Pathological Processes Flashcards

Question

When it is cancer, what can histopathologists tell us?

Answer 1

Type of cancer Grade of cancer Stage of cancer TNM Completeness of excision and if margins are involved, which ones Likely efficacy of further treatments eg. HER2 receptor presence--->herceptin treatment All of which influence decisions on further treatment and management

Answer 2

Inactivate tissue enzymes + denature proteins Prevent bacterial growth Harden tissue

Answer 3

Pathologist | Cassette

Answer 4

Blocking-Tissue taken out of cassettes by hand and put into metal blocks. Molten paraffin wax is added and allowed to harden. Metal tray is removed.

Answer 5

A microtome

Answer 6

H&E Haematoxylin- stains acidic components of tissue (nuclei) purple Eosin- stains basic components of tissue (cytoplasm and CT) pink

Answer 7

Mounting- mounting medium is applied to the slide. Coverslip is put on top. Mounting medium dries and hardens, preserving the tissue and attaching the coverslip.

Answer 8

Demonstrates substances in/on cells by labelling them with specific antibodies. Antibodies are bound to enzymes that catalyse a colour changing reaction when then the antibody is bound to its receptor. (Brown stain)

Answer 9

Any substance that is antigenic can be detected: – Contractile protein actin, identifies smooth muscle cells – Cadherins, cell adhesion molecules, deficient in some carcinomas, e.g. lobular breast carcinoma – Hormone receptors, e.g., ER, PR, Her2 receptor (growth factor receptor) predicts response of breast cancer to Herceptin – Microorganisms, e.g., CMV, HPV, herpes simplex -Cytokeratins-give information about primary site of carcinoma

Answer 10

Immunohistochemistry for specific cytokeratins found in epithelia. Cytokeratins act as markers for epithelial differentiation and show tissue-specific distribution in epithelia. Therefore, they give information about the primary site of a carcinoma, particularly when used in combination.

Answer 11

The study of how diseases are caused by alterations in normal cellular molecular biology. This can be due to altered DNA, RNA or protein, but most often molecular pathology refers to changes in DNA.

Answer 12

1. Fixation with formalin 2. Cut-up (trimming) 3. Embedding in paraffin wax 4. Blocking 5. Microtomy 6. Staining 7. Mounting 9. Microscopy

Answer 13

1. Rapidly freeze small piece of fresh tissue in a cryostat. 2. Microtomy 3. Staining 4. Mounting 5. Microscopy

Answer 14

Skips fixation and embedding

Answer 15

Establishing the presence and nature of a lesion while the patient is still under anaesthetic Only used when the result will influence the course of operation.

Answer 16

- More difficult to interpret - Errors and false negatives can occur-correct diagnosis is about 96% of cases. Errors due to misinterpretation of frozen section or because lesion of interest is not present in tissue submitted for frozen section.

Answer 17

Type of injury Duration of injury/Severity of injury Type of tissue-neurones can only survive a few minutes before they suffer serious damage whereas fibroblasts can survive a few hours

Answer 18

1. Hypoxia 2. Physical agents 3. Chemical agents and drugs 4. Microorganisms 5. Immune mechanisms 5. Dietary insufficiency and dietary excess 6. Genetic abnormalities

Answer 19

Hypoxaemic hypoxia Anaemic hypoxia Ischaemic hypoxia Histiocytic hypoxia

Answer 20

Histiocytic hypoxia - inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes. Cyanide binds to mitochondrial cytochrome oxidises.

Answer 21

Anaemic hypoxia- reduced ability of haemoglobin to carry oxygen

Answer 22

Hypoxaemic hypoxia- arterial content of oxygen is low due to reduced absorption of oxygen in the lungs.

Answer 23

Lack of oxygen due to interruption in blood supply caused by: Blockage of a vessel Heart failure

Answer 24

Ischaemia is caused by interruption to blood supply to a region depriving it of oxygen and other nutrients. Hypoxia is lack of oxygen to a region. Ischaemic hypoxia is lack of oxygen to a region due to interruption to blood supply.

Answer 25

Reduced inspired partial pressure of oxygen at high altitudes Reduced absorption of oxygen secondary to lung disease.

Answer 26

Brain tissue will suffer a greater degree of injury than skin tissue. Neurones can only survive a few minutes with hypoxia whereas fibroblasts in the dermis of the skin can survive a few hours.

Answer 27

A hypersensitivity reaction | host tissue is injured secondary to an overly vigorous immune reaction

Answer 28

An autoimmune reaction | Immune system fails to distinguish self from non-self

Answer 29

Hypersensitivity reactions-host tissue is injured due to an overly vigorous immune reaction eg. Hives Autoimmune reactions-immune system fails to distinguish self from non-self eg. Grave's disease of thyroid

Answer 30

1. Cell membranes- fragile 2. Nucleus- site of DNA 3. Proteins- structural proteins and enzymes 4. Mitochondria- site of oxidative phosphorylation

Answer 31

Cell is deprived of oxygen. Mitochondrial ATP production by oxidative phosphorylation stops. Less ATP in cell causes: 1. ATP-driven Na+/K+ pump inhibition---> Na+ and water influx---> the cell swells and the plasma membrane is stretched/RER swelling/loss of microvilli 2. Rate of glycolysis increases to produce ATP until glycogen stores deplete ---> drop in pH---> clumping of nuclear chromatin 3. Detachment of ribosomes from RER---> decreases protein synthesis---> lipid deposition (particularly in hepatocytes)/the cell initiates a heat shock (stress response) which probably will not be able to cope if hypoxia persists

Answer 32

Large influx of Ca2+ into the cell.

Answer 33

- Large influx of calcium into the cytosol mainly from intracellular compartments but also from extracellular environment as NCX reverses. Calcium activates: 1. Phospholipases- cell membranes lose phospholipids 2. Proteases- damage cytoskeletal structures and attack membrane proteins 3. ATPase- causing further loss of ATP 4. Endonucleases- breaks down DNA - ER and other organelles swell. Enzymes leak out of lysosomes and digest cytoplasmic components. - Damaged cell membranes start to show blebbing and at some point the cell dies, possibly by the burst of a bleb.

Answer 34

Calcium activates: • phospholipases- causing cell membranes to lose phospholipid • proteases-damage cytoskeletal structures and attacking membrane proteins • ATPase- causes further loss of ATP • endonucleases-breaks down DNA and causes the nuclear chromatin

Answer 35

Free radicals are reactive oxygen species. They have a single unpaired electron in their outer shell. This is an unstable configuration so they react with other molecules, often producing further free radicals.

Answer 36

OH• (hydroxyl) (the most dangerous) 02- (superoxide) H202 (hydrogen peroxide).

Answer 37

- Free radicals are particularly produced by: - Normal metabolic reactions eg. Oxidative phosphorylation - Inflammation: oxidative burst of neutrophils - Radiation : H20 -->OH• - Contact with unbound metals within the body: iron and copper Clinical relevance: free radical damage occurs in Wilson's disease and haemachromatosis - Drugs and chemicals eg. In the liver, during metabolism of paracetamol or carbon tetrachloride by P450 system - Ischaemia-reperfusion injury - Cellular ageing - High oxygen concentrations.

Answer 38

- Free radical scavengers donate electrons to the free radical: vitamins A C E - Metal carrier and storage proteins (transferrin, ceruloplasmin) sequester iron and copper (these transition metals form free radicals) - Enzymes neutralise free radicals: superoxidase dismutase, catalase, glutathione peroxidase

Answer 39

When there is greater free radical production than free radical scavenging so free radicals build. The cell or tissue is now in oxidative stress.

Answer 40

• CELL MEMBRANE Attack lipids in cell membrane--->Lipid peroxidation, further generation of free radicals (autocatalytic chain reaction) • Oxidise proteins, carbohydrates and nucleic acids---> molecules become bent out of shape, broken or cross-linked--->mutagenic/carcinogenic

Answer 41

They oxidise nucleic acids. Cause DNA molecules to become bent out of shape/broken or cross-linked. This leads to mutations and can cause cancer depending what gene this mutation is in (p53 important).

Answer 42

When cells are submitted to stress, they turn down protein synthesis of their usual proteins and increase synthesis of heat shock proteins. Heat shock proteins maintain protein viability by refolding and correcting proteins and thus maximise cell survival.

Answer 43

Heat shock proteins

Answer 44

ANY form of injury - not just heat

Answer 45

Blood released. Iron released from haemoglobin. Contact of unbound iron with free radicals produces more reactive oxygen species.

Answer 46

Cytoplasmic changes Nuclear changes Abnormal intracellular accumulations

Answer 47

Injured cells- cytoplasm is pale and swollen (high water content due to Na+ influx) Dead cells- cytoplasm is stained deeply pink (proteins have denatured and coagulated)

Answer 48

Pyknosis - nucleus shrinks and becomes very dark Karyorrhexis- nucleus breaks up into different bits Karyolysis- nucleus disappears Karyorrhexis and karyolysis are characteristic of apoptosis.

Answer 49

• Swelling – both of the cell and the organelles due to Na+/K+ pump failure • Cytoplasmic blebs, which are symptomatic of cell swelling and proteases are breaking down cytoskeleton • Clumped chromatin due to reduced pH • Ribosome separation from the endoplasmic reticulum due to failure of energy-dependant process of maintaining ribosomes in the correct location

Answer 50

• Increased cell swelling • Nuclear changes - pyknosis, karyolysis, or karyorrhexis • Swelling and rupture of lysosomes – reflects membrane damage • Membrane defects • The appearance of myelin figures (which are damaged membranes) • Lysis of the endoplasmic reticulum due to membrane defects • Amorphous densities in swollen mitochondria

Answer 51

Die exclusion test- cells that take up the dye are dead as their membranes are damages. Cells that do not stain are not dead. Testing function is better than looking at the cell down a microscope because it is often difficult to distinguish between cells that have undergone reversible injury and irreversible injury (death).

Answer 52

The spectrum of changes that occur prior to cell death by swelling in cells injured by hypoxia and some other agents.

Answer 53

Morphological changes that occur after a cell has been dead for some time (4-24 hours). Not a type of cell death- appearance not a process.

Answer 54

Coagulative Liquifactive Caseous Fat necrosis

Answer 55

Morphological changes in cell death caused by swelling and protein denaturation (hence clumping).

Answer 56

Morphological changes in cell death caused by swelling and dissolution of proteins by enzymes.

Answer 57

Ischaemia of solid organs (organs that have a lot of CT support) Eg. Kidneys

Answer 58

- Ischaemia of loose tissue (organs without much CT support) Eg. Brain - Inflammation with lots of neutrophils

Answer 59

Denaturation of proteins>enzyme degradation | Ghost outline of cells- cellular architecture is somewhat preserved.

Answer 60

Enzyme degradation of proteins> protein denaturation Leads to enzymatic digestion of tissues Cannot recognise what the tissue was- NO ghost outline of cells. Can see liquid with naked eye.

