MOD Flashcards
List the main methods of cell injury
- Hypoxia
- Toxins
- Heat
- Cold
- Trauma
- Radiation
- Micro-organisms
- Immune mecha`nisms
What is Hypoxia
Hypoxia is reduced O2. It is often due to Ischaemia, the interruption of blood supply. Ischaemia is used as a model for understanding the pathogenesis of cell injury:
Reversible Changes:
o Oxidative phosphorylation decreases
o Amount of ATP decreases
o Increased amount of anaerobic glycolysis, decreasing pH (Lactate)
o Low ATP means Na+ accumulates in the cell
o This means the cell swells via osmosis
o Detachment of ribosomes also leads to a decrease in protein synthesis
Irreversible Changes:
o Massive accumulation of cytosolic Ca2+
o Several enzymes activated resulting in cell death
Different cells react differently, e.g. a neurone can only withstand Ischaemic conditions for a few minutes, whereas fibroblasts can last for hours.
What are the structural changes seen in hypoxia
Structural Changes
Structural changes can be seen under the electron microscope
Reversible o Swelling o Chromatin clumping o Autophagy o Rinosome dispersal o Blebs (Little bumps on membrane surface where cytoskeleton has detached)
Irreversible o Nuclear changes o Lysosome rupture o Membrane defects o Endoplasmic reticulum lysis
LO 1.2 Define Necrosis and Apoptosis
Necrosis – Changes that occur after cell death in living tissue
Apoptosis – Programmed cell death
LO 1.3 Discuss Coagulative Necrosis
o More protein denaturation than enzyme release
o Cellular architecture is somewhat preserved, creating a ‘ghost outline’.
o Tends to be due to Infarcts (Infarct in the brain = Liquefactive)
LO 1.3 Discuss Liquefactive Necrosis
o More enzyme release than protein denaturation
o Tissue is lysed and disappears
o Tends to be due to infection
LO 1.3 Discuss Caseous Necrosis
o Tissue appears amorphous
o “Half way” between Coagulative and Liquefactive
o Caseous necrosis in the lung is very likely to be TB.
LO 1.3 Discuss Fat Necrosis
Occurs when cell death occurs in adipose tissue
LO 1.3 Discuss Gangrene
o Clinical term for grossly visible necrosis
‘Dry’ gangrene
o Coagulative
o E.g. umbilical cord after birth
‘Wet’ gangrene
o Liquefactive
o Infection -> Neutrophils -
> Proteolytic enzymes
What is an Infarct
Necrosis due to ischaemia
Can be white or red, depending on how much haemorrhage there is
White Infarct
o E.g. kidney
o Occlusion of end artery, no peripheral blood vessels, leaving the area entirely without blood
Red Infarct
o E.g. Bowel
o Occlusion of blood vessel leads to build up of blood, which all haemorrhages at once. Increased pressure decreases blood flow, leading to ischaemia and infarct.
LO 2.1 Discuss the major causes and biological purposes of acute inflammation
Acute inflammation is the response of living tissue to injury, initiated to limit the tissue damage.
Causes of Acute Inflammation:
o Microbial infections - E.g. Pyogenic Organisms
o Hypersensitivity reactions (acute phase)
o Physical agents
o Chemicals
o Tissue necrosis
LO 2.2 List the macroscopic features of acute inflammation
Calor – Heat
Rubor – Erytherma (Redness)
Tumor – Oedema (Swelling)
Dolor – Pain
And Loss of function
LO 2.3 Characterise the microscopic features of acute inflammation, including how they are brought about and relate to the macroscopic ones
- Vasodilation
Small adjacent blood vessels dilate with increased blood flow. - Gaps form in endothelium
Endothelial cells swell and retract; there is no longer a completed intact internal lining. - Exudation
Vessels become leaky. Water, salts and small plasma proteins leak through. (Exudate) - Margination and Emigration
Circulating neutrophils adhere to swollen endothelial cells. (Margination.)
Neutrophils then migrate through the vessel basement membrane. (Emigration). - Macrophages and Lymphocytes
Migrate in a similar way to Neutrophils.
LO 2.4 Briefly mention some of the chemical mediators of acute inflammation
Vasodilation -Histamine, Prostaglandins, C3a, C5a
Inc. Vascular Permability -Histamine, Prostaglandins, Kinins
Emigration of Leukocytes - Leukotrienes, IL-8, C5a
LO 2.5 Discuss the action of neutrophils
Neutrophils phagocytose microorganisms, by making contact, recognising and internalising them. Phagosomes are then fused with lysosomes to destroy the contents.
Neutrophils move to the site of injury by chemotaxis. An activated neutrophil may also release toxic metabolites and enzymes, causing damage to the host tissue.
LO 2.6 Discuss the systemic consequences of acute inflammation
Decreased appetite, raised heart rate, altered sleep patterns and changes in plasma concentration of Acute Phase Proteins, such as C-Reactive Protein (CRP), Fibrinogen and 1-antitrypsin.
The spread of micro-organisms and toxins can lead to Shock, a clinical syndrome of circulatory failure (See CVS Session 12)
Fever Endogenous pyrogens (substances that produce fever) IL-1, TNFA and prostaglandin are produced.
Leukocytosis
IL-1 and TNFA produce an accelerated release from marrow. Macrophages, T-Lymphocytes produce colony-stimulating factors.
LO 2.7 What may happen after the development of acute inflammation?
- Complete resolution
- Continued acute inflammation with chronic inflammation (Abscess)
- Chronic inflammation and fibrous repair, probably with tissue regeneration
- Death
Resolution
All mediators of acute inflammation have short half-lives and may be inactivated by degradation, dilution in exudate or inhibition.
Gradually all of the changes of acute inflammation reverse, and the vascular changes stop. Neutrophils no longer marginate, and the vessel permeability and calibre returns tot normal.
Therefore, the exudate drains via the lymphatics, fibrin is degraded by plasmin/other proteases and the neutrophils die.
Damaged tissue may then be able to regenerate, but if tissue architecture has been destroyed, complete resolution is not possible.
LO 2.8 Describe some possible complications of acute inflammation
Swelling
Blockage of tubes, e.g. bile duct, intestine
Exudate
Compression, e.g. cardiac tamponade
Serositis
Loss of fluid
E.g. burns
Pain and loss of function
Especially if prolonged
LO 2.9 Give a few clinical examples of acute inflammation - Skin Blister
Caused by heat, sunlight, chemicals
Pain and profuse exudate
Collection of fluid strips off overlying epithelium
Inflammatory cells relatively few, therefore exudate is clear
Resolution or scarring
LO 2.9 Give a few clinical examples of acute inflammation - Abscess
Solid Tissues
Inflammatory exudate forces tissue apart
Liquefactive necrosis in centre
May cause high pressure, therefore pain
May cause tissue damage and squash adjacent structures
LO 2.9 Give a few clinical examples of acute inflammation - Pericarditis
Inflammation of serous cavity
Pericardium becomes inflamed and increases pressure on the heart
LO 2.10 Discuss inherited disorders of the acute inflammatory process - general
Disorders of Acute Inflammation are rare diseases, but illustrate the importance of apparently small parts of this complex web of mechanisms.
