliferation and migration of smooth muscle cells.

Platelets – key to haemostasis, stimulate proliferation and
migration of smooth muscle cells (PDGF)

Smooth muscle cells – take up LDL to become foam cells, synthesise
collagen

Macrophages – oxidise LDL, take up lipids to become foam cells,
secrete proteases which modify matrix, stimulate proliferation and
migration of smooth muscle cells

Lymphocytes – stimulate proliferation and migration of smooth
muscle cells

Neutrophils – secrete proteases leading to continued local damage
and inflammation

Endothelial injury due to LDL/toxins/hypertension, causes platelet adhesion, PDGF release = SMC
proliferation and migration, LDL oxidation, uptake of lipid by SMC and macrophages, SMC produce
matrix, foam cells produce cytokines causing further SMC stimulation and increased recruitment of
inflammatory cells.


Session 7 – Cellular Adaptations
Control of Cell Growth
Cells in multicellular organisms communicate through chemical signals. Hormones act over a long
range and local mediators are secreted into the local environment and some cells communicate
through direct contact.

Cells are stimulated when extracellular signalling molecules bind to a receptor, each receptor
recognises specific ligand then act as transducers that convert the signal from one form to another.

Signalling molecules such as hormones and local mediators – epidermal growth factor (EGF), platelet
derived growth factor (PDGF), Fibroblast growth factor (FGF), TGF-beta, cytokines.
Receptors

There are two main types of receptors that are important in cell growth; these are G-protein-linked
receptors and enzyme-linked receptors.

G-protein-linked receptors activate GTP-binding proteins (G-proteins) these are molecules switches,
they are turned on for brief periods while bound to GTP. Then they switch themselves off by
hydrolysing GTP to GDP.

Enzyme linked receptors have intracellular domains with enzyme function. Most are receptor
tyrosine-kinases these are activated by growth factors, thus being important in cell proliferation.
Also some activate a small GTP-binding protein, Ras (important in cancer).

The Cell Cycle




Cell cycle machinery is subordinate to a control system this consists mainly of protein complexes
which in turn consist of a cyclin subunit and a CdK subunit. The cyclin has regulatory function, the
Cdk catalytic function.

Different cyclin-Cdk complexes trigger different cell
cycle steps. The cell cycle control system has in-built
molecular breaks (checkpoints). These ensure that
the next step does not begin until the previous one is
complete.

The G1 checkpoint – the retinoblastoma protein plays
a key role, the RB protein function is determined by
its phosphorylation status, S phase cyclin-Cdk
complexes phosphorylate Rb.

Cellular proliferative capacity
     Labile cell populations contain cells that move
       rapidly form one cell cycle to the next
     Stable cell populations dismantle their cell
       cycle control machinery and exit the cell cycle, but re-enter it when stimulated
     Permanent cell populations have left the cell cycle and cannot re-enter it.
       The regeneration in labile and stable cell populations correlates with stem cell activation.

Regeneration: increase in cell number in a tissue or organ to replace losses.

Mammals can replace cells and tissues but not whole organs.

Hyperplasia: increase in cell number in a tissue or organ above normal

Only occurs in labile or stable cells it may occur pathologically or physiologically (e.g. hormonal
action on endometrium). Pathological occurs in several situations, hyperplasia and hypertrophy
often occur together, association with increased risk of caner.

Hypertrophy: acquired increase in size of a cell, tissue or organ

Occurs in permanent cells due to synthesis of more cellular structural components it is again due to
physiological or pathological causes. Physiological reasons such as increased functional demand e.g.
skeletal muscle, and hormonal e.g. uterus in pregnancy. Pathological increased functional demand
e.g. cardiac muscle due to valvular disease or hypertension.

Atrophy: acquired decrease in size of cell, tissue or organ

Atrophy of whole organs is often due to reduction in cell size and apoptosis. Causes reduced
workload, loss of innervation (Alzheimer’s) , reduced blood supply, inadequate nutrition, loss of
endocrine stimulation and ageing.

Metaplasia: change of one differentiated cell type to another.

Direct = cell A  cell B

Indirect: stem cell to either differentiated cell A or differentiated cell B

Causes: an adaptive response to various stimuli, new cell type is better than old, the stimulus that
induced metaplasia may, later, induce cancer e.g. squamous cell carcinoma of the bronchus.