Answer 61

Enzymatic dissolution of proteins = denaturation of proteins In between coagulative and liquifactive necrosis

Answer 62

Structureless debris

Answer 63

Tuberculosis (in lungs)

Answer 64

Death due to swelling of fat cells.

Answer 65

Acute inflammation and injury to pancreas Membrane integrity of cells is lost and pancreatic enzymes escape. Lipases digest fat in the abdomen and produce fatty acids. Fatty acids that are produced react with calcium and form calcium soaps. Calcification is shown on X-rays

Answer 66

Pancreatitis | Breast due to trauma-forms a very hard lump in the breast

Answer 67

Cancer Fat necrosis Pathologists can differentiate between the two.

Answer 68

Necrosis visible to the naked eye. (An appearance of necrosis).

Answer 69

Dry gangrene Necrosis modified by exposure to air Underlying process: coagulative necrosis Wet gangrene Necrosis modified by infection Underlying process: liquifactive process

Answer 70

Wet gangrene where tissue is infected with anaerobic bacteria that produces visible and palpable bubbles of gas within tissues.

Answer 71

Necrosis caused by reduction in arterial blood flow- ischaemia. (A cause of necrosis, can result in gangrene).

Answer 72

Liquifactive necrosis

Answer 73

Coagulative necrosis

Answer 74

``` Anaemic Solid organs (good stromal support) after occlusion of an end artery (terminal sole artery to an organ) ```

Answer 75

An area of necrotic tissue which is the result of loss of arterial blood supply (An area of ischaemic necrosis).

Answer 76

Common: Thrombosis- blood clot Embolism- bit of a thrombus has broken and travelled in artery and has blocked off supply elsewhere Others: External pressure on arteries eg. Testicular torsion. See lecture for pictures with examples.

Answer 77

Haemorrhagic Organs with dual blood supply. Eg. Lungs (systemic and pulmonary artery) Organs with collateral blood supply eg. Bowel (numerous anastomoses) Raised venous pressure Re-perfusion

Answer 78

- Alternative blood supply - Speed of ischaemia (more serious if faster) - Tissue involved (more serious if in brain than in feet) - Oxygen content of the blood (more serious if anaemic to begin with)

Answer 79

If blood flow is returned to an ischaemic but not yet necrotic tissue, damage sustained can be worse than if blood flow hadn't been returned.

Answer 80

Increased production of oxygen free radicals Increased number of neutrophils resulting in more inflammation/tissue injury Delivery of complement proteins and activation of the complement pathway

Answer 81

Arrhythmia

Answer 82

Potassium - disrupts electrical activity of the heart Enzymes- indicate the organ involved, extent, timing and evolution of tissue damage Myoglobin- released from dead striated muscle (cardiac and skeletal)

Answer 83

1. Reversible hypoxic cell injury 2. Irreversible hypoxia cell injury 3. Ischaemia-reperfusion injury 4. Cyanide poisoning 5. Free radicals

Answer 84

1.Myoglobin blocks glomerus of kidney---> Renal failure 2. Passes into urine--->Brown urine

Answer 85

Death of skeletal muscle fibres leading to the release of myoglobin into the blood stream.

Answer 86

Cell death with shrinkage is the death of a single cell (or small cluster of cells) due to activation of an internally controlled suicide programme where a cell activates enzymes that degrade its own nuclear DNA and proteins.

Answer 87

Cytotoxic T cell killing of virus-infected or neoplastic cells When cells are damaged, particularly with damaged DNA Graft versus host disease

Answer 88

shrunken intensely eosinophilic Chromatin condensation, pyknosis and karyorrhexis are seen and these take on a distinctive appearance in apoptosis.

Answer 89

``` cytoplasmic budding (not blebbing as is seen in oncosis) which progresses to fragmentation into membrane-bound apoptotic bodies which contain cytoplasm, organelles and often nuclear fragments The apoptotic bodies are eventually removed by macrophage phagocytosis. No leakage of cell contents occurs and therefore apoptosis does not induce inflammation. ```

Answer 90

The initiating signal comes within the cell: - irreparable DNA damage - withdrawal of growth factors/hormones

Answer 91

Initiated by extracellular signals: - Cells that are a danger eg. Tumour cells/virus-infected cells - TNFa secreted by T killer cells. Binds to cell membrane receptor and activates caspases

Answer 92

Activation of the p53 protein causes the outer mitochondrial membrane to become leaky. Cytochrome C is released from the mitochondria and this causes the activation of caspases.

Answer 93

Oncotic affects a group of contagious cells whereas apoptosis affects single cells. Oncosis causes swelling of cells whereas apoptosis causes shrinkage of cells. In oncosis, nuclear changes can be seen as: pyknosis, karyorrhexis and karyolysis. In apoptosis, fragmentation of DNA into similar sized fragments occurs to form clumps beneath the nuclear membrane and generally shows: pyknosis or karyorrhexis. In oncosis, the plasma membrane is disrupted whereas in apoptosis, the plasma membrane remains intact. In oncosis, cellular contents are digested by enzymes or leak out of the cell whereas in apoptosis, cellular contents are released in apoptotic bodies. Oncosis causes inflammation whereas apoptosis does not. Oncosis is always pathologic, whereas apoptosis can be physiological or pathological.

Answer 94

Cell injury can cause: Abnormal metabolism Alterations in protein folding/transport Deficiency of critical enzymes Inability to degrade phagocytised particles

Answer 95

1. Water and electrolytes 2. Lipids 3. Proteins 4. Pathological pigments 5. Carbohydrates

Answer 96

Steatosis - often sen in the liver as this is the major organ of fat metabolism.

Answer 97

Alcohol Diabetes mellitus Obesity Toxins

Answer 98

Cannot be broken down and is insoluble Can only be eliminated through the liver Excess stored in cell vesicles

Answer 99

Macrophages

Answer 100

Liver produces incorrectly folded α1-antitrypsin protein | These cannot be packaged by the ER so the unfolded enzyme accumulates within the ER and is not secreted.

Answer 101

Haemosiderin is an iron storage molecule which is derived from haemoglobin. Forms when there is a systemic or local excess of iron eg. Bruise With systemic overload of iron, haemosiderin is deposited in many organs. This is seen in catalytic anaemias, blood transfusions and hereditary haemochromatis.

Answer 102

hereditary haemochromatosis Genetically inherited disorder Results in increased intestinal absorption of dietary iron Iron is deposited in skin, liver, pancreas, heart and endocrine organs. Therefore symptoms include liver damage, heart dysfunction, multiple endocrine failures.

Answer 103

Accumulation of a bright yellow pigment - bilirubin. This is a breakdown product of heme- stacks of porphyria rings. Formed in all cells of the body as cytochromes contain heme but must be eliminated in bile. Taken from tissues by albumin to liver, conjugated with bilirubin and excreted in bile. If bile flow is obstructed or overwhelmed, bilibrubin in blood rises and jaundice results. Bilirubin is deposited in tissues extracellularly or in macrophages

Answer 104

Dystrophic calcification | Metastatic calcification

Answer 105

Dystrophic- localised Occurs in an area of dying tissue, in atherosclerotic plaques, in ageing or damaged heart valves, in TB lymph nodes Metastatic calcification-generalised Occurs throughout the body

Answer 106

No abnormality in calcium metabolism or serum calcium or phosphate concentrations Local change/disturbance favours nucleation of hydroxyapetite crystals

Answer 107

Organ dysfunction | Eg. Calcified heart valves---> heart failure

Answer 108

Hypercalcaemia secondary to disturbances in calcium metabolism Hydroxyapetite crystals are deposited in normal tissues throughout the body

Answer 109

Increased secretion of parathyroid hormone (PTH) resulting in bone resorption: •Primary - due to parathyroid hyperplasia or tumour •Secondary – due to renal failure and the retention of phosphate •Ectopic - secretion of PTH-related protein by malignant tumours (e.g., carcinoma of the lung) Destruction of bone tissue: • Primary tumours of bone marrow, e.g., leukaemia, multiple myeloma • Diffuse skeletal metastases • Paget’s disease of bone – when accelerated bone turnover occurs • Immobilisation

Answer 110

Telomerase

Answer 111

The response of vascularised living tissue to injury

Answer 112

To deliver defensive materials (leucocytes, plasma proteins and fluid) to a site of injury. It aims to: -protect the body against infection (particularly bacterial infection) -to clear damaged tissue -to initiate tissue repair IN ORDER TO... Limit tissue damage

Answer 113

Rapid response - hours to days Innate Stereotyped

Answer 114

Chemical mediators

Answer 115

Microbial infections Acute phase hypersensitivity reactions Physical agents Chemicals Tissue necrosis Foreign bodies

Answer 116

``` Rubor Tumour Calor Dolor Loss of function ```

Answer 117

Every mediator has inhibitors The duration of inflammation is limited as mediators have short lives (seconds to minutes) and their effects last minutes to hours

Answer 118

Sustained production of mediators

Answer 119

Vasoactive amines- histamine and serotonin (from mast cells and platelets) Mediators derived from phospholipids- Prostaglandins (from many cells)

Answer 120

Vasoactive amines- Histamine and Serotonin (from mast cells and platelets) Vasoactive peptides- Bradykinin (from the plasma precursor kininogen) Mediators derived from phospholipids- Leukotrienes (from leucocytes) Complement components- C3a, C4a and C5a (from complement plasma precursors).

Answer 121

Mediators derives from phospholipids- Leukotriene B4 (from leukocytes) Complement components-C5a and C3a (from complement plasma precursors) Chemokines (from leucocytes and other cells) Exogenous mediators- Bacterial products (from bacterial metabolism) Clotting and fibronolytic cascades- Thrombin and fibrin degradation products

Answer 122

Complement components- opsonin C3b (from complement plasma precursor

Answer 123

Vasoactive peptides- bradykinin (from the plasma precursor kininogen) Mediators derived from phospholipids- Prostaglandins (from many cells)

Answer 124

Unlike many other mediators, histamine and serotonin are available immediately from preformed supplies and are already present within cells in the tissues and platelets at the site of injury when vessels are damaged.

Answer 125

mast cells, basophils and platelets (stored in granules in these cells)

Answer 126

They block the production of prostaglandins by inhibiting the enzyme cycle-oxygenate (the enzyme that produces prostaglandins from arachadonic acid)

Answer 127

Circulates in the blood as part of the larger molecule kininogen (produced in liver) The enzyme kallikrein cleaves kininogen to produce bradykinin

Answer 128

Complement components form a tube (membrane attack complex) which punches holes in bacteria causing them to die. When it assembles into its tube structure, it generates as by products, powerful inflammatory mediators:

Answer 129

Cytokines are polypeptides that are produced by many cells- act as messengers between them. Chemokines are a group of cytokines involved in chemotaxis. Eg. Interleukins, tumour necrosis factor (TNF), Interferons They have local and systemic effects.

Answer 130

- when released into tissue---> inflammation | - when released into blood---> numerous inflammatory mechanisms at once resulting in septic shock

Answer 131

1. Transient vasoconstriction of arterioles. 2. Vasodilation of arterioles. 3. Increased permeability of blood vessels 4. Exudation of fluid and concentration of red blood cells in small vessels leads to increased viscosity of blood = STASIS

Answer 132

1. The semipermeable membrane becomes leaky. 2. The main force driving he fluid out of the vessels is increased-arterioles dilate increasing capillary pressure. 3. The main force driving fluid back into the blood is reduced- plasma proteins escape into the tissue spaces raising the osmotic pressure there so that it roughly equals that of blood. 4. Net flow of fluid out of vessel

Answer 133

Transudate | Exudate

Answer 134

Transudate- Fluid loss due to hydrostatic pressure imbalance (low protein content) Exudate- Fluid loss in inflammation (protein rich)

Answer 135

Delivery of nutrients, oxygen, cells and plasma proteins to the site of injury: - inflammatory mediators: opsonise, complement - antibodies - fibrinogen Excess fluid drains from tissues into the lymphatics taking with it microorganisms and antigens which are thus presented to the immune system

Answer 136

Neutrophils

Answer 137

Chemotaxis, diapedesis, emigration

Answer 138

Movement along concentration gradients of chemoattractants

Answer 139