Examples include: o A1 anti-trypsin deficiency o Inherited complement deficiencies o Defects in neutrophil function o Defects in neutrophil numbers
LO 2.10 Discuss inherited disorders of the acute inflammatory process - Hereditary Angio-Oedema
o Hereditary Angio-Oedema is caused by a deficiency of C1 inhibtor.
o C1 is a complement protein that cleaves C2 and C4 to form C3.
o C1 inhibitor does not only inhibit C1, but Bradykinin too. Uninhibited Bradykinin vastly increases the permeability of endothelia, causing Oedema.
o Hereditary Angio-Oedema is treated with C1 inhibitor infusion or fresh frozen plasma.
LO 2.10 Discuss inherited disorders of the acute inflammatory process - α1-antitrpysin Deficiency
o α1-antitrpysin inhibits Elastase.
o Without this inhibition elastase breaks down lung/liver tissue
o Causes emphysema and Liver Sclerosis.
LO 2.10 Discuss inherited disorders of the acute inflammatory process - Chronic Granulomatous Disease
o Recessive sex linked
o Immune phagocytes can’t form ROS
o Can’t kill some bacteria without ROS
o Granulomas formed in an attempt to contain the bacteria
What is chronic inflamation
Chronic response to injury with associated FIBROSIS
LO 3.1 Discuss how Chronic Inflammation Arises
- May ‘take over’ from acute inflammation
o If damage is too severe to be resolved within a few days… - May arise de novo
o Some autoimmune conditions (E.g. RA)
o Some Chronic Infections (E.g. viral hepatitis)
o “Chronic low-level irritation” - May develop alongside acute inflammation
o In severe, persistent or repeated irritation
LO 3.2 List the effects of Chronic Inflammation
o Fibrosis Gall bladder (chronic cholecystitis), chronic peptic ulcers, cirrhosis
o Impaired function
Chronic Inflammatory Bowel Disease
Rarely, increased function, e.g. mucus secretion, thyrotoxicosis
o Atrophy
Gastric mucosa, adrenal glands
o Stimulation of immune response
Macrophage-Lymphocyte interactions
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Macrophages
Important in acute and chronic inflammation
Various levels of activation
Functions
o Phagocytosis and destruction of debris and bacteria
o Processing and presentation of antigen to the immune system
o Synthesis of cytokines, complement components, clotting factors and proteases
o Control of other cells via cytokine release
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Lymphocytes
Sometimes called ‘chronic inflammatory cells’
Functions
o Complex, mainly immunological
o B Lymphocytes (Plasma Cells) differentiate to produce antibodies
o T Lymphocytes involved in control (CD4+) and some cytotoxic (CD8+) functions
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Eosinophils
Allergic reactions
Parasite infections
Some tumours
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Fibroblasts/Myofibroblasts
Recruited by macrophages, make collagen
LO 3.3 List the cells principally involved in chronic inflammation and the role of each - Giant’ Cells
Giant cells are multinucleate cells made by the fusion of macrophages, through the process of frustrated phagocytosis. There are several types recognised:
Langhans -> Tuberculosis
Foreign Body Type
Touton -> Fat Necrosis
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Chronic Cholecystitis (Fibrosis)
Repeated obstruction of the gall bladder with gallstones. Repeated acute inflammation leads to chronic inflammation and fibrosis of the gall bladder wall.
Treated with the surgical removal of the gall bladder.
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Gastric Ulceration (Fibrosis)
Acute gastritis (alcohol, drugs) Chronic gastritis (Helicobacter pylori)
Ulceration occurs because of an imbalance between acid production and mucosal defence.
H. pylori triple treatment:
o PPI Inhibitor – E.g. Omeprazole
o 2 Antibiotics – E.g. Clarithromycin / Amoxicillin
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Inflammatory Bowel Disease (Impaired Function)
Inflammatory disease affecting the large and small bowl. Patients present with diarrhoea, rectal bleeding and other symptoms.
Ulcerative colitis o Superficial o Diarrhoea o Bleeding o Treat with immunosuppression, surgical removal of the large bowel (colectomy)
Crohn’s disease
o Transmural
o Strictures
o Fistulae (Abnormal connection between two epithelia)
o Treat with lifestyle modifications, diet/hydration, immunosuppression
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Liver Cirrhosis (Fibrosis + Impaired Function)
Chronic inflammation with fibrosis leading to disorganisation of architecture and attempted regeneration -> Cirrhosis.
Common causes of cirrhosis: Alcohol Infection with HBV/HCV Immunological Fatty liver disease Drugs and toxins
Liver cirrhosis cannot be reversed, so treatment involves lifestyle changes to prevent further damage, and transplantation of a new liver if necessary.
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Thyrotoxicosis (Increased Function)
Graves disease
LO 3.4 Give some major clinical examples of chronic inflammation, how they arise, the complications which ensue and the treatment which is available - Rheumatoid arthritis
Autoimmune disease
Localised and systemic immune response
Localised chronic inflammation leads to joint destruction
Systemic immune response (Can affect other organs and cause amyloidosis)
LO 3.5 Describe and give examples of Granulomatous Inflammation
Chronic inflammation and immune responses overlap.
Immune diseases cause pathology by chronic inflammation
Chronic inflammatory processes can stimulate immune responses
Granulomas form when the immune system walls off something that it is unable to eliminate, for example bacteria, fungi and other foreign material. Granulomas arise with persistent, low-grade antigenic stimulation and hypersensitivity.
Main Causes of Granulomatous Inflammation
Mildly irritant foreign material
Infections
o Mycobacteria: Tuberculosis, leprosy
o Syphilis
o Some fungi
Unknown causes
o Sarcoid
o Wegener’s Granulomatosis
o Crohn’s disease
Tuberculosis
Caused by mycobacteria
Produces no toxins/lytic enzymes
Causes disease by persistence and induction of cell-mediated immunity
Outcomes of Granulomatous Inflammation
- Arrest, fibrosis, scarring
- Erosion into bronchus
- Tuberculous empyema (collection of pus)
- Erosion into blood stream
LO 4.1 Understand and describe Fibrous repair - the first step
Initiate fibrous repair by combining to form granulation tissue.