Hypoplasia: incomplete development of an organ with reduced cell numbers.


Neoplasia
Tumour

A tumour is a swelling of any nature:

Inflammatory, traumatic (e.g. haematoma), Neoplasm

Neoplasm – Abnormal growth of cells which persists after initiating stimulus has been removed.

Benign Neoplasm – cells grow as a compact mass and remain at their site of origin.

Malignant Neoplasm – Growth of cells is uncontrolled. Cells can spread into surrounding tissue and
spread to distant sites. CANCER = a malignant neoplasm.
Development  change to DNA  which must cause an alteration in cell growth and behaviour 
oncogenes & tumour suppressor genes

Change must be non-lethal and be passed onto daughter cells  monoclonal population.

Difference in Neoplastic cells – Alteration in growth control, factors regulating growth (receptors).
Alterations in cellular interaction.

Growth control: Increased cell proliferation, due to more cells entering cell cycle. Or cell cycle is
“sped up”. Cells have a changed life span; there are alterations in cell death-decreased apoptosis.
Modification of cell metabolism and angiogenesis can occur.

Increased or decreased growth factor receptors or altered receptors. Synthesis of growth factors
increases – autocrine or paracrine effect. Excess/modified growth control proteins.


Benign                                               Malignant
Nuclear variation in size and shape                  Nuclear variation in size and shape minimal to
minimal                                              marked, often variable
Diploid                                              Range of ploidy
Low mitotic count, normal mitosis                    Low to high mitotic count, abnormal mitosis
Structural differentiation retained                  structural differentiation shows wide range of
                                                     changes
organised                                            Not organised
Functional                                           Some failure of differentiation
Retention of specialisation                          Loss of specialisation.
Dysplasia – premalignant condition, increased cell growth, cellular atypia, altered differentiation,
can range from mild to severe. It occurs in the cervix, bladder, breast and others.




Benign                                                      Malignant
Smooth muscle: Leiomyoma                                    Smooth muscle: Leiomyosarcoma
Fibrous tissue: Fibroma                                     Bone: Osteosarcoma
Bone: Osteoma                                               Fibrous tissue: Fibrosarcoma
Cartilage: Chondroma                                        Cartilage: Chondrosarcoma
Fat: Lipoma                                                 Fat: Liposarcoma
Nerve: Neurofibroma                                         Nerve: Neurofibrosarcoma
Nerve sheath: Neurilemmoma                                  Nerve sheath: Neurilemmosarcoma
Glial cells: Glioma                                         Glial cells: Malignant glioma
Lymphoid – malignant lymphoma – Hodgkin’s disease/non-Hodgkins (Reed Sternberg cell/ not reed
Sternberg cell)

Bone Marrow – acute and chronic leukaemia

Germ Cell – Testis – teratoma, seminoma

        Ovary - dermoid cyst/mature cystic teratoma.

Invasion and Metastasis
Invasion

Is the ability of cells to break through basement membrane and then spread through the stroma.

Either into surrounding tissue or lymphatic/vascular channels.

It involves many factors:

    1. Malignant cells do not adhere to the same extent as normal cells
            Cadherins are Ca2+ dependent glycoproteins present at cells membrane. They
               interact homotypically between cells that link them together. Linked to the actin
               cytoskeleton by cadherins. Reduced expression occurs in cancer cells allowing cells
               to move apart.
            Integrins are cell surface glycoproteins composed of two subunits alpha, beta.
               Reduced expression, in malignant cell means less contact with stroma allowing
               movement.
    2. Altered cell synthesis of enzymes that breakdown basement membrane and stroma.
            Different enzymes can modify stroma allowing cells to break through basement
               membrane and spread. Matrix metalloproteinases (MMP2 MMP 9 break type 4
               collagen and MMP 1 breaks down type 1 collagen).
    3. Factors produced that help cells become motile.
            Cells propelled though the degraded basement membrane and lysed stromal matrix
            Mediated by cell derived motility factors – autocrine signalling factors
            AND cleavage products of matrix proteins
            AND other ligands
            AND Increased expression of receptors for motility factors.

Metastasis

Metastasis is the ability of malignant cells to invade into lymphatics, blood vessels and cavities and
spread to distant sites. Cells must be able to invade out of channels and colonise a different site.
Cancer cells are selective at where they grow.