``` Activation of complement releases C3a C4a C5a Bacterial peptides eg. Endotoxins Injured tissues Substances produced by leucocytes Thrombin and fibrin degradation products ```

Answer 140

1. Chemotaxis 2. Activation 3. Margination 4. Rolling 5. Adhesion 6. Emigration and diapedesis 7. Phagocytosis

Answer 141

- Ca2+ and Na+ enter the cell - Cell swells - Rearrangement of cytoskeleton assuming a roughly triangular shape pointing in the direction of the chemotactic stimulus - Production and release of pseudopodia - Activated cell is sticky

Answer 142

Exudate escapes via the gaps in the endothelial lining of the blood vessel Leucocytes dig their way out of the blood vessel walls: - relaxation of inter-endothelial cell junctions - digestion of vascular basement membrane - movement

Answer 143

Substances which make it easier for phagocytes to recognise targets, attach to pathegons making phagocytosis more effective. Eg. C3b

Answer 144

-O2 dependent-oxygen burst /respiratory burst Produces free radicals which are released into the phagosome -O2 independent- using enzymes Lysozyme, proteases, phospholipases, nucleases Bactericidal permeability increasing protein (BPI)

Answer 145

Oedema Exudation of fluid into tissues Inflammation Infiltration of inflammatory cells

Answer 146

- damage to normal tissue - swelling- obstruction of tubes, compression of vital structures eg. Bile duct and intestine - exudate-compression eg. Cardiac tamponade - loss of fluid-if fluid accumulates the tissue pressure increases until it reaches a level that prevents further exudation. However, fluid can continuously leak from a surface wound - pain and loss of function

Answer 147

Fever Leucocytosis Acute phase response Shock

Answer 148

Fever occurs when the thermostat of the body (situated in the anterior hypothalamus) is switched to a higher setting. Macrophages when they are stimulated to do so by exogenous (bacterial) pyrogens (endotoxins) produce pyrogenic cytokines

Answer 149

Some bacteria cannot survive at high temperatures (40-41degrees celsius) Inflammation has been demonstrated to be more effective at higher temperatures

Answer 150

The number of circulating leucocytes increases. In bacterial infection, the number of neutrophils increases. In viral infection, the number of lymphocytes increases;

Answer 151

Changes in the levels of some plasma proteins seen because the liver changes its patterns of protein synthesis. This occurs within hours of injury. Albumin and other proteins are produced in smaller amounts. Fibrinogen, ceruloplasmin, c3, alpha-1 antitrypsin, c-reactive protein are produced in greater amounts. This causes: - altered sleep patterns - decreased appetite - raised pulse rate

Answer 152

– Exudate drains to lymphatics – Fibrin is degraded by plasmin and other proteases – Neutrophils die, break up and are carried away or are phagocytosed – Damaged tissue might be able to regenerate. However, if regeneration cannot occur or damage is extensive, a fibrous scar forms. – Note that if tissue architecture has been destroyed, complete resolution is not possible.

Answer 153

• All mediators of acute inflammation have short half- lives. • May be inactivated by degradation, e.g. heparinase • Inhibitors may bind e.g. various anti-proteases • May be unstable e.g. some arachidonic acid derivatives • May be diluted in the exudate, e.g. fibrin degradation products. • Specific inhibitors of acute inflammatory changes – e.g. lipoxins, endothelin

Answer 154

1. Pus/abcess 2. Haemorrhagic exudate 3. Serous exudate 4. Fibrinous exudate

Answer 155

A haemorrhagic exudate contains enough red blood cells to appear bloody to the naked eye. It indicates that as well as inflammation significant vascular damage has also occurred. It is seen in destructive infections or when the exudate is a result of infiltration by a malignant tumour.

Answer 156

Serous exudates contain plasma proteins but few leucocytes suggesting that there is no infection by micro-organisms. They are clear and are seen typically in blisters, e.g., after a mild burn. Note serous exudates differ from transudates because they contain plasma proteins and they differ from plasma because they don’t contain fibrinogen. NB. A seroma is a tissue space filled with clear, sterile fluid that occurs as a post-operative complication.

Answer 157

In a fibrinous exudate there is significant deposition of fibrin (i.e., a blood clot without the red blood cells). When fibrinous exudates occurs in the pericardial or pleural spaces the fibrin that is deposited means that the serosal surfaces no longer slide smoothly over each other. This results in friction between the serosal surfaces which can be heard as a rubbing sound.

Answer 158

Post-mortem examination

Answer 159

Performed on behalf of HM coroner | No consent needed as it is a legal requirement

Answer 160

- deceased unknown - deceased not seen by a doctor within 14 days of death- can avoid post mortem examination if a doctor signs death certificate - attending doctor not able to give cause of death - obviously unnatural death (murder, accident, suicide) - death related to occupational disease/accident - death related to medical treatment or procedure - death of those who are in care of the state eg. Detained in hospital under mental health act, prisoners, young offenders

Answer 161

History-circumstances before death from hospital reports, medical records (often limited) External examination-natural disease, injury, medical intervention (scars), imaging Internal examination-all systems examined in most cases but limited sometimes

Answer 162

``` Histology Toxicology Biochemistry Microbiology Genetics ```

Answer 163

Cells die so electrolyte levels are no longer maintained as this is an active process. Bacteria use nutrients so glucose concentration can not be measured.

Answer 164

Diabetic/alchoholic ketoacidosis- ketone concentration in the blood stays the same after death Renal failure- urea and creatinine concentration stay the same after death

Answer 165

In the brain

Answer 166

``` Usually trauma at side of head. Skull is thin here Running underneath is the middle meninges artery (with an anterior and posterior branch) Blood gradually leaks from artery Compression of brain as skull is rigid ```

Answer 167

Abnormal heart valves | IV drug abuse

Answer 168

From the aorta | From the heart

Answer 169

Chronic response to injury with associated fibrosis

Answer 170

Redness and heat resolve but swelling and pain persist

Answer 171

After or alongside acute inflammation Chronic persistent infections Autoimmune conditions Prolonged exposure to toxic agents

Answer 172

Mononuclear cells- macrophages and lymphocytes

Answer 173

Chronic inflammation is a response to injury with associated production of granulation tissue (fibrous tissue).

Answer 174

Acute inflammation is a stereotyped, immediate, transient response of vascularised living tissue to injury.

Answer 175

1) complete resolution 2) continued acute inflammation with chronic inflammation = abcess 3) chronic inflammation and fibrous repair possibly with tissue regeneration 4) death- due to shock

Answer 176

Streptococcus pneumoniae

Answer 177

Streptococcus pneumonia in alveoli Acute inflammation stimulates the formation of exudate which collects in the alveolar sacs Results in inefficient gas exchange Hypoxaemia and breathlessness

Answer 178

Acute inflammation in meninges. Brain swells leading to compression as skull is rigid. Inflammatory exudate damages blood vessels. Vascular thrombosis and reduced cerebral perfusion.

Answer 179

Heat Sunlight Chemicals

Answer 180

Relatively few inflammatory cells. | Exudate is clear unless bacterial infection develops