- Cell Migration
Inflammatory Cells
o Phagocytosis of debris: Neutrophils, macrophages
o Chemical Mediators: Lymphocytes, macrophages
Endothelial Cells
o Angiogenesis
Fibroblasts/Myofibroblasts
o ECM proteins e.g. collagen
o Wound contraction
What is Fibrous repair
The replacement of functional tissue by scar tissue
LO 4.1 Understand and describe Fibrous repair - the second step
- Angiogenesis
The development of a blood supply is vital to wound healing, to provide access to the wound for the above cells, and to deliver oxygen and other nutrient.
o Endothelial proliferation induced by proangiogenic growth factors such as VEGF
o Preexisting blood vessels sprout new vessels
o These mechanisms are exploited by malignant cells
o Endothelial proteolysis of basement membrane
o Migration of endothelial cell via chemotaxis
o Endothelial proliferation
o Endothelial maturation and
tubular remodelling
o Recruitment of periendothelial cells
LO 4.1 Understand and describe Fibrous repair - the third step
- ECM production/remodelling
o Supports and anchors cells o Separates tissue compartments (e.g. basement membrane) o Sequesters growth factors o Allows communication between cells o Facilitates cell migration
What are the 3 main stages of fibrous repair
Key Components:
- Cell migration
- Blood vessels – angiogenesis
- ECM production/remodelling
Describe the actual steps of fibrous repair as a whole
- Inflammatory cell infiltrate
Blood clot forms
Acute inflammation around the edges
Chronic inflammation – Macrophages and lymphocytes migrate into the clot - Clot replaced by granulation tissue (A combination of capillary loops and myofibroblasts).
Angiogenesis – Capillaries and lymphatics sprout and infiltrate
Myo/fibroblasts migrate and differentiate.
ECM is produced by myo/fibroblasts
3. Maturation Comparatively long lasting Cell population falls Collagen increases, matures and remodels Myofibroblasts contract – Reduces volume of defect Vessels differentiate and are reduced Left with fibrous scar
Describe the control of fibrous repair
Inflammatory cells are recruited by chemotaxis
Angiogenesis is due to angiogenic cytokines
Fibrosis is due to macrophages releasing pro-fibrotic cytokines causing fibroblast proliferation.
LO 4.2 What is Regeneration
Regeneration – The replacement of dead or damaged cells by functional, differentiated cells. Differentiated cells are derived from stem cells.
What are Stem Cells
Stem cells have potentially limitless proliferation, daughter cells either remain as a stem cell to maintain the stem cell pool or differentiate to a specialised cell type. In early life stem cells develop into many different cell types.
Unipotent – Can only produce one type of differentiated cell – E.g. epithelia
Multipotent – Can produce several types of differentiated cell – E.g. Haematopoietic
Totipotent – Can produce any type of cell – I.e. embryonic stem cells
Describe the propensity of different cell types to regenerate
- Labile Cells
E.g. Epithelial or haematopoietic cells
Normal state is active cell division: G1 – M - G1
Usually rapid proliferation - Stable cells
E.g. Hepatocytes, osteoblasts, fibroblasts
Resting state: G0
Speed of regeneration variable - Permanent cells
E.g. Neurones, cardiac myocytes
Unable to divide – G0
Unable to regenerate
Describe the factors controlling regeneration
Growth factors
o Promote proliferation in the stem cell population
o Promote expression of genes controlling cell cycle
o Hormones, oestrogen, testosterone, growth hormone
o Autocrine, paracrine and endocrine cells from many cell types, inflammatory, mesenchyme etc.
o Proteins, PDGF, EGF etc
Contact between basement membranes and adjacent cells
o Signalling through adhesion molecules
o Inhibits proliferation in intact tissue
o Contact inhibition
o Loss of contact promotes proliferation
o Exploited in cancer
LO 4.3 Describe and discuss the healing of a clean incised skin wound
Healing by Primary Intention
Incised wound
Apposed edges
Minimal clot/granulation tissue
Epidermis regenerates
Dermis undergoes fibrous repair
Sutures out at 5-10 days. Approx 10% normal strength.
Maturation of scar continues up to two years
Minimal contraction and scarring, good strength
Risk of trapping infection -> Abscess
LO 4.4 Describe and discuss the healing of a large skin defect
Healing by Secondary Intention
Infarct, ulcer, abscess or any large wound
Quantitative differences o Unapposed wound edges o Large clot dries to form ‘scab’ o Epidermis regenerates from the base up o Repair process produces much more granulation tissue
Comparison with primary intention:
o Produces more contraction to reduce volume of defect
o Produces a larger scar; not necessarily weaker
o Takes longer
LO 4.5 Discuss factors influencing the efficacy of healing and repair - local factors
Local Factors
1. Type, size, location of wound
2. Apposition, lack of movement
o Skin wounds, bone fractures, severed nerves
3. Blood supply: Arterial, venous
4. Infection: Suppuration, gangrene, systemic
5. Foreign material: dirt, glass, sutures, necrotic tissue
6. Radiation damage
LO 4.5 Discuss factors influencing the efficacy of healing and repair - General Patient Factors
General Factors 1. Age 2. Drugs (steroids) and hormones 3. General dietary deficiencies e.g. protein 4. Specific dietary deficiencies o Vitamin C – Alpha chain hydroxylation o Essential amino acids 5. General State of Health o Chronic diseases, e.g. diabetes, RA etc 6. General Cardiovascular status
LO 4.6 Describe and discuss special aspects of haling and repair in various tissues
Cardiac Muscle
o Fibrosis
Bone
o Callus formation
Liver
o Acute damage -> Regeneration
o Chronic damage -> Cirrhosis
Live hepatocytes have some regenerative capacity, but hepatocyte architecture does not regenerate. The imbalance between hepatocyte regeneration and the ability to regenerate architecture leads to cirrhosis and nodules.
Peripheral Nerve
o Wallerian degeneration
o Proximal degeneration, distal proliferation (~1mm/day)
CNS
o No regenerative capacity
o Glial cells can proliferate -> Gliosis
Muscle
o Cardiac / Smooth -> Permanent tissues. Will be replaced by a scar
Vascular smooth muscle has some, limited, regeneration
o Skeletal
Limited regenerative capacity due to satellite cells
LO 5.1 Define and discuss Haemostasis
Haemostasis is the body’s response to stop bleeding and loss of blood.