They are selective because

       Incorrect receptors
       Metabolic factors
       Failure of angiogenesis  formation of blood vessels. Growth factors produced by cancer
        cells e.g. VEGF, can aid invasion. Angiogenic inhibitors try and stop this.
Primary – The site where the malignant neoplasm arises

Secondary – Metastasis, where the carcinoma has come from another organ.

Routes: Lymphatics, blood vessels, coelemic spaces (pleural cavity, peritoneal cavity)

Lymphatics

Spread to local and distant lymph nodes, frequent spread of carcinomas.

Vascular spread

Spread though capillaries and veins to various organs, common sites are lung, liver, bone and brain.

Lung

High occurrence, many malignant neoplasms can metastasise here. Sarcomas e.g. osteosarcomes
and carcinomas e.g. breast, stomach, large intestine, kidney and testis.

Blood travels there twice in the system, systemic and pulmonary.

Liver

Common site for carcinomas of large intestine (linked to hepatic portal), bronchial carcinoma, breast
carcinoma.

Bone

Can cause destruction to bone: bronchial carcinoma, breast carcinoma, thyroid carcinoma, renal
carcinoma. Also brain, thyroid, kidney, prostate and liver Pneumonic: British transport keeps people late

Can cause production of dense bone: prostate.

Brain

Can cause problems within the brain and the meninges. From bronchial carcinoma, breast
carcinoma, testicular carcinoma, malignant melanoma. Pneumonic: Bridget Bordeaux, kinky cool
men.

Effects of Tumours
In certain sites a small tumour can have devastating effects. Adversely people can survive a long
time with very extensive metastatic spread.

Local effects of benign neoplasms.

Cause compression – pressure atrophy, altered function

In a hollow viscus cause partial or complete obstruction. Ulceration of surface mucosa and bleeding.

Local effects of malignant neoplasms

Tend to destroy surrounding tissue. In a hollow viscus cause partial or complete obstruction and
constriction. Ulceration occurs. Infiltration around and into nerves, blood vessels and lymphatics.
Systemic effects

Haematological – anaemia – due to ulceration, infiltration of bone marrow, haemolysis

                   -Low white cell and platelets - infiltration of bone marrow, treatment

                   -Thrombosis – carcinoma of pancreas

Endocrine – Excessive secretion of hormones- neoplasms of endocrine glands

        Ectopic hormone secretion – E.g. ACTH, PTH, ADH by small cell carcinoma of bronchus

Cutaneous: Increased pigmentation – gastic, others

        Herpes zoster – lymphoma, others

        Pruritis (itching) – Jaundice, hodgkin’s

        Dermatomyositis – Bronchial carcinoma

Neuromuscular – Sensory/sensorimotor neuropathies

    -   Myopathy and Myasthenia
    -   Progressive multifocal leucoencephalopathy
    -   May mimic metastasis to brain
    -   Problems with balance.

Largely unknown:

Cachexia – severe wasting

Malaise – weary

Pyrexia – fever.

How and why do Tumours occurs
Intrinsic factors: Inherited susceptibility, age, immune status and hormones

Extrinsic factors: radiation, chemicals, parasites and viruses

Inheritance

Inherited conditions which predispose to the development of tumours – relate to DNA repair.

Inherited susceptibility to development of a tumour or a group of tumours due to alteration of one
or more genes.

Defects in DNA repair mechanisms

Retinitis pigmentosa  photosensitivity  susceptible to skin cancer

Ataxia telangiectasia  defective response to radiation damage  presents in childhood
Fanconi’s anaemia  sensitivity to DNA cross-linking agents  results in impaired ability to make
RBCs

Alteration in Gene

Name                       Gene                Where           Other
Polyposis coli             APC                 5q21            High risk in developing colon cancer
Hereditary non             Mismatch repair     eg. 2p21-22     No polyps but causes colon cancer
polyposis cancer
Li Fraumeni syndrome       p52                 17p             causes many cancers
Familial breast/ovarian    BRCA1/BRCA2         17q21/13q12
cancer
Retinoblastoma             Rb                  13q14
Extrinsic factors

Radiation: Causes a wide range of different types of damage to DNA: Single and double stranded
breaks or base damage. Effects depend on quality of radiation and dose, DNA repair mechanisms
important, incorrect repair of DNA damage  mutation.