Answer 181

``` Abscesses form in solid tissues. Inflammatory exudate forces tissues apart Liquefactive necrosis in centre May cause: High pressure---> pain Tissue damage Squashed adjacent structures ```

Answer 182

Exudate pours into cavity Localised fibrin deposition Peritoneum--->ascites Pleurae---> pleural effusion---> lungs cannot expand- respiratory impairment Pericardium--->pericardial effusion---> cardiac tamponade- cardiac impairment

Answer 183

Phagocytes are unable to generate the free radical superoxide. Bacteria are phagocytised but the phagocytes cannot kill them as they can’t generate an oxygen burst.

Answer 184

A protease inhibitor which deactivates enzymes released from neutrophils at the site of inflammation.

Answer 185

Liver disease occurs as the hepatocytes produce an abnormal version of the protein which is incorrectly folded. It polymerises and cannot be exported from the endoplasmic reticulum. This causes hepatocyte damage and eventually cirrhosis.

Answer 186

Rapid oedema of the dermis, subcutaneous tissue, mucosa and submucosal tissues

Answer 187

Acute inflammation in the pleural cavity

Answer 188

Acute inflammation = stereotyped Chronic inflammation = modulated, heterogenous Main mechanism acute inflammation = vascular changes Main mechanism chronic inflammation = fibrosis Acute inflammation = redness, heat, swelling, pain Chronic inflammation = swelling, pain Acute inflammation = predominantly neutrophils Chronic inflammation = predominantly macrophages Acute inflammation = immediate response Chronic inflammation = after a few hours Acute inflammation---> resolution possible Chronic inflammation---> repair and scarring Acute inflammation = most of the time has no significant long term consequences Chronic inflammation = long term consequences

Answer 189

Chronic persistent infections eg. TB Autoimmune conditions eg. Rheumatoid arthritis Prolonged exposure to toxic agents eg. Silica

Answer 190

An ongoing bacterial infection

Answer 191

NO | Repair and scarring

Answer 192

NO Resolution possible or Death due to shock or Repair and scarring by chronic inflammation

Answer 193

- Phagocytosis (particularly with difficult to kill bacteria eg. Myobacterium tuberculosis) - Professional antigen presenting cells - synthesis of cytokines, complement components, blood clotting factors, proteases - stimulate angiogenesis important in wound healing - induce fibrosis - induce fever, acute phase response, cachexia

Answer 194

Mainly plasma cells This is an autoimmune disease in which antibodies are produced by plasma cells which attack articular cartilage at joints resulting in pain, joint stiffness and swelling.

Answer 195

Mainly macrophages | Macrophages phagocytise protozoa ???? Idk im guessing

Answer 196

Mainly lymphocytes but also plasma cells Chronic gastritis is atrophy of the gastric mucosa resulting in the mucosa becoming thin and losing its function (no acid or enzymes produced) This is a result of chronic inflammation and a cell-mediated response.

Answer 197

Allergic reactions, parasite infections, some tumours

Answer 198

Respond to chemotactic stimuli | Recruited by macrophages

Answer 199

Lobed nucleus | Pink cytoplasm

Answer 200

Abundant golgi and cytoplasm visible | Mononucleate

Answer 201

Multinucleate cells made by fusion of macrophages when phagocytosis cannot destroy an antigen

Answer 202

1) Langhans giant cell Nuclei arranges around the periphery of the giant cell 2) Foreign body giant cell Nuclei arranged randomly in the cell 3) Touton giant cell Nuclei arranged in a ring toward the centre of the cell

Answer 203

Granuloma with caseous necrosis in the centre- appears as pink mush in centre Langhans type giant cells - nuclei at periphery

Answer 204

Small- phagocytised by giant cell and can be seen within it | Large- giant cell sticks to its surface

Answer 205

Lesions with high lipid content eg. Fat necrosis

Answer 206

These appear in lesions with high lipid contents eg. Fat necrosis ``` Therefore, Foam cells (macrophages whose cytoplasm appears foamy as they have phagocytised lipid) are also found here ```

Answer 207

Touton giant cell

Answer 208

1. Tissue destruction due to involvement in inappropriate immune responses. 2. Excessive fibrosis 3. Impaired function 4. Atrophy

Answer 209

When macrophages and lymphocytes meet with specific targets, mediators are released that cause inflammation. The immune system uses inflammation as a non-specific mechanism to destroy its targets. The immune system does not always get it right and can attack inappropriate targets in certain diseases.

Answer 210

Chronic inflammation | Fibroblasts are stimulated by cytokines to produce excess collagen.

Answer 211

Production of collagen is initially helpful in chronic inflammation as it helps to wall off infected areas and the production of a fibrous scar to replace damaged tissue is essential in wound healing

Answer 212

Excess fibrous tissue/inappropriate fibrosis can replace normal parenchyma (functional tissue of an organ) tissue and impair the function of an organ eg. Interstitial fibrosis of the lung If an area of fibrosis contains enough myofibroblasts, it can slowly contract and cause further problems. Eg. Contraction in a cirrhosis liver will impair the flow of portal blood resulting in ascites

Answer 213

Usually decreased function eg. Chronic obstructive bowel disease Rarely increased function e.g. mucus secretion, thyrotoxicosis

Answer 214

Example of chronic inflammation leading to excessive fibrosis and acute inflammation occurring simultaneously with chronic inflammation. - Repeated attacks of acute inflammation - Repeated obstruction of cystic duct (liver to gall bladderor common bile duct (gall bladder to small intestine) by gall stones - Muscle attempts to remove the stone (leaves and returns) causing mucosal damage -Triggers repeated acute inflammation leads to chronic inflammation -Fibrosis of gall bladder wall

Answer 215

Translucent tube

Answer 216

Excessive fibrosis leading to markedly impaired function

Answer 217

Mainly alcohol in UK Fatty liver disease Infection with HBV, HCV in other countries

Answer 218

Grave's disease leading to thyrotoxicosis Autoimmune disease Antibodies for the TSH receptor are formed Results in chronic inflammation Thyroid produces and releases too much thyroxin

Answer 219

Family of idiopathic inflammatory diseases affecting the large and small bowel

Answer 220

-repeated attacks of acute inflammation and chronic inflammation simultaneously -acute inflammation results in acute symptoms -chronic inflammation influences long term pathology of the disease, this leads to: Scarring, atrophy and reduces function of the bowel

Answer 221

Ulcerative colitis | Crohn's disease

Answer 222

Ulcerative colitis

Answer 223

Crohn's disease

Answer 224

1.Gastric mucosa is not replaced and is atrophic -becomes thin and does not produce enzymes or acid 2.Causes pernicious anaemia Pernicious anemia is defined as a type of vitamin B12 deficiency that results from impaired uptake of vitamin B-12 due to the lack of a substance known as intrinsic factor (IF) produced by the stomach lining.

Answer 225

Produces autoantibodies that destroy cells in the gastric mucosa Chronic inflammation Atrophy of gastric mucosa This gastric mucosa is not replaced and is atrophic (becomes thin and does not produce enzymes or acid)- has a major effect on its function

Answer 226

Group of macrophages and lymphocytes stuck together | Contains epithlioid cells- macrophages modified to look like epithelial cellls (elongated and tightly packed)

Answer 227

Giant cell = fused macrophages to create ONE multinucleate cell Granuloma = group of macrophages AND lymphocytes stuck together (MORE THAN ONE CELL)

Answer 228

1. Foreign bodies present 2. Persistent low-grade antigenic stimulation 3. Hypersensitivity/autoimmune 4. Unknown causes

Answer 229

A granuloma is the body's way of dealing with particles that are poorly soluble or difficult to eliminate for some reason. A granuloma forms around the particle, which can be free of phagocytise within the centre of the granuloma and walls it off whilst concentrating mononuclear cells within its centre with which it hopes to destroy the particle

Answer 230

``` Foreign body type- contain macrophages foreign body giant cells epithelioid cells some fibroblasts (at the periphery) few, if any, lymphocytes, ``` Hypersensitivity/immune type- contain macrophages giant cells (which may be of Langhans type) Epithelioid cells (which are usually more prominent than in foreign body granulomas) some fibroblasts (at the periphery) lymphocytes

Answer 231

BCG granuloma Caused by an organism which ellicits an immune response making you immune to TB Therefore, it produces granulomas that are very similar to those seen in TB

Answer 232

Lymph nodes, lungs

Answer 233

TB granulomas have caseous necrosis in the centre whereas sarcoidosis granulomas do not

Answer 234

Crohn's disease

Answer 235

A granuloma is a group of macrophages and lymphocytes stuck together consisting of epithelioid macrophages. Often contain multinucleate giant cells. Granulation tissue is formed in chronic inflammation and consists of fibroblast, myofibroblasts, chronic inflammatory cells and developing capillaries. Eventually turns into a scar.

Answer 236

Around 10 days after healing

Answer 237

Regeneration= proliferation of cells to replace lost structures and return to normal Hyperplasia= excessive proliferation of cells so there are more cells than normal

Answer 238

Haemostasis is the process of preventing or stopping bleeding in cases of trauma or disease while maintaining blood in its fluid state. Haemostasis is the stopping of haemorrhage.

Answer 239

Happens on a phospholipid surface where vessel integrity has been compromised

Answer 240

Seal the hole until tissues are repaired. | Mechanisms are then in place to dissolve the clot once vessel integrity has been restored (fibrinolysis).

Answer 241

- applying pressure to a bleeding point - suturing of an injury - application of a topical agent that aids clotting

Answer 242

Primary haemostasis 1. Vasoconstriction - severed artery contracts, not enough to stop bleeding but enough to decrease the pressure downstream (contraction doesn't occur in veins but the pressure in them is much lower) 2. Primary haemostatic plug - temporary blockage of a break by an unstable platelet plug - this sticks to the injured vessel and connective tissue outside it. Fragile but may control bleeding. Forms in seconds to minutes 3. Secondary haemostatic plug - blood coagulation or formulation of a fibrin clot which stabilises the friable platelet plug into a stable clot. This formed in approximately 30 mins.

Answer 243

Bud off from the cytoplasm of megakaryocytes in the bone marrow

Answer 244

Aspirin inhibits cyclooxygenase - one of the enzymes responsible for the production of thromboxane A2. Thromboxane A2 is a powerful platelet aggregator released by activated platelets, so aspirin prevents platelet aggregation and hence step 2 of haemostasis. Platelets have a normal life span of 7-10 days so patients should stop taking the medication 7-10 days before surgery so that platelets are present that have not been affected by the drug.

Answer 245

1. Platelet adhesion Occurs when there is damage to the vessel wall and exposure of the underlying tissue 2. Platelet activation Platelets are activated by many different substances in the blood. 3. Platelet aggregation This is how the platelet plug (primary haemostatic plug) grows.

Answer 246

- collagen surfaces (within extravascular areas) - ADP (released by activated platelets, injured red blood cells) - thromboxane A2 (powerful platelet aggregator released by activated platelets) - thrombin (informs platelets that clotting sequence is activated)

Answer 247

Occurs when there is damage to the vessel wall and exposure of underlying tissue Platelets stick to the exposed basement membrane specifically to VonWillebrands factor

Answer 248

- involved in platelet adhesion to the vessel wall - involved in platelet aggregation - stabilises factor VIII (8)

Answer 249

Platelets and endothelial cells

Answer 250

Vasoconstriction when an artery is damaged Subendothelial layer traps platelets (Von willebrands factor) Subendothelial layer performs a balancing act between opposing and avoiding clotting: - produces vWF, exposure of collagen and tissue factor which initiates activation of clotting factors by the extrinsic pathway - secretion of thrombomodulin (activates protein C) and plasminogen activator (fibrinolytic) that oppose clotting

Answer 251

Amplification system activation of precursor proteins to generate thrombin. Thrombin converts fibrinogen into insoluble fibrin. This enmeshes the initial platelet plug to make a stable clot.

Answer 252

Intrinsic pathway - involves all factors - triggered by a negatively charged surface - vessel does not need to be broken for it to occur Extrinsic pathway -triggered by a tissue factor present outside of the blood (thromboplastin)

Answer 253

Extrinsic pathway Tissue factor activates factor VII (7) which activates factor X (10)

Answer 254

PT = extrinsic pathway + common pathway

Answer 255

Intrinsic pathway + common pathway

Answer 256

Inherited or acquired defects of haemostasis resulting in a predisposition to thrombosis eg. Deep vein thrombosis)

Answer 257

-dilution of clotting factors by blood flow -natural anticoagulants that oppose the formation of fibrin. Main ones are: Antithrombin III, protein C, protein S, nitric oxide, prostaglandins, heparin -fibrin degradation products

Answer 258

Natural anticoagulants that oppose the formation of fibrin. If someone lacks any of these, they will experience repeated episodes of thrombosis.

Answer 259

Platelets in the clot die. As they die, they cling to the fibrin and pull by their actin-myosin filaments in a mechanism same as muscle contraction Clot retraction helps in pulling the sides of small wounds together and may toughen the clot by squeezing out fluid

Answer 260

Fibrinolysis - dissolves the clot once vessel integrity is restored - macrophages recognise the clot and break it down - plasmin breaks down fibrin into fibrin degradation products

Answer 261

Plasminogen (from liver) is cleaved by to form plasmin

Answer 262

- tissue plasminogen activation (tPA) - urokinase (found in urine) - streptokinase (obtained from streptococci so not usually found in the body)

Answer 263

Thrombi and thromboemboli break down

Answer 264

It is antigenic

Answer 265

- higher affinity for fibrinogen than streptokinase | - not antigenic so can be given more than once

Answer 266

Bleeding commonly from gums or nose but more seriously can occasionally occur in the brain

Answer 267

The clotting cascade. Fibrin increases the activity of tissue plasminogen activator which produce plasminogen which in turn breaks down fibrin to fibrin degradation products.