Successful Haemostasis depends on:
o Vessel wall - Constricts to limit blood loss
o Platelets
- Adhere to the damages vessel wall and to each other
-Form platelet plug
o Coagulation System
- Cascade, series of inactive components -> active components
- 1ml of blood can generate enough Thrombin to convert all of the fibrinogen in the body to fibrin, so tight regulation is required
- Balance of procoagulant and anticoagulant forces
o Fibrinolytic System
LO 5.2 Discuss the regulation of the coagulation system
Thrombin positively feeds back on factors V, VIII and XI - Thrombin inhibitors o Anti-thrombin III* o Alpha 1 anti-trypsin o Alpha 2 macroglobulin o Protein C/S*
*Inherited deficiencies in antithrombin III or Protein C/S -> Thrombophilia and thrombosis
Fibrinolysis
The breakdown of fibrin, by Plasmin.
Fibrinolytic therapy is widely used, e.g. Streptokinase, which activates Plasminogen. They are known as clot/thrombus busters. This is a very drastic treatment, used only in a serious situation, e.g. coronary artery occlusion or thrombus cutting off circulation to a limb.
LO 5.3 Define Thrombosis
Thrombosis – The formation of a solid mass of blood within the circulatory system during life
What are the factors affecting thrombus formation
Virchow’s Triad
Changes in blood flow
o Stagnation, turbulence
Changes in vessel wall
o Atheroma, injury, inflammation
Changes in blood components
o Smokers, pregnancy
Compare arterial and venous thrombi
Arterial Thrombi Pale Granular Lines of Zahn Lower Cell Content
Venous Thrombi Deep Red Soft Gelatinous Higher Cell content
LO 5.4 Discuss the effects of thrombosis
Arterial
- Ischaemia
- Infarction
- Depends on site and collateral circulation
Venous
- Congestion
- Oedema
- Ischaemia (If Tissue Pressure due to Oedema > Arterial Pressure)
- Infarction
LO 5.5 Discuss the outcomes of thrombosis
Lysis – Complete dissolution of the thrombus, Fibrinolytic system active, blood flow re-established. This is most likely when thrombi are small
Propagation – The progressive spread of thrombosis, distally in arteries, proximally in veins
Organisation – A reparative process with ingrowth of fibroblasts and capillaries. Lumen remains obstructed
Recanalisation – Blood flow re-established but usually incompletely. One of more channels formed through organising thrombus.
Embolism – Part of the thrombus breaks off, travels through the bloodstream and lodges as a distant site, e.g. coronary artery -> MI
LO 5.6 Define Embolism
Embolism – The blockage of a blood vessel by a solid, liquid or gas at a site distant from its origin.
What are the types of embolism
- Thrombo-emboli - 90%
- Air
- Amniotic fluid
- Nitrogen (divers get ‘the bends’)
- Medical equipment
- Tumour cells
Where do thromboembolisms travel to?
From Systemic Veins
Pass to the lungs (Pulmonary Emboli), as they will not get stuck in the large veins near the heart. The next time the emboli meets a vessel smaller than itself where it can get stuck is the lung.
From the Heart
Pass via the aorta to renal, mesenteric and other arteries
From Atheromatous Carotid Arteries
To the brain (Stroke)
From Atheromatous Abdominal Aorta
To the arteries of the legs
What is a Pulmonary Embolism
Massive PE > 60% reduction in blood flow - Rapidly fatal
Major PE – Medium sized vessels blocked
o Shortness of breath, cough, blood stained sputum
Minor PE – Small peripheral pulmonary arteries blocked
o Asymptomatic or minor shortness of breath
Recurrent PE’s -> Pulmonary hypertension
What are the causes Deep Vein Thrombosis
o Immobility/bed rest o Post-operative o Pregnancy and post-partum o Oral contraceptives o Severe burns o Cardiac failure o Disseminated cancer
What are the treatments of Deep Vein thrombosis
Intravenous Heparin
o Anticoagulant
o Co-factor for anti-thrombin III
Oral Warfarin
o Interferes with synthesis of vitamin K dependent clotting factors
o Slow effect
Descrbie Fat Embolism - causes and symptoms
o Fractures of long bones or Lacerations of adipose tissue
Rash, shortness of breath, confusion
Describe Cerebral Embolism
Atrial fibrillation -> Stasis -> Thrombus
If in left heart, can go to the brain and cause a stoke or transient ischaemic attack
Describe an Iatrogenic Embolism
Embolism due to medical treatment, e.g. air embolism from an injection
Nitrogen Embolism
Nitrogen bubbles form in the blood with rapid decompression e.g. The bends
Describe Disseminated Intravascular Coagulation (DIC)
DIC is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases.
Small clots form throughout the body, disrupting normal coagulation as they use up all the clotting factors.
Abnormal bleeding occurs from the skin.
Triggers: Infection, trauma, liver disease, obstetric complications
Describe Haemophilia
Type A and Type B
X-linked recessive, so more common in boys
Deficiencies in different clotting factors
o A = Factor VIII
o B = Factor IX
o Can be mild, moderate or severe due to various mutations
o Due to a nonsense point mutation
o Haemorrhage into major o joints, synovial hypertrophy, pain
p Muscle bleeding causes pressure and necrosis of nerves (painful)
p Can haemorrhage into retroperitoneum / urinary tract
o Treat with self-administered factor replacement therapy
Describe Thrombocytopenia
Platelet count is way below the reference range
Due to either:
o Failure of platelet production
o Increase in platelet destruction
o Sequestering of platelets
Usually accompanied by a bone marrow dysfunction, E.g. leukaemia, anaemia
If it is due to sequestering, cause may be DIC
LO 6.1 Define Atheroma, Atherosclerosis, Arteriosclerosis
Atheroma – The accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries
Atherosclerosis – The thickening and hardening of arterial walls as a consequence of atheroma
Arteriosclerosis – The thickening of the walls of arteries and arterioles, usually as a result of hypertension or diabetes mellitus
LO 6.2 Describe the morphological appearance of Atheroma - macroscopic
Macroscopic
Fatty Streak
o Lipid deposits in the intima
o Yellow, slightly raised
Simple Plaque o Raised yellow/white o Irregular outline o Widely distributed o Enlarge and coalesce
Complicated Plaque o Thrombosis o Haemorrhage into plaque o Calcification o Aneurysm formation
LO 6.2 Describe the morphological appearance of Atheroma - Microscopic
Early changes
o Proliferation of smooth muscle cells
o Accumulation of foam cells
o Extracellular lipid
Later changes o Fibrosis o Necrosis o Cholesterol clefts - Cholesterol deposition in the tissue, not the plaque o +/- Inflammatory cells
Describe the cellular events in atheroma formaiton
Endothelial damage -
> Platelets -> PDGF -> Smooth muscle proliferation
Proliferation and migration of smooth muscle takes the lipid with it.