Chemicals: carcinogenic interacts with DNA in one of a number of ways. For example, it can cause
specific base damage or single strand breaks. Damage repaired but may be imperfect.

Also some act directly, others are changed due to metabolism. If enzymes are required, tumours
occur in that organ, if not then at point of entry.

Examples

         Polycyclic aromatic hydrocarbons: in coal tar and cigarette smoke
              o 3,4-benzpyrene most important converted to active form by hydroxylation  aryl
                  carbonate hydroxylase.
              o Causes: lung cancer, bladder cancer and skin cancer
         Aromatic amines
              o Beta-napthylamine hydroxylated in liver to 1, hydroxy- 2napthylamine, which is
                  conjugated with glucuronic acid.  deconjugated to active form in urinary tract
              o Found in rubber and dye workers forming bladder cancer.
         Nitrosamines nitrates/nitrites to nitrosamines by gut bacteria cause GI cancer.
         Alkylating Agents  bind directly to DNA, nitrogen mustard
         Asbestos  mesothelioma (cancer in a protective covering of most of the body’s organs)
         Aflatoxins  liver cancer

Viruses

Hepatitis B  heptatocellular carcinoma

Epstein Barr  Burkitt’s lymphoma, nasopharyngeal carcinoma

Human papilloma virus (HPV)  cervical carcinoma

Helicobacter  gastric cancer and lymphoma
Parasite: Schistosoma  bladder cancer

Malaria  Burkitt’s lymphoma.

Geographical variation in cancer

Genetic, viruses present or not, parasites present or not, diet (high fibre stops GI cancers),
reproduction and breast cancer (early first pregnancy).

Age: incidence of cancer increases because:

        Cumulative exposure to carcinogens
        Latency
        Accumulating genetic lesions
        Innate defence

Genes:

The function of the genes which are modified by radiation/chemicals/viruses is critical for the
development of neoplasms.

Proto-oncogenes: present in all normal cells, involved in normal growth and differentiation. DNA
sequence identical to viral oncogenes. ALTERATION (mutation, amplification, translocation) 
ONCOGENE. Examples:

        C-myc binds to DNA stimulates synthesis  this is amplified in neuroblastoma and breast
         cancer. Translocation 8 to 14, adjacent to immunoglobulin (inappropriate transcription) in
         Burkitt’s lymphoma.
        Ras  intracellular signalling mutation, causes colon and lung cancer
        C-erbB-2 (HER-2)  growth factor receptor, amplification, adenocarcinoma. (Herceptin,
         stops agents which cause this).
        Ret  thyroid carcinoma in children

Tumour suppressor genes: in normal cells the protein encoded by the gene suppresses growth.
Loss/alteration to the gene results in loss of growth suppression. E.g. retinoblastoma/P53.

P53  gene encodes a nuclear protein which binds to and modulates expression of genes important
for DNA repair, cell division and cell death by apoptosis. Found in many cancers.
Carcinogenesis: Long period of time elapses between exposure to stimulus and the emergence of a
clinical cancer

         Initiating stimulus  effect modified by genetic factors, DNA repair
               o Agents render the cell susceptible to neoplasm but genetic change.
         Promotion  hormones, local tissue responses, immune responses.
               o Transient exposure to a promoting agent will not cause neoplasm
               o They cause increase cell turnover. With continued exposure to the agent cells which
                   have an initial genetic abnormality develop secondary genetic abnormalities.
         Progression  Number and type of genes modified
               o New genetic mutations occur, with development of sub-clones of neoplastic cells.
         Development  of Neoplastic cell

   To Note: It is not just an alteration to one gene it is an accumulation of alterations and many
   factors are involved.

Incidence, Prognosis and treatment
4 most common cancers, breast, lung, large bowel and prostate

Age

<10 – childhood neoplasms (nephroblastoma, neuroblastoma, retinoblastoma), leukaemia, CNS
tumours

10-19 – Leukaemia (generally acute myeloid type), osteosarcomes (in long bones)

20-29 – Leukaemia, teratomas, lymphoma

30-39 – Carcinoma, seminoma, lymphoma sarcoma

40-49- carcinoma, lymphoma, glioma, sarcoma

50> - carcinoma, sarcoma, lymphoma, (chronic) leukaemia.