Answer 268

Fibrin degradation products

Answer 269

Any conditions where there is thrombosis: - disseminated intravascular coagulation - deep vein thrombosis - pulmonary embolism

Answer 270

Fibrinolytic activity drops and remains low for 7-10 days

Answer 271

The clot will eventually become organised (undergo fibrous repair) and be replaced initially by granulation tissue and then by a scar

Answer 272

Increased bleeding time (abnormal adhesion of platelets to vessel wall) APTT prolonged (vWF stabilises factor VIII) PTT normal

Answer 273

Autosomal dominant

Answer 274

- bone marrow infiltration by malignancy - drugs (cytotoxic) - infections eg. Measles HIV - B12 and folate deficiency

Answer 275

- immunological destruction eg. immune thrombocytopenia purpurin - non-immunological destruction eg. DIC

Answer 276

Sequestration

Answer 277

Dilutional | Blood stored for >24 hours has no platelets

Answer 278

Bleeding time prolonged Normal PT Normal APTT

Answer 279

Pinpoint haemorrhages Seen because of bleeding in capillaries typically due to vasculitis or abnormalities in the number of function of platelets

Answer 280

Decreased megakaryocytes

Answer 281

- an activator of clotting gets into the blood - microthrombi are formed throughout the circulation - process consumes platelets, fibrin and coagulation factors and activates fibrinolysis - patient may then experience haemorrhage

Answer 282

It is always a complication of another condition - sepsis (especially gram negative sepsis as such bacteria produce endotoxins which activates clotting) - severe trauma (eespecially to the brain as it contains large amounts of tissue factor (thromboplastin) - extensive burns - complications of childbirth - malignancy - snake bite

Answer 283

``` Presentation: Microvascular thrombosis causes -gangrene of skin -renal failure -respiratory distress -GI ulceration Haemorrhagic componet causes -intracerebral bleeding -petechiae -haematuria -GI bleeding ``` Clinical investigations: - raised FDP's eg. D-dimers - haemolytic anemia - RBC fragmented as they squeeze past thrombi - raised APTT - raised PT - low fibrinogen

Answer 284

X-linked recessive

Answer 285

Congenital lack in factor VIII (8) | Involved in intrinsic pathway

Answer 286

``` PT normal APTT prolonged (intrinsic pathway Bleeding time prolonged ```

Answer 287

Treat underlying cause If bleeding is a prominent feature: Platelets, fresh frozen plasma (contains clotting factors), cyroprecipitates), RBC may be needed Anticoagulants such as heparin may be required

Answer 288

X-linked recessive

Answer 289

``` PT normal APTT prolonged (measures intrinsic pathway) Bleeding time prolonged ```

Answer 290

Congenital lack of factor IX (9) | Involved in intrinsic pathway

Answer 291

Anticoagulant - disrupt clotting factors and hence the clotting cascade eg. Heparin, warfarin Antiplatelet - prevent platelet plug formation eg. Aspirin

Answer 292

It is a co-factor for anti thrombin 3 Anti thrombin 3 inhibits factor II (prothrombin) and factor X of the clotting cascade disrupting the common pathway of the clotting cascade APTT prolonged Bleeding time prolonged

Answer 293

Inhibits vitamin K Vitamin K dependent clotting factors cannot work Dosage is titrated to the patients PT test results, specifically INR results (INR is the ratio of the patients PT to a normal control)

Answer 294

Inhibits cyclooxygenase pathway which produced thromboxane A2 Thromboxane A2 is produced and released by activated platelets and is a powerful platelet aggregator Prevents platelet plug formation Bleeding time prolonged

Answer 295

The formation of a solid mass from the constituents of the blood within the circulatory system during life.

Answer 296

Haemostasis is the process of preventing or stopping bleeding in cases of trauma or disease while maintaining blood in its fluid state. A thrombus is a solid mass formed from the constituents of the blood within the heart or vessels during life. Thrombosis is the process of formation of a thrombus. It occurs when normal haemostatic mechanisms are turned on inappropriately.

Answer 297

ANYWHERE in the circulatory system | Eg. Arteries, veins, heart

Answer 298

``` There are three fundamental predisposing factors to thrombosis. • Abnormalities of the flow of blood ◦ Stagnation ◦ Turbulence • Abnormalities of the blood vessel wall ◦ Atheroma ◦ Direct injury ◦ Inflammation • Abnormalities of the constituents of the blood ◦ Smokers ◦ Post-partum ◦ Post-op ```

Answer 299

Myocardial infarction - damage to the area of endothelium overlying the infarct

Answer 300

As in clotting, when there is endothelial damage, platelets adhere to exposed von Willebrand factor. When blood flow is swift, for example in arteries, the platelet thrombi generally don't grow because the current washes away platelets, chemical mediators and clotting factors. However, if there is also stasis, a thrombus will form.

Answer 301

Abnormal blood flow gives platelets a better chance to stick to the endothelium and clotting factors a chance to accumulate. Turbulent flow can itself produce endothelial damage.

Answer 302

They have slow flow and valves produce pockets of stagnant blood which gives platelets a better chance to stick to the endothelium and clotting factors a chance to accumulate.

Answer 303

- cardiac failure - bed rest - immobilised (lack of muscular contractions in the calves)

Answer 304

Thee are increased levels of fibrinogen and factor VIII in the blood so it is hypercoaguable. There is pressure on the large veins of the pelvis by the gravity uterus causing stasis of blood

Answer 305

Activates factor XII (intrinsic pathway)

Answer 306

Causes hypercoagualability

Answer 307

- platelets are the smallest formed elements in the blood so are more concentrated along the endothelium - platelets are most likely to catch behind a valve - here, other platelets aggregate and settle on the wall of the vessel particularly if 1. There is endothelial injury 2. Blood flow is slow - as in haemostasis, fibrinogen binds the platelets together and fibrin grows out of the platelet layer - fibrin traps red blood cells, the surface of the red later is thrombogenic and platelets stick to the exposed fibrin - a second layer of platelets forms and the process continues

Answer 308

• Lines of Zahn -Laminated structure (red layer is red blood cells, white layer is platelets) these are more obvious in arterial thrombi as opposed to venous thrombi as blood flows over the surface of the forming thrombus in arteries

Answer 309

* Post-mortem clots form when blood is not flowing so are not laminated * More rubbery and shiny and are not attached to the intima

Answer 310

Thrombophlebitis refers to such painful superficial thrombi and have associated inflammation in the wall of the vein.

Answer 311

Parietal - attached to the wall of the vessel and restrict the lumen. Arterial thrombi tend to remain parietal. Occlusive - fill and obstruct the lumen. When occlusive thrombi do form in an artery it tends to be over an atherosclerotic plaque that has cracked open. Such thrombi in coronary arteries can be fatal.

Answer 312

Vegetation. These easily embolise. They usually form on the valves of the left heart as they are exposed to greater pressures and therefore microtrauma which exposes the thrombogenic subendothelial tissue. They can become infected and this is particularly common in IV drug users.

Answer 313

Likely to be due to abnormality of the vessel wall | Usually due to endothelial injury or turbulence eg. Atherosclerosis

Answer 314

- coronary arteries - carotid arteries - abdominal aortic aneurysms

Answer 315

* Pale * Granular * Lines of Zahn - change colour as the constituents of blood change * Lower cell content - than in veins

Answer 316

More likely to be due to abnormality of blood flow, blood components Usually where there is stasis

Answer 317

* Soft * Gelatinous * Deep red * Higher cell content

Answer 318

1. Resolution/lysis 2. Propagation 3. Organisation 4. Recanalisation 5. Embolism

Answer 319

Complete dissolution of the thrombus by the fibrolytic system Blood flow is re-established Most likely when thrombi are small

Answer 320

Progressive spread and enlargement of the thrombus in direction of blood flow. Distally in arteries Proximally in veins There is stagnation of blood distal to the original thrombus causing new thrombi to form

Answer 321

Reparative process Ingrowth of fibroblasts and capillaries (similar to granulation tissue) Haemorrhage, acute inflammation, chronic inflammation, wall of vessel replaced by fibrous tissue Lumen remains obstructed

Answer 322

Blood flow re-established but usually incompletely | One or more channels deformed through organising thrombus

Answer 323

Part of the thrombus breaks off Travels through the bloodstream Lodges at a distant site

Answer 324

* Ischaemia * Infarction (depends on site- if an end artery, this usually doesn't happen if there is collateral blood supply to the affected area)

Answer 325

* Congestion * Oedema * Ischaemia * Infarction

Answer 326

Arterial: Less blood supply to the region that the artery affected by a thrombus supplies Lack of oxygen and glucose to this region If an end artery, there is no collateral supply leading to necrosis and hence an infarct Venous: Thrombus blocking the vein causes pressure in the veins to increase, eventually causing fluid to leak out of the veins into the surrounding tissue Tissue pressure eventually equals arterial pressure Blood cannot flow to region a there is no hydrostatic pressure gradient

Answer 327

Thrombosis of uteroplacental vasculature leading to ischaemia

Answer 328

Embolism is the blockage of a blood vessel by an embolus which is solid, liquid or gas at a site distant from its origin.

Answer 329

In veins, blood flow is from smaller to larger vessels. Objects carried by the blood in veins will therefore go through the right heart and embolise in the pulmonary arteries. In arteries, blood flow is from large to small arteries so objects carried by the blood in large arteries will become impacted into smaller arteries. Therefore, emboli from the left heart or aorta can end up anywhere in the systemic circulation but especially in the lower limbs.

Answer 330

Lungs (unless there is a CHD)

Answer 331

Systemic arteries | Typically in the lower limbs

Answer 332

Arteries in the lower limb

Answer 333

- immobility/bed rest - post operative - pregnancy and post-partum - oral contraceptives - severe burns - cardiac failure - DIC

Answer 334

Approximately 80% from thrombi in deep veins of the thigh and popliteal vein

Answer 335

* Small pulmonary emboli - small and clinically silent * Multiple small pulmonary emboli - pulmonary hypertension * Large pulmonary emboli - resulting in more than 60% occlusion of the pulmonary circulation can cause sudden death, right sided heart failure, cardiovascular collapse * Large saddle emboli - become lodged at the bifurcation of the pulmonary arteries and result in sudden death

Answer 336

Thromboemboli in systemic arteries arises from the left heart, aneurysms and thrombi on arteries with ulcerated atherosclerosis. They embolise to the lower extremities, brain, intestines, kidneys, spleen and arms.

Answer 337

* Infarcts commonly affect the left ventricle. Thrombi can then form on the affected necrotic endothelium in the ventricular cavity. As the heart is beating these often embolise. * Atrial fibrillation results in decreased atrial contraction, dilatation of the left atrium, stagnation of blood in the left atrium and hence thrombus formation * Vegetations are commoner on valves of the left side of the heart because LHS is under higher pressure

Answer 338

Thromboemboli that form in the systemic veins but embolise to the systemic arteries. They manage to bypass the lungs in one of two ways: 1. Small emboli are able to pass through the arterio-venous anastomoses in the pulmonary circulation. Incidentally, this is also the way that fat droplets through the lungs in fat embolism. 2. Larger emboli can only enter the systemic circulation by passing through defects in the interventricular septum or a patent foramen ovale during coughing, lighting or straining (increases pressure in the right side of the heart to greater than that in the left, pushing the thrombus through the defect).