Macrophages arrive and phagocytose the fat, becoming foam cells
LO 6.3 Explain some of the effects of severe atherosclerosis at specific anatomical sites - Coronary Artery
Ischaemic Heart Disease o Sudden Death o MI o Angina pectoris o Arrhythmias o Cardiac Failure
LO 6.3 Explain some of the effects of severe atherosclerosis at specific anatomical sites - Cerebral Ischaemia
Transient ischaemic attack
o Infarction of part of the brain. Symptoms for 24hrs (transient)
Cerebral infarction (stroke)
Multi-infarct dementia
LO 6.3 Explain some of the effects of severe atherosclerosis at specific anatomical sites - Mesenteric Ischaemia
Ischaemic colitis
Malabsorption
Intestinal infarction
Anneurism due to the high pressure, hardening and weakening
LO 6.3 Explain some of the effects of severe atherosclerosis at specific anatomical sites - Peripheral Vascular Disease
Intermittent claudication
Leriche syndrome
Ischaemic rest pain (Intermittent claudication in the iliac artery -> Gluteal pain)
Gangrene
LO 6.4 Discuss the risk factors for Atheroma
Age
o Slowly progressive throughout adult years
o Risk factors operate over years
Gender
o Women protected relatively before menopause
o Presumed hormonal basis
Hyperlipidaemia o High plasma cholesterol associated with atheroma o LDL most significant o HDL protective o Familial Hyperlipidaemia o Corneal Arcus o Xanthalasma
Cigarette Smoking
o Risk factor for IHD
Hypertension
o Strong link between IHD and high BP
o Endothelial damage caused by raised BP?
Diabetes mellitus
o Doubles IHD risk
o Also associated with high risk of cerebrovascular and peripheral vascular disease
Alcohol
o >5 units/day Inc risk of IHD
Infection
o Chlamydia
o Helicobacter pylori
Lack of exercise
Obesity
Oral contraceptives
Stress
LO 6.5 Discuss the Unifying Hypothesis of Atherogenesis
Endothelial injury due to o Raised LDL o ‘Toxins’ e.g. cigarette smoke o Hypertension o Haemodynamic stress
Endothelial injury causes
o Platelet adhesion, PDGF release, SMC proliferation and migration
o Insudation of lipid, LDL oxidation, uptake of lipid by SMC and macrophages
o Migration of monocytes into intima
Stimulated SMC produce matrix material - Foam cells secrete cytokines causing
o Further SMC stimulation
o Recruitment of other inflammatory cells
LO 6.6 Discuss the prevention of Atheroma
- Stop smoking
- Modify diet
- Treat hypertension
- Treat diabetes
- Lipid lowering drugs
Coronary Heart Disease
Susceptibility
Genetic – Disorders can increase risk, e.g. Familial Hypercholesterolemia
Geographical – Less common in the Mediterranean (diet)
Ethnicity – CHD common in Asians
Risk Factors
- Smoking
- Gender – More common in men
- Hypertension – Increased epithelial damage (see cellular events above)
- Diabetis – Increased IHD risk
- Alcohol - > 5 units per day is harmful
- Infection – H. pylori (recent evidence, unsure how but there is an association)
LO 7.1 Describe the different phases of the cell cycle and their control
The restriction (R) point, towards the end of G1, is the most critical checkpoint.
Passage beyond the R point is governed by the phosphorylation of the Retinoblastoma Protein (pRb)
LO 7.2 Describe Labile, stable and permanent cells
- Labile Cells
o E.g. Epithelial or haematopoietic cells
o Normal state is active cell division: G1 – M - G1
o Usually rapid proliferation - Stable cells
o E.g. Hepatocytes, osteoblasts, fibroblasts
o Resting state: G0
o Speed of regeneration variable - Permanent cells
o E.g. Neurones, cardiac myocytes
o Unable to divide – G0
o Unable to regenerate
Tissue stem cells power proliferative capacity, replenishing loss of differentiated cells.
Labile Cell populations
o Stem cells divide persistently to replenish losses
Stable Cell populations
o Stem cells normally quiescent or proliferate very slowly
o Proliferate persistently when required
Permanent Cell Populations
o Stem cells present, but cannot mount an effective proliferative response to significant cell loss
Define Regeneration
Replacement of cell losses by identical cells to maintain tissue or organ size.
Define Hyperplasia
Increase in tissue or organ size due to increased cell numbers.
Can only occur in labile or stable cell populations
Physiological Causes
o Proliferative endometrium
o Bone marrow at altitude
Pathological Causes
o Thyroid goitre
Define Hypertrophy
Increase in tissue or organ size due to increased cell size.
Permanent cells cannot divide, so increase organ size by hypertrophy
In cells where division is possible, hypertrophy may occur with hyperplasia
Physiological Causes
o Skeletal Muscle
o Pregnant uterus (hypertrophy AND hyperplasia)
Pathological Causes
o Ventricular cardiac muscle hypertrophy
o Bladder smooth muscle hypertrophy
Define Atrophy
Shrinkage of a tissue or organ due to an acquired decrease in size and/or number of cells.
Organ/Tissue atrophy is typically due to a combination of atrophy and apoptosis
Physiological Causes
o Ovarian atrophy in post menopausal women
Pathological Causes
o Muscle Atrophy (denervation)
o Cerebral atrophy (Alzheimer’s disease)
Define Metaplasia
Reversible change of one DIFFERENTIATED cell type to another.
Most clearly adaptive in epithelial tissues
Change in epithelium to be more suited to new environment
o E.g. Smoker. Pseudostratified Ciliated -> Squamous cells (more robust)
Sometimes a prelude to dysplasia and cancer
Define Aplasia
Complete failure of a specific tissue or organ to develop
Define Hypoplasia
Incomplete development of a tissue or organ
Define Dysplasia
Abnormal maturation of cells within a tissue
LO 9.1 Define Neoplasia
Benign Neoplasia – The abnormal growth of cells, which persists after initiating stimulus has been removed.
o Rounded mass due to the pushing growth. Remains at site of origin.
Malignant Neoplasm – Abnormal growth of cells, which persists after initiating stimulus has been removed AND invades and spreads to distant sites
o Irregular mass due to infiltrative growth edges. May spread to distant site forming secondary growth (Metastasis).
LO 9.2 Describe the alterations to DNA which cause neoplasia
For neoplasms to develop there has to be a change in DNA. The change must cause an alteration in cell growth and behaviour, and the change must be not lethal and passed onto daughter cells.
Neoplasms arise from a series of genetic alterations (~7).
These alterations occur in Proto-oncogenes OR Tumour Suppressor Genes. If a mutation permanently activates a proto-oncogene so it becomes an Oncogene or if a Tumour Suppression gene is permanently inactivated neoplasia will occur.