Staging

How the tumour has spread, the size of the tumour and the node status.
It is a mixture of biochemical tests, pathology and scans.

Dukes staging for neoplasm of rectum:

A – Not extending through muscularis propria >90% 5 year survival

B – Extending through muscularis propria 70% 5 year survival

C – Lymph nodes involved 30% 5 year survival

TNM (tumour, node, metastasis)

e.g. breast, lung

T1 = <2cm size T2 = 2-5cm T3=Skin and/or chest wall involved

N0- no axillary nodes involved

N1 = mobile nodes involved

M0 – no metastases

M1 – demonstrable metastases

Hodgkin’s Disease

   i.    one group of nodes involved
  ii.    two separate groups, same side of diaphragm
 iii.    nodes involved both sides of diaphragm plus spleen
 iv.     Bone marrow, lung, other sites
    A.   no symptoms
    B.   Fever itching

Prostate Cancer

        T1 too small to be seen on scans or felt during examination.
        T2 is completely inside the prostate gland
        T3 has broken through the capsule of the prostate gland
        T4 has spread into other body organs nearby, such as the rectum or bladder.
        N0 No cancer cells found in any lymph nodes
        N1 One positive lymph node smaller than 2cm across
        N2 More than one positive lymph node. Or one that is between 2 and 5cm across
        N3 Any positive lymph node that is bigger than 5 cm across
        M0 No cancer spread outside the pelvis
        M1 Cancer has spread outside the pelvis

Grading

Predicts prognosis, how differentiated it is. It is a measure of aggressiveness and how it is likely to
behave. It determines treatment and prognosis.
Prognosis = Grade and stage. They are independent variables

Breast  degree of differentiation which means degree of tubule formation, extent of nuclear
variation and number of mitoses.

Prostate scale 1 to 5 of degree of gland formation and architectural pattern. Gleason system.

Grade 1 – well formed glands ... Grade 5 – sheets of cells, poorly formed glands

Squamous cell carcinomas  well differentiated (grade 1) to anaplastic (>75% undifferentiated)

Colon  G1 looks like normal tissue to grade 4 very abnormal tissue.

Treatment

(surgery?) Primary  depends on nature of tumour and the stage

Radiotherapy

Cells and tissue of the body and their tumours vary in their capacity to sustain injury. Depends on
phase of cell cycle, repair mechanisms and their oxygenation.

Sensitivity

High  lymphoma, leukaemia and seminoma

Fairly high  squamous carcinomas

Moderate  GI, breasta

Low  sarcoma

Chemotherapy

Drugs used have effects at particular stages of the cell cycle. Effects depend on tumour cells being in
cell cycle. But also have an effect on rapidly diving cells e.g. bone marrow.

       Cyclophosphamide – can act on cells in G1, S phase and mitosis
       Vincristine – can block cells entering cell cycle and act on mitosis
       Methotrexate – acts on cells in S phase.

Predicting response

In breast cancer if HER-2 present as detected by hercep Test, then can use Herceptin for treatment.

Tumour markers are products liberated from tumour into blood stream. May aid diagnosis and can
be used to gauge response to therapy and for follow up.

       Alpha fetoprotein – Hepatocellular carcinoma or germ cell tumours
       Human chorionic gonadotrophin – trophoblastic tumours
       Acid phosphatase or prostate specific antigen – prostatic carcinoma
       Carcinoembryonic antigen – GI tract antigen
       Hormone products – endocrine tumours
       Parathyroid hormone – parathyroid adenoma.

Screening

Aims to detect pre-malignant, non invasive and early invasive cancers to improve prognosis

Cervical – relies on cytological examination of smears to detect ‘early’ changes – dysplasia

Factors include – age range screened, population at risk, adequate smear, cytological examination

Breast – Aims to identify invasive cancers before they can be felt (10 -15 mm) and DCIS (ductal
carcinoma in situ)

Relies on mammography between 5-69 years. Factors frequency of screening, age range and
whether all lesions would progress.

Improving prognosis – Identify ‘at risk’ groups familial occupational. Detect at an earlier stage. Lastly
prevention.

				
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