Answer 339

Patients with a stroke are four times more likely to have a patent foramen ovale when compared with the general population so a paradoxical embolus.

Answer 340

Atheroma is the gruel-like necrotic material present in atherosclerotic plaques. It can be released into the blood when a plaque breaks open. This can happen spontaneously and also during surgery or catheterisation for coronary artery disease. Such emboli often affect the intestine and present with abdominal pain.

Answer 341

Episodes of neurological dysfunction that appear suddenly, last minutes to hours and then disappear. They are the result of microscopic emboli, usually atheroemboli to the brain. The atheroembolus usually comes from the carotid arteries. Sometimes the are the result of thromboemboli that arise in the left heart. As the emboli are very small they break up quickly before any lasting damage is done so neurological symptoms dissappear after a short time.

Answer 342

* Complication of bone fractures - when bone is fractured the bone marrow fat cells that are injured break up and release oil droplets. These come together over a period of a few days and are then sucked into gaping venules that have been torn by the fracture. Symptoms of fat embolism (respiratory distress and neurological symptoms) are therefore seen 1-3 days after the fracture. * Fat emboli can occur after liposuction

Answer 343

• Respiratory symptoms - result of emboli that lodge in the lungs • Some droplets pass through the lungs in a similar way to small thromboemboli to organs such as the brain, kidneys and skin where they cause: ◦ Agitation ◦ Coma ◦ Renal failure ◦ Petechial rash

Answer 344

There is negative pressure in the veins of the chest and head during inspiration in the upright position. These veins can draw in air after trauma here. The fatal amount of air is approximately 100mls. The air is transported to the right heart where bubbles gather as a frothy mass that stops the circulation.

Answer 345

Air can enter the uterus and be forced into open veins during uterine contraction

Answer 346

* Complication of labour and caesarean section | * Amniotic fluid enters the maternal circulation through a tear in the amniotic membranes.

Answer 347

Talcum emboli - microscopic foreign bodies with which drugs have been cut are found in the lungs of intravenous drug abusers. These can produce a marked foreign body reaction and pulmonary symptoms.

Answer 348

* Mobilise early after an operation or illness * During and after an operation legs can be elevated and measures to increase venous return such as compression stockings, calf muscle stimulation, passive calf muscle exercises can be employed

Answer 349

Anticoagulants: - aspirin - heparin - warfarin

Answer 350

pulmonary emboli can be prevented by putting an umbrella shaped filter in the inferior vena cava.

Answer 351

Ratio of the patients PT to a normal control

Answer 352

Hardening of the arteries. In this condition the walls of the arteries are thickened and lose their elasticity. It includes three diseases: atherosclerosis, arteriolosclerosis, monkeberg's disease

Answer 353

The thickening of the walls of arteries and arterioles. The disease affects arterioles throughout the body especially those of the kidney. It has little or no connection with atherosclerosis and usually occurs as a result of hypertension or diabetes mellitus

Answer 354

Atherosclerosis is the accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries. Plaques form filled with atheroma and these often calcify.

Answer 355

It is the necrotic core of the atherosclerotic plaque consisting of dead cells, debris and cholesterol crystals.

Answer 356

Uncommon disease where there is calcification of the media of large arteries

Answer 357

* Cells - macrophages, leucocytes, smooth muscle cells * Intracellular and extracellular lipid * Extracellular matrix

Answer 358

1. Chronic endothelial insult from conditions such as hyperlipidaemia, hypertension, smoking or from haemodynamic factors result in endothelial dysfunction. 2. Lipid droplets, mainly from low density lipoproteins and monocytes cross the endothelium and accumulate in the intima. The lipids become oxidised and the macrophages ingest the lipid. When they do so their cytoplasm appears bubbly microscopically and they are called foam cells. 3. The crowded foam cells cause the endothelium to bulge. Smooth muscle cells migrate into the lesion from the media and start to proliferate. The lesion at this stage is called a fatty streak. 4. The plaque grows as the number of foam cells and smooth muscle cells increase. Some smooth muscle cells take up the lipid and appear foamy. Some smooth muscle cells lie over the plaque but beneath the endothelium forming a 'roof'. This roof is reinforced by collagen, elastin and other matrix proteins and the result is a fibrous cap. As the endothelium stretches over the plaque, gaps appear between the endothelial cells. Platelets adhere to the gaps. 5. Cells in the centre of the plaque die and necrosis develops. The dead cells release cholesterol and cholesterol crystals appear in the plaque (these are removed during tissue processing for microscopy leaving behind linear holes in the tissue section = cholesterol clefts. Small blood vessels from into the plaque from the adventitia and the plaque may undergo calcification.

Answer 359

Lipid deposits in intima. Thought to predispose to atherosclerosis but there is some debate about this as many fatty streaks do not develop into atherosclerosis.

Answer 360

The fibrous cap is eroded from underneath and the core of the plaque is exposed to the blood. This core is highly thrombogenic.

Answer 361

A local dilatation may result when elastic tissue within the arterial wall is destroyed by the plaque. This weakens the wall and may result in rupture of the vessel.

Answer 362

- accumulation of foam cells - proliferation of smooth muscle cells - extracellular lipid deposition

Answer 363

- fibrosis - necrosis - cholesterol clefts - increase in inflammatory cells - disruption of internal elastic lamina - extension into media - ingrowth of blood vessels - plaque fissuring

Answer 364

Local dilatation of an artery due to weakening of the arterial wall. In large arteries they are almost always secondary to atherosclerosis. Like atherosclerosis, they are a disease of arteries. Dilatations in veins are called varicies.