Neoplastic cells have key differences from normal cells: Self sufficient growth signals o HER2 gene amplification Resistance to anti-growth signals o CDKN2A gene deletion Grow indefinitely o Telomerase gene activation Induce new blood vessels o Activation of VEGF expression Resistance to apoptosis o BCL2 gene translocation Invade and produce metastases o Altered E-cadherin expression
LO 9.3 Describe the clonality of neoplasms
Neoplasms are monoclonal. They are a cell population that are descended from a common ancestral cell (the cell which originally acquired the mutation to escape normal growth control).
LO 9.4 Describe and compare benign and malignant tumours
Benign
Variation in size and shape (Pleomorphism) minimal
Low mitotic count. Mitoses have normal form.
Retention of tissue specialisation
(Well differentiated)
Malignant
Variation in size and shape (Pleomorphism) minimal to marked
Low to high mitotic count. Mitoses may have abnormal forms.
Variable loss of tissue specialisation
(Well to poorly differentiated)
LO 9.6 Distinguish between in-situ and malignancy
Carcinoma In-Situ has all of the features of a malignant neoplasm in an epithelium, but no invasion through the basement membrane.
LO 9.7 Discuss how Neoplasms are classified/named
Neoplasms are classified by:
1. Benign or malignant
2. By tissue type o Epithelial o Connective tissue o Lymphoid/haematopoietic o Germ cell
LO 9.8 Describe the basic histological types of benign and malignant neoplasm - Benign Epithelial Neoplasms
Benign
Stratified Squamous
o Squamous papilloma
o Any tumour with finger-like projections
o E.g. Skin, buccal mucosa
Transitional
o Transitional cell papilloma
o E.g. Bladder mucosa
Glandular
o Adenoma
o E.g. Adenomatous polyp of the colon
LO 9.8 Describe the basic histological types of benign and malignant neoplasm - Malignant Epithelial Neoplasms
Malignant – CARCINOMA
Squamous Cell Carcinoma
o Skin, larynx, oesophagus
Transitional Cell Carcinoma
o Bladder, ureters
Adenocarcinoma
o Stomach, colon, lung, prostate, breast, pancreas
Basal Cell Carcinoma
o Skin
What is the name for as benign and a malignant neoplasm of Smooth Muscle
Leiomyoma - Leiomyosarcoma
What is the name for as benign and a malignant neoplasm of Fibrous Tissue
Fibroma - Fibrosarcoma
What is the name for as benign and a malignant neoplasm of Bone
Osteoma - Osteosarcoma
What is the name for as benign and a malignant neoplasm of Cartilage
Chondroma - Chondrosarcoma
What is the name for as benign and a malignant neoplasm of Fat
Lipoma - Liposarcoma
What is the name for as benign and a malignant neoplasm of Nerve
Neurofibroma - Neurofibrosarcoma
What is the name for as benign and a malignant neoplasm of Nerve Sheath
Neurilemmoma - Neurilemmosarcoma
What is the name for as benign and a malignant neoplasm of Glial cells
Glioma - Malignant Glioma
Lymphoid and Haematopoietic Neoplasms
All regarded as malignant (Cells in blood already)
Lymphoid = Lymphoma (B and T)
- Occurs in lymphoid tissue
- Usually lymph nodes
- Hodgkins Disease and Non Hodgkins lymphoma
Haematopoietc = Acute and Chronic Leukaemia
- Occurs in bone marrow
- Abnormal cells then enter the blood
Myeloma
- Sounds like a benign muscle neoplasm
But its not! Malignant plasma cell neoplasm in bone marrow, destroying adjacent bone
Germ Cell Neoplasms
Testis
Malignant Teratoma
Seminoma
Ovary Benign Teratoma (Dermoid cyst)
LO 10.1 Define invasion and metastasis
Invasion – The ability of cells to break through the basement membrane and spread
o Direct invasion – Into surrounding tissue
Into Lymphatic/vascular channels
Metastasis – The spread of a malignant tumour to a distant (i.e. non adjacent) site
o A metastasis is often referred to as a secondary tumour, with the site of origin being the primary tumour.
LO 10.2 Describe the mechanisms facilitating invasion and metastasis
Altered Cell Adhesion
Angiogenesis
Altered Enzyme Synthesis and Interaction
Descirbe Altered Cell Adhesion in cancer
Cell – Cell Interactions
Reduced expression of Cadherins, which normally bind cells together, allows cells to move apart.
Cell – Stroma Interactions
Reduced expression of Integrins in malignant cells allows for movement.
Describe Altered Enzyme Synthesis and Interaction in cancer
Metastatic cells synthesise and release Matrix Metalloproteinases. These enzymes digest collagen, allowing the metastatic cells to digest the ECM and move to and break through the basement membrane.
MMP1 – Type I Collagen
MMP2/9 – Type IV Collagen
Describe Angiogenesis in cancer
Once a tumour has reached 1-2mm3 it’s growth is halted due to lack of nutrients/oxygen. This alters the tumour’s microenvironment, making it hypoxic. This causes the upregulation of pro-angiogenesis factors, e.g. angiopoietin, VEGF.
This causes the growth of new, thin wall blood vessels that not only allows for the continued growth of the tumour but provides another opportunity to enter the bloodstream as well.
LO 10.3 Describe the routes and common sites of metastasis- Lymphatics
Spread to local and distant lymph nodes
Frequent route of spread of carcinomas (malignant epithelial tumour)
Can involve lymphatics of the lung
Vascular
Spread through capillaries and veins to various organs. Common sites are lung, liver, bone and brain.
To Lung
o Can occur with a wide range of malignant neoplasms
o Sarcomas, e.g. osteocarcoma
o Carcinomas, e.g. breast, stomach, large intestine
o Kidney, e.g. “cannonball”
o Testis, e.g. malignant teratoma
To Liver
o Common site for carcinomas of the large intestine (portal vein)
o Carcinomas, e.g. Bronchial, Breast
To Bone
o Can cause destruction of bone, leading to pathological fracture
Carcinomas, e.g. Bronchial, Breast, Thyroid, Renal
o Can cause produce of dense bone (Osteosclerosis) - Prostate
To Brain
o Cause a wide range of neurological symptoms and act as a space occupying lesion (SOL)
In what cancers are metastases common?
Bronchial carcinoma
Breast carcinoma
Testicular carcinoma
Malignant melanoma
LO 10.4 Describe the local effects of benign and malignant neoplasms - Benign
Cause compression
o Pressure atrophy
o Altered function e.g. pituitary
In a hollow viscus cause partial or complete obstruction
Ulceration of surface mucosa
Space occupying lesion (brain)
LO 10.4 Describe the local effects of benign and malignant neoplasms - Malignant
Tend to destroy surrounding tissue
In a hollow viscus cause partial or complete obstruction, constriction
Ulceration
Infiltration around and into nerves, blood vessels, lymphatics
Space occupying lesion (brain)
LO 10.5 Describe the systemic effects of benign and malignant neoplasms -
Haematological
- Anaemia
o Due to malignant infiltration of bone marrow (Leukaemia, metastasis)
Low white cell and platelets
o Infiltration of bone marrow
o Consequence of treatments
Thrombosis
o Carcinoma of pancreas
LO 10.5 Describe the systemic effects of benign and malignant neoplasms -
Endocrine
Excessive secretion of hormones
o Benign and malignant neoplasms of endocrine glands e.g. parathyroid hormone, corticosteroids
Ectopic hormone secretion
o ACTH by small cell carcinoma of bronchus
LO 10.5 Describe the systemic effects of benign and malignant neoplasms - Skin
Increased pigmentation
o Many carcinomas
Pruritis (Itching)
o Jaudice, Hodgkin’s disease
Herpes zoster
o Lymphoma
Dermatomyositis
o Bronchial carcinoma
LO 10.5 Describe the systemic effects of benign and malignant neoplasms -
Neuromuscular
- Problems with balance
- Sensory/sensorimotor neuropathies
- Myopathy and myasthenia
- Progressive multifocal leucoencepalopathy
- Not due to metastasis to the brain
LO 10.5 Describe the systemic effects of benign and malignant neoplasms - General
Cachexia – Loss of weight, muscle atrophy, loss of appetite in someone who is not actively trying to lose weight
Malaise – A feeling of general discomfort or uneasiness
Pyrexia - Fever
LO 10.6 Explain why Neoplasms kill people
Local Effects – Raised ICP, perforation, haemorrhage (Benign or malignant)
Systemic Effects – Replacement of essential body organs, bone marrow, lung tissue, liver parenchyma (Malignant neoplasms).
LO 11.1 Give examples of inherited susceptibility to the development of tumours
Retinitis (Xeroderma) Pigmentosum
Increased risk of skin cancers when exposed to UV rays in sunlight
Ataxia Telangiectasia
Defective response to radiation damage, profound susceptibility to lymphoid malignancies, usually die before age 20
Fanconi’s Anaemia
Sensitivity to DNA cross-linking agents, marrow hypo function and multiple congenital anomalies, predisposition to cancer
LO 11.2 Give examples of the inheritance of certain tumours
Familial Adenomatous Polyposis - APC gene
Breast Cancer - BRCA1/2 gene
Li Fraumeni Syndrome -
p53 gene
LO 11.3 Discuss the functions of oncogenes and the changes which occur in neoplasia
Proto-Oncogenes – A normal gene that can become an oncogene due to mutations or increased expression
Proto-oncogenes are present in all normal cells, and are involved in normal growth and differentiation. They have a DNA sequence identical to viral oncogenes.
Proto-Oncogenes can be modified to become oncogenes (Mutation, amplification, translocation), making their products oncoproteins.
This allows the cell to escape normal growth control, becoming self sufficient without external signals required to grow.
Only one allele of a proto-oncogene needs to be mutated to cause neoplasia.
LO 11.3 Discuss the functions of tumour suppressor genes and the changes which occur in neoplasia
Tumour Suppressor Genes – A gene that encodes proteins that suppress growth and therefore cancer
In normal cells, Tumour Suppressor Genes encode proteins that suppress growth. Loss or alteration of the gene results in the loss of growth suppression.
Both alleles of a Tumour Suppressor gene need to be mutated to produce neoplasia (Knudson’s 2-hit hypothesis).
Inheritance of the ‘First Hit’ can lead to susceptibility to cancers (see above).
E.g. Retinoblastoma:
LO 11.4 Discuss the role of certain oncogenes
Ras
- Normally transmits growth-promoting signals to the nucleus
- Mutant Ras is permanently activated resulting in continuous stimulation of cells
- 15-20% of all Cancers
- Colon and lung cancer
C-myc - Binds to DNA, stimulates synthesis - Amplified (over-expressed) o Neuroblastoma, breast cancer - Translocation 8 14 o Burkitt’s lymphoma
HER-2
- Encodes for a growth factor receptor
- Amplified (over-expressed)
- ~25% of breast cancers
- Herceptin is a competitive antagonist at the HER-2 Receptor
LO 11.5 Discuss the role of certain tumour suppressor genes
pRb
- Passage beyond the R checkpoint at G1S boundary is governed by the phosphorylation of pRb.
- A defect in both alleles of pRb leads to the cell escaping cell cycle control.
- Retinoblastoma
p53
- ‘Guardian of the genome’
- Approximately 50% of tumour contain p53 mutations
- Gene encodes a nuclear protein, which binds to and modulates expression of genes important for cell-cycle arrest, DNA repair and Apoptosis
LO 11.6 Discuss the initiator stage in carcinogenesis
Carcinogenic agent, e.g. polycyclic hydrocarbon, radiation
- Exposure of cells to a sufficient dose of initiator
- Cell is altered, potentially capable of producing tumour
- Permanent DNA damage (mutations)
- Irreversible and has ‘memory’
- Effect modified by genetic factors, DNA repair
- Initiation alone is not sufficient for tumour formation
LO 11.6 Discuss the promoter stage in carcinogenesis
E.g. Hormones, local tissue responses, immune responses
- Can induce tumours in initiated cells
- Non-tumourigenic on their own
- Need exposure after initiation
- Cellular changes are reversible
o Remove promoter and`cell should be okay and return to normal
- Enhance proliferations, especially in mutated cells and increase incidence of further mutations – can result in cancer
o Think of all the mutations necessary for metastasis… this makes it more likely
LO 11.7 List the Agents that can result in the development of tumours
Radiation
Chemicals
Viruses
Other Agents
LO 11.7 Discuss Agents that can result in the development of tumours and their mechanisms of action - Radiation
Causes a wide range of different types of damage to DNA, including single/double strand breaks and base damage. The effect depend on the quality of radiation and the dose. If DNA repair mechanisms are overwhelmed, leaving DNA damage unrepaired, mutations in oncogenes/Tumour suppressor genes can lead to cancer.
Ionising radiation
o E.g. Hiroshima (Early leukaemia/lymphoma -> Late Thyroid/breast)
Ultraviolet radiation
o E.g. Squamous cell carcinoma, Basal cell carcinoma, Malignant melanoma
LO 11.7 Discuss Agents that can result in the development of tumours and their mechanisms of action - Chemicals
Carcinogens interact with DNA in one of a number of ways. Some act directly, others require metabolic conversion to an active form.