Answer 365

``` • Saccular aneurysm ◦ Shaped like a sac ◦ Lined or filled with thrombus which may be advantageous as it can protect the thrombus from bursting • Fusiform aneurysm ◦ Shaped like a spindle ```

Answer 366

• Dissecting aneurysm ◦ Only occurs in the aorta and its major branches ◦ Form within a couple of minutes ◦ Inner layer of arterial wall tears open, blood enters and separates media into 2 layers, tear fills with blood and the lumen of the artery can be occluded. Second tear can push blood back into lumen • Ruptured aneurysm ◦ Leads to retroperitoneal haemorrhage

Answer 367

• Transient ischaemic attack (mini stroke) ◦ Presentation? Similar to stroke eg. Face drop, neurological impairment but these resolve in 24 hours • Cerebral infarction (stroke) ◦ Presentation? Ipsilateral neurological problems, does not resolve within 24 hours • Multi-infarct dementia ◦ Lots of small cerebral infarcts that on their own do not present clinical symptoms

Answer 368

• Intermittent claudication ◦ Presentation? Pain in calves on walking, pain will resolve if you stop and rest, pain will reoccur after a short distance (claudication distance- decreases if you stop and rest for longer) • Leriche syndrome ◦ Presentation? Pain in the buttocks, may be associated with impotence • Ischaemic rest pain ◦ Not enough blood supply to the peripheries to maintain them in resting state • Gangrene ◦ Not able to maintain tissues at all

Answer 369

narrowing/blockage of vessels or embolism of plaque material or thrombus that has formed on a plaque.

Answer 370

- cell proliferation - cell differentiation - cell death by apoptosis

Answer 371

Chemical signals from micro-environment Signalling molecule binds to a receptor which results in modulation of gene expression. Receptors are usually in the cell membrane but can be in the cytoplasm or nucleus (steroid receptors) Proto-oncogenes regulate normal cell proliferation

Answer 372

When a cell receives an instruction to divide, the cell enters the cell cycle (G1--->S--->G2--->M). After cell cycle completion, the cell either re-starts the process from G1 or exits (G0) until further growth signals occur. Cells in G0 can undergo terminal differentiation where there is a permanent exit from the cell cycle.

Answer 373

You can't see interphase (G1, S, G2) by light or electron microscopy Mitosis (nuclear division) and cytokinesis (cell division) can be seen under a light and electron microscope

Answer 374

Increased growth occurs by: - shortening the cell cycle - conversion of quiescent cells (in G0) to proliferating cells (to G1) by making them enter the cell cycle

Answer 375

Indicates what grade of cancer it is

Answer 376

No. There are checkpoints in the cell cycle to check whether: • there is damage to the DNA • all of the DNA has been replicated. If there is damage to the DNA: • DNA repair mechanisms aim to fix the DNA • Apoptosis triggered if DNA cannot be repaired

Answer 377

* Restriction point at end of G1--> activates p53 protein for DNA repair/apoptosis * G1/S transition ---> checks for DNA damage before DNA replication * G2/S transition ---> checks for DNA damage after DNA replication

Answer 378

Restriction (R) point - checkpoint activation activates p53 protein which: • delays cell cycle • triggers ◦ DNA repair mechanisms OR ◦ apoptosis When? After G1 Why is it important? • Majority of cells that pass R point will complete the cell cycle • It is the most commonly altered checkpoint in cancer cells

Answer 379

* Cyclins (proteins) that bind to and activate... * Cyclin dependent kinases (CDKs) that phosphorylate... * Target proteins that are critical for progression of the cell to the next stage of the cell cycle (eg. Retinoblastoma susceptibility protein)

Answer 380

Inhibitors of CDK tightly regulate cyclin-CDK complexes and concentration or structure of these may change in cancer

Answer 381

- stimulate the production of cyclin | - decrease the production of CDK inhibitors

Answer 382

• As a cell divides, its' telomeres get shorter and shorter until coding DNA is lost • Therefore, the telomerase enzyme determines how many times a cell can divide as this adds telomeres and hence lengthens the chromosome. Hayflick limits demonstrate the maximum number of times a cell can divide. Humans have an average Hayflick number of 61.3.

Answer 383

Replacement of cell losses by identical cells in order to maintain the size of a tissue or organ.

Answer 384

No. It can be a normal process eg. The replacement of red and white blood cells by bone marrow But it can also occur after injury if the harmful agent is removed and if there is limited tissue damage. However, if the harmful agent persists, if there is extensive tissue damage or if the damage occurs to a permanent tissue, then regeneration and resolution is not possible and instead the tissue will heal with a scar.

Answer 385

- growth factors in the micro environment | - cell to cell communication

Answer 386

Stable or labile tissues

Answer 387

Poor Heal very slowly as they have few cells and few blood vessels. Therefore, secondary rupture at a site of previous injury is not uncommon.

Answer 388

Poor - avascular

Answer 389

There is no regeneration. New fat cells are formed by undifferentiated but committed cells that lie among the adipocytes

Answer 390

Very good | Exceptions: lens of eye and renal podocytes

Answer 391

Too little/too much Scars in pigmented skin are usually pale

Answer 392

None. | Lost neurones cannot be replaced- they cease to multiply before birth. Severed CNS axons do not grow back effectively

Answer 393

Regenerate in a predictable way

Answer 394

Hyperplasia - cells increase in number above normal Hypertrophy - cells increase in size Atrophy - cells become smaller and/or decrease in number Metaplasia - cells are replaced by cells of a different type

Answer 395

Yes | Atrophy is the least reversible

Answer 396

Increase in tissue or organ size due to increased cell numbers

Answer 397

Labile or stable tissues

Answer 398

- increased functional demand | - hormonal stimulation or growth factor stimulation

Answer 399

- hyperplasia remains under physiological control and is reversible unlike neoplasia - hyperplasia can occur secondary to a pathological cause but the proliferation itself is a normal response whereas in neoplasia the proliferation itself is abnormal

Answer 400

Repeated cell divisions exposes the cell to the risk of mutations and neoplasia

Answer 401

- proliferative endometrium under influence of oestrogen - bone marrow produces erythrocytes in response to hypoxia (erythropoietin production by the kidneys increases in response to hypoxia as it is detected by interstitial peritubular cells in the kidney)

Answer 402

- eczema - hyperplasia of epidermis - thyroid goitre in iodine deficiency. Reduced thyroxine levels lead to increased TSH. This leads to generalised thyroid enlargement as it has trophic effects on the thyroid gland that result in increased vascularity, increased size, increased number of follicle cells as well as stimulating all aspects of the synthesis and secretion of T3 and T4

Answer 403

Increase in tissue or organ size due to increased cell size. The cells contain more structural components so the workload is shared by a greater mass of cellular components.

Answer 404

Labile, stable but especially permanent tissues as they cannot replicate In labile and stable tissues, hypertrophy usually occurs along with hyperplasia.

Answer 405

(Like hyperplasia) • Increased functional demand • Hormonal stimulation when the stimulus for hypertrophy and hyperplasia disappears, the cells and organs become normal size once again.

Answer 406

Skeletal muscle Pregnant uterus (hypertrophy and hyperplasia)

Answer 407

Heart When the heart is under increased demand to pump blood due to increased preload (pulmonary or systemic hypertension) or afterload (valvular disease), the cardiac muscle hypertrophies as this is a permanent tissue. Normal heart weights 300g. Hypertrophied heart up to 1kg. Prostate gland If there is enlargement of the prostate gland (by hypertrophy and hyperplasia), then the smooth muscle of the bladder pushes against an increased resistance to pass out urine so there is hypertrophy and hyperplasia of the smooth muscle. Bowel If there is a stricture of the bowel, the piece of bowel proximal to the stricture hypertrophies to push material through this restricted area.

Answer 408

Athletes get hypertrophy of the heart but not to the extent of pathological hypertrophy. Athletes rest after exercise, so the heart is not constantly under increased demand but with pathology eg. systemic hypertension, the heart does not rest. Cardiac muscle hypertrophy is damaging because the heart cannot grow enough coronary arteries to supply all of the hypertrophied heart muscle. Therefore, some of the heart muscle dies and bands of fibrosis form between the cardiac muscle and bits of muscle are always hypoxic and there can be disruption of the electrical activity of the heart. Since the heart does not work strenuously for a long period of time, the hypertrophic effects are short term and rather than long term and constant as is the case with pathological hypertrophy of the heart.

Answer 409

When there is damage to one of the prime organs. When you have damage to one kidney, the other kidney enlarges. Usually hypertrophy and hyperplasia occurs.

Answer 410

Shrinkage of a tissue or organ due to an acquired decrease in size or number of cells. (If a cell atrophies- it gets smaller) (If an organ or tissue atrophies- cells get smaller and number of cells decrease)

Answer 411

* Shrinkage in the size of the cell to a size at which survival is still possible. * Reduced structural components of the cell disposed of in auto phagosomes * May eventually result in cell death

Answer 412

Atrophy is reversible up to a point but after years or months it is less so particularly when parenchyma cells are replaced by connective tissue

Answer 413

Ovarian atrophy in post menopausal women

Answer 414

• Reduced functional demand/workload = atrophy of disuse muscle atrophy after disuse, reversible with activity • Loss of innervation = denervation atrophy wasted hand muscles after median nerve damage • Inadequate blood supply (this happens when it is gradual, if sudden then there will be an infarct) thinning of skin on legs with peripheral vascular disease • Inadequate nutrition wasting of muscles with malnutrition, brain is last to atrophy

Answer 415

• Loss of endocrine stimuli occurs in the breast and reproductive organs with withdrawal of hormonal stimulation, wasting of the adrenal gland with loss of pituitary ACTH following hypophysectomy. • Persistent injury polymyositis (inflammation of muscle) • Ageing = senile atrophy Why? Cells can no longer divide due to Hayflick number+ DNA is damaged due to lots of cell division brain or heart • Pressure tissues around an enlarging benign tumour (secondary to ischaemia)

Answer 416

Biggest stimulus of bone production is pressure and movement so immobility will decrease bone matrix

Answer 417

Reversible change of one differentiated cell type to another.

Answer 418

Altered stem cell differentiation Represents adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment Involves expression of a new genetic programme

Answer 419

Metaplastic cells are fully differentiated and the process is reversible whereas in dysplasia and cancer the process is irreversible. Metaplastic epithelium is fully differentiated whereas dysplastic tissue is disorganised and abnormally differentiated.

Answer 420

Metaplasia is sometimes a prelude to dysplasia and cancer.

Answer 421

No. Epithelium changes to epithelium Mesenchyme changes to mesenchyme

Answer 422

Labile or stable cell types

Answer 423

Bronchial pseudostratified ciliated epithelium ---> Stratified squamous epithelium

Answer 424

Stratified squamous epithelium in the oesophagus changed to gastric glandular epithelium with persistent acid reflux. This can lead to oesophageal adenocarcinoma

Answer 425

When bone marrow is damaged, splenic tissue undergoes metaplasia to bone marrow

Answer 426

Metaplasia of fibroblasts to osteoblasts in muscle. This forms bone. Metaplastic bone can develop unto skeletal muscle following trauma when fibroblasts within the muscle tissue undergo metaplastic change to osteoblasts. This is often seen in young people and usually after a premature return to activity before proper healing has occurs.

Answer 427

* Epithelial metaplasia. * Often columnar epithelium (fragile) undergoes metaplasia to become squamous epithelium (resistant). * Epithelial metaplasia is common on surface linings because they are exposed to insults. * The metaplastic epithelium may lose functions that the original epithelium performed eg. Mucus secretion is lost when columnar epithelium becomes squamous epithelium, metaplastic

Answer 428

Complete failure of a specific tissue or organ to develop- it is an embryonic developmental disorder Eg. Thymic aplasia aplasia of kidney Also used to describe an organ whose cells have ceased to proliferate. Eg. Aplasia of bone marrow in aplastic anaemia

Answer 429

Underdevelopment or incomplete development of tissue or organ at embryonic stage Inadequate number of cells In a spectrum with aplasia

Answer 430

No - hypoplasia is a congenital condition whereas hyperplasia is not.

Answer 431

Hypoplasia is underdevelopment or incomplete development of a tissue or organ whereas atrophy occurs when existing parts waste away

Answer 432

Overlaps with atrophy. Normal programmed shrinkage of an organ.

Answer 433

- uterus after childbirth | - thymus in early life

Answer 434

Replacement of a lost part of the body - doesn't happen in humans, when a scar is formed it is hairless and stretched

Answer 435

No origins eg. Congenital imperforation of an opening Anus Angina Small bowel

Answer 436

Abnormal maturation of cells within a tissue. Potentially reversible. Often pre-cancerous.

Answer 437

An abnormal growth of cells that persists after the initial stimulus is removed.

Answer 438

An abnormal growth of cells that persists after the initial stimulus is removed and invades surrounding tissue with potential to spread to distant sites.

Answer 439

A tumour is any clinically detectable lump or swelling.

Answer 440

Cancer is any malignant neoplasm (an abnormal growth of cells that persists after the initial stimulus is removed and invades surrounding tissue with potential to spread to distant sites)

Answer 441

A malignant neoplasm that has spread from its original site to a new contiguous site (particular by blood vessels/lymphatics) The original site is the primary site and the place to which it has spread is a secondary site.

Answer 442

Dysplasia is a pre-neoplastic alteration in which cells show disordered tissue organisation. It is not neoplastic because the change is reversible. A neoplasm is an abnormal growth of cells that persists after the initial stimulus is removed. Neoplasia is irreversible.

Answer 443

Abcess | Haematoma

Answer 444

Benign neoplastic tumours are abnormal growths of cells that persist after the initial stimulus is removed. They are confined to their site of origin and do not produce metastases. Malignant neoplastic tumours are abnormal growths of cells that persist after the initial stimulus is removed and invades surrounding tissue with potential to metastasise to distant sites. It is the massive tumour burden that is dangerous to the host.

Answer 445

Benign tumours grow in a confined local area so have a pushing outer margin. This is why they are rarely dangerous. They often have a fibrous tissue around them- removal is clean. Malignant tumours have an irregular outer margin and shape and may show areas of necrosis and ulceration (if on a surface). It shows areas of necrosis because it is relatively ischaemic in places since the tumour cannot induce blood vessels in all places or is growing faster than angiogenesis can occur.

Answer 446

A benign tumour in specific places can have severe consequences due to pressure on surrounding tissues.

Answer 447

A benign neoplasm has cells that closely resemble the parent tissue - they are well differentiated. Malignant neoplasms range from well to poorly differentiated. Cells with no resemblance to any tissue are called anaplastic.

Answer 448

No. | Although benign tumours are well differentiated, malignant tumours range from well to poorly differentiated

Answer 449

Clinicians use the term grade to indicate differentiation. High grade is poorly differentiated. Grade is an important factor for prognosis in certain cancers.

Answer 450

Carcinoma in situ - malignant epithelial tissue above basement membrane Invasive carcinoma - malignant epithelial tissue beyond basement membrane

Answer 451

Accumulated mutations in somatic cells. The mutations are caused by initiators, which are mutagenic agents, and promoters which cause cell proliferation. In combination, initiators and promoters result in an expanded monoclonal population of mutant cells. Chemicals, infections and radiation are the main initiators but some of these agents can acts as promoters. In some neoplasms, mutations can be inherited rather than from an external mutagenic agent. A neoplasm emerges from this monoclonal population through a process called progression, characterised by the accumulation of yet more mutations.

Answer 452

It is thought external factors (mutagens) are more important External initiators include chemicals, infections, radiation. (Internal initiations are inherited mutated genes)

Answer 453

A collection of cells is monoclonal if they all originated from a single founding cell.

Answer 454

Proto-oncogenes become abnormally activated (when they are then called oncogenes) Tumour suppressor genes which normally suppress neoplasm formation become inactivated.

Answer 455

One allele

Answer 456

-carcinoma

Answer 457

Malignant neoplasm of blood-forming cells arising in the bone marrow.

Answer 458

Malignant neoplasms of lymphocytes mainly affecting lymph nodes.

Answer 459

Myeloma is a malignant neoplasm of plasma cells.

Answer 460

Arise from pluripotent cells mainly in the testes or ovaries.

Answer 461

Arise from cells distributed throughout the body

Answer 462

They occur mainly in children and are formed from immature precursor cells.

Answer 463

The ability of malignant cells to invade and spread to distant sites leads to a greatly increased tumour burden. Untreated, this results in vast numbers of 'parasitic' malignancies.

Answer 464

1. Malignant neoplasm grows and invades at the primary site. 2. It enters a transport system and lodges at a secondary site. 3. It grows at the secondary site to form a new tumour (colonisation). At all points the cells evade destruction by immune cells.

Answer 465

Metastasis is inefficient so requires many cells. Inefficiency tends to lie in: - travelling through a vessel- most cancer is carcinoma, epithelial cells are not designed to travel through blood vessels so are damaged by the flow of blood and vessel wall - growth at a secondary site - has to be enough cells there sufficient for growth

Answer 466

- altered adhesion - stromal proteolysis - motility Together, these three changes create a carcinoma cell phenotype that sometimes appears more like a mesenchymal cell than an epithelial cell, hence this is called epithelial to mesenchymal transition.

Answer 467

- reduction in E-cadherin expression. (E-cadherin is initially reduced so the cell can detach but is then increased so cells can join together in the blood vessel). Changes are dynamic. - altered adhesion between malignant cells and stromal proteins involves integrin expression.

Answer 468

The cells must degrade basement membrane and stroma to invade. This involves altered expression of proteases, notably matrix metalloproteinases (MMPs) Malignant cells take advantage of nearby non-neoplastic cells, which together form a cancer niche. These normal cells (fibroblasts and inflammatory cells) provide some growth factors ad proteases.

Answer 469

Changes in the actin cytoskeleton. Signalling through integrins is important occurs via small G protein members use as members of Rho family.

Answer 470

1. Blood vessels via capillaries and venules 2. Lymphatic 3. Fluid in body cavities (pleura, peritoneal, pericardial, brain ventricles) - transcoelomic spread

Answer 471

At a secondary site malignant cells must grow. This is called colonisation. Failed colonisation is considered to be the greatest barrier to successful formation of metastasis because many malignant cells lodge at secondary sites but these tiny cell clusters either die or fail to grow into clinically detectable tumours. Surviving microscopic deposits that fail to grow are called micrometastases. These are surviving micro deposits of malignant cells that have failed to colonise at secondary sites. This may be because of: - immune attack - reduced angiogenesis - hostile secondary site

Answer 472

An apparently disease-free person may harbour many micrometastases. These are surviving micro deposits of malignant cells that have failed to colonise at secondary sites. This may be because of: - immune attack - reduced angiogenesis - hostile secondary site

Answer 473

One or more micrometastases start to grow.

Answer 474

(1) Regional drainage of blood, lymph or coelomic fluid. For lymphatic metastasis this is very predictably to draining lymph nodes. For transcoelomic spread this is predictably to other areas in the coelomic space or to adjacent organs. For blood-borne metastasis this is sometimes (but not always) to the next capillary bed that the cells encounter. Therefore lungs are a very common place for blood-borne metastasis- this is the first capillary bed after entering from the venous system into the heart. From GI tract, the next capillary bed is the liver (2) The “seed and soil” phenomenon, which may explain the seemingly unpredictable distribution of blood-borne metastases, is due to interactions between malignant cells and the local tumour environment (i.e. the niche) at the secondary site

Answer 475

Carcinomas typically spread first to draining lymph nodes and then to blood-borne distant sites. Common sites of blood borne metastasis are lung, bone, liver and brain. The neoplasms that most frequently spread to bone are breast, bronchus, kidney, thyroid and prostate.

Answer 476

Via the blood stream

Answer 477

Some malignant neoplasms are more aggressive and metastasise very early in their course. Eg. Small cell bronchial carcinoma. Others almost never metastasise eg. Basal cell carcinoma of the skin. The likelihood of metastasis is related to the size of the primary neoplasm.

Answer 478

- direct invasion and destruction of normal tissue - ulceration at a surface leading to bleeding - compression of adjacent structures - blocking tubes and orifices

Answer 479

Increased tumour burden with secreted factors such as cytokines results in: - reduced appetite and weight loss (cachexia) - malaise - immunosuppression (can also be due to direct bone marrow destruction) - thrombosis Benign neoplasms of endocrine glands are well differentiated so typically produce hormones, e.g. a thyroid adenoma produces thyroxine. Malignant tumours sometimes also produce hormones; e.g. bronchial small cell carcinoma can produce ACTH or ADH while bronchial squamous cell carcinoma can produce a PTH-like hormone. Miscellaneous systemic effects include neuropathies affecting the brain and peripheral nerves, skin problems such as pruritis and abnormal pigmentation, fever, finger clubbing and myositis. Many other signs and symptoms can also occur and the pathogenesis is poorly understood

Answer 480

* Endothelial injury * Inflammation * Increased permeability to lipid from plasma

Answer 481

atherosclerosis is a chronic inflammatory response of the arterial wall initiated by injury to the endothelium. Lesion progression is sustained by interaction between modified lipoproteins, macrophages, T lymphocytes and cells of the arterial wall.

Answer 482

plaques are formed by repeated thrombi overlying thrombi. The lipid core is derived from the thrombi.

Answer 483

this hypothesis arose following the finding that some plaques are monoclonal or oligoclonal. This raised the question of whether plaques are benign neoplastic growths, perhaps induced by cholesterol or a virus. However as some areas of normal arteries are clonal this theory hasn’t gained widespread popularity.

Answer 484

- hyperlipidaemia - diabetes mellitus - hypertension - age - gender - familial predisposition - cigarette smoking - alcohol consumption - infection - lack of exercise - obesity

Answer 485

High plasma cholesterol - high LDL (most significant), HDL (protective - removed cholesterol from atheromatous plaques and delivers it to the liver for excretion in bile) Diabetes mellitus causes hypercholesterolaemia

Answer 486

Genetic variations in Apo E are associated with changes in LDL levels Polymorphisms of the genes involved lead to at least 6 Apo E phenotypes Polymorphisms can be used as risk markers for atherosclerosis

Answer 487

• Genetically determined abnormalities of lipoproteins • Leads to early development of atherosclerosis in teens/early 20's • Associated physical signs ◦ Arcus ◦ Tendon xanthomas ◦ Xanthelasma

Answer 488

Decreasing total and LDL cholesterol and increasing HDL. This is probably the most important strategy and can generally be achieved with diet and lipid-lowering drugs. Dietary measures include a low fat and high fibre diet. Food high in soluble fibre reduces circulating lipid, • Stopping smoking, • Controlling hypertension, • Controlling weight and regular exercise, • Sensible alcohol intake. A moderate intake (1-2 units/day) appears protective. Excess alcohol produces secondary hyperlipidaemia, • Treating diabetes mellitus, • Anti-oxidants, such as vitamin E, may be protective.

Answer 489

Fracture caused by trivial trauma due to a disease that has led to weakness of bone structure.

Answer 490

Weakness and wasting of the body due to severe chronic illness

Answer 491

Any malignant neoplasm (an abnormal growth of cells that persists after the initial stimulus is removed and invades surrounding tissue with the potential to spread to distant sites)

Answer 492

Growth of cells with no resemblance to any tissue.

Answer 493

Hyperchromasia - increasing nuclear staining More mitotic figures Pleomorphism - increasing variation in size and shape of cells and nuclei

Answer 494

Increasing variation in size and shape of cells and nuclei seen with worsening differentiation

Answer 495

Squamous papilloma

Answer 496

A benign connective tissue neoplasm of smooth muscle

Answer 497

Benign - lipoma Malignant - liposarcoma

Answer 498

Benign - glioma Malignant - malignant glioma

Answer 499

Benign teratoma of the ovary

Answer 500

Carcinoid tumours - various organs Phaeochromocytoma - adrenal Small cell carcinoma of bronchus

Answer 501

Immature precursor cells - mainly in children

Answer 502

Alterations are needed for carcinoma cells to invade a new site: Altered adhesion Altered proteolysis Altered motility These three changes create a carcinoma cell phenotype that sometimes appears more like a mesenchymal cell than an epithelial cell so this is called EMT.

Answer 503

Lung - first capillary bed after returning to RHS of heart Liver - first capillary bed from GI tract (hepatoportal system) Brain

Answer 504