- Polycyclic aromatic hydrocarbons
o Produced in combustion of tobacco and fossil fueld
o Hydroxylated to active form
o Lung Cancer, bladder cancer, skin cancer (scrotal skin in chimney sweeps) - Aromatic Amines
o Hydroxylated in liver and conjugated with glucuronic acid (Phase 2 drug metabolism, non toxic)
o Deconjugated to active form in urinary tract by urinary glucuronidase
o Active form sits in bladder -> Bladder cancer
o Rubber and dye workers - Alkylating Agents
o Bind directly to DNA – Nitrogen mustard
LO 11.7 Discuss Agents that can result in the development of tumours and their mechanisms of action - Other Agents
Asbestos
o Malignant mesothelioma, lung cancer
Aflatoxins
o Hepatocellular carcinoma (collaborates with HBV)
Schistosoma
o Bladder cancer
Helicobacter
o Gastric cancer and lymphoma
Hormones
o Androgens and hepatocellular carcinoma
LO 11.8 Describe some conditions that predispose tumours
Ulcerative Colitis
- Colorectal carcinoma
- DNA damage and microsatellite instability
- May mask symptom of cancer
Cirrhosis
- In west present in 85-90% of hepatocellular carcinoma
- Some of association due to chronic viral hepatitis
Adenoma of colon/rectum
- Adenocarcinoma
LO 12.1 Describe the Staging of Malignant Tumours - use breast cancer as an example
TMN Staging System
- T = Primary Tumour
- N = Regional Lymph Node involvement
- M = Metastasis
TMN varies for each specific form of cancer, but the general principles are:
- With increasing size in primary lesion, T1 -> T4
- N0 = No nodal involvement, N1 -> N3 = involvement of an increasing no./range of nodes
- M0 = No distant metastases, M1 = Presence of blood borne metastases
TNM Staging for Breast Cancer TIS – Carcinoma in situ T1 - < 2cm T2 – 2-5cm T3 - > 5 cm T4 – Through the chest wall/skin
N0 – No nodal
N1 – Axillary
N2 – Mammary
N3 - Supraclavicular
M0 – No metastasis
M1 – Presence of metastasis
What is the staging system for colorectal cancers
Dukes’ Staging for Colorectal Carcinomas
- A
o Confined to bowel wall
o Not extending through muscularis propria
o >90% 5 year survival - B
o Through bowel wall (Muscularis propria)
o 70% 5 year survival
- C1/2 o Lymph nodes involved o 30% 5 year survival o C1 = Regional Lymph nodes involved o C2 = Apical node (furthest away node) involved
LO 12.3 Know which systems are used to classify Hodgkin’s disease and Prostate Carcinoma
Hodgkin’s Disease – Ann Arbor Classification
I – One lymph node involved
II – Two lymph nodes on one side of the diaphragm
III - > Two lymph nodes on both sides of the diaphragm
IV – Multiple foci (Bloody everywhere)
LO 12.5 Define and discuss Grading
Grading – Based on the degree of differentiation of tumour cells. Attempts to judge the extent to which tumour cells resemble or fail to resemble their normal counterparts.
Graded 1-3 or 1-4 with increasing anaplasia.
Gx = Grade of differentiation cannot be assessed
G1 = Well differentiated
G2 = Moderately differentiated
G3 = Poorly differentiated
G4 = Undifferentiated
What is the grading system used for Grading of Breast Carcinoma
Scarff-Bloom-Richardson Grading system
- Degree of tubule formation
- Extent of nuclear variation
- Number of mitoses
Grade 1 – 85% 10-year survival
Grade 2 – 60% 10-year survival
Grade 3 – 15% 10-year survival
What grading system is used for Prostate Carcinoma
Gleason Grading System
LO 12.4 Discuss the biological basis for the use of different cancer treatments - Radiotherapy
Radiotherapy
- External radiation to rumour at fractionated doses with shielding of adjacent normal tissues
- Causes damage to DNA of rapidly dividing cells
- If DNA damage is extensive -> Apoptosis
Sensitivity: - High o Lymphoma o Leukaemia o Seminoma (Testicular)
- Fairly High
o Squamous carcinomas - Moderate
o GI, Breast - Low
o Sarcoma
LO 12.4 Discuss the biological basis for the use of different cancer treatments - Chemotherapy
Drugs used have effects at particular stages of the cell cycle. Also have effects on rapidly dividing cells, e.g. bone marrow.
- Cyclophosphamide
o Act on cells in G1/S and mitosis
- Vincristine
o Block cells entering cell cycle/act on mitosis - Methotrexate
o Acts on cells in S phase
LO 12.4 Discuss the biological basis for the use of different cancer treatments - Hormone Therapy
- Tamoxifen
o Competes for binding to Oestrogen Receptor
o 50-80% of Breast Cancers express oestrogen receptors
o Surgical (Orchidectomy)/clinical castration - Herceptin
o HER-2 Growth factor receptor
o Overexpressed in 20-30% of breast carcinomas
o Herceptin = Humanised monoclonal antibody
o Side effects – Cardiac/pulmonary toxicity, can be fatal - Prostate Cancer
o Depends on androgens
o To treat, deprive tumour of testosterone
LO 12.5 Discuss the use of tumour markers in diagnosis and monitoring of disease
Carcinoembryonic Antigen
Normally only in embryonic tissue, but cancer basically does what it wants and expresses it again. It is clinically useful to see if there is any residual disease left after the removal of tumours.
Human Chorionic Gonadotrophin
Used in:
- The evaluation of testicular masses
- To indicate residual disease after Orchidectomy
- In monitoring response to therapy and prediction of recurrence
- Raised in nonseminomatous testicular tumours, especially when choriocarcinomatous elements present (high levels)
- Seminomas with syncytiotrophoblastic giant cells
Alpha-Fetoprotein (AFP)
- Normally synthesised early in foetal life by yolk sac, foetal liver and foetal GIT.
- Raised plasma levels associated with cancer of liver and yolk sac tumour of testis (nonseminomatous testicular tumours)
LO 12.6 Discuss the value of screening
Screening aims to detect pre-malignant, non invasive and early invasive cancers to improve prognosis
What cancers are screening tools used for
Cervix
Breast
Describe Breast screening
- Identify invasive cancers before they can be felt
o 10-15mm in size - Relies on mammography (x-ray of breast)
o Identifies densities and calcifications - Of every 500 women screened, one life will be saved
- 50-69 years
o Every 3 years
Describe cervical screening
- Cytological smears to detect “early” pre-cancerous changes
o Cervical Intraepithelial Neoplasia (CIN) - Treatment can then be given before invasion occurs and is curative
25 Years First invitation
25-49 -3 Yearly
50-64 - 5 Yearly
65+ - Those who have no been screened since age 50 or who have had recent abnormalities