``` Neoplasms that most frequently spread to bone: • Breast • Bronchus • Kidney • Thyroid • Prostate ```

Answer 505

Lytic regions - destroys bone (all cancers except prostate) Sclerotic regions - abnormal bone produced (prostate)

Answer 506

Pathological fractures - minor trauma leads to fracture

Answer 507

Primary tumour (which has migrated) growing at a secondary site to form a new tumour

Answer 508

Altered E-Cadherin expression

Answer 509

Changes in integrin expression

Answer 510

Signalling through integrins | Altered motility for invasion of a primary tumour to occur

Answer 511

Altered expression of proteinases for invasion of a primary tumour to occur

Answer 512

Malignant cells take advantage of nearby non-neoplastic cells to form a cancer niche. These provide growth factors and proteases (Inflammation provides these factors)

Answer 513

ACTH or ADH

Answer 514

PTH-like hormone

Answer 515

Excessive itching often seen with lymphomas

Answer 516

Age Sex (hormones) Heredity (genes)

Answer 517

Environment Lifestyle - BMI, low fruit + veg intake, lack of physical activity, tobacco use, alcohol use

Answer 518

Inherited mutation Chronic inflammation

Answer 519

Chemicals Viruses Radiation

Answer 520

True - the dependence on dosage is why industrial carcinogens and tobacco smoke are especially important causes of cancer.

Answer 521

True Eg. 2-napthylamine causes bladder carcinoma

Answer 522

Initiators - mutagens Promoters - cause sustained proliferation

Answer 523

Initiator + promoter

Answer 524

- polycyclic aromatic hydrocarbons - aromatic amines - nitrosamines - alkylating agents - natural products

Answer 525

Converted to carcinogens by the cytochrome P450 enzymes in the liver

Answer 526

Aromatic amine Bladder cancer

Answer 527

Radiation is any type of energy travelling through space. • Ultraviolet (UV) light - does not penetrate deeper than skin (MOST IMPORTANT - exposed daily to sunlight leading to increased skin cancer risk) • Ionising radiation - strips electrons from atoms (MAIN EXPOSURE - radon which seeps from earth's crust) ◦ X- rays ◦ Nuclear radiation from radioactive elements ‣ Alpha particles ‣ Beta particles ‣ Gamma rays

Answer 528

``` Acts as an initiator (mutagen) • Directly - Damages DNA ◦ Altered bases ◦ Single strand breaks ◦ Double strand breaks • Indirectly - Generates free radicals ```

Answer 529

Directly • Damages DNA bases • Single strand breaks • Double strand breaks

Answer 530

* Directly - affect genes that control cell growth * Indirectly - cause chronic tissue injury where the resulting regeneration acts either as a promoter for any pre-existing mutations or else causes new mutations from DNA replication errors.

Answer 531

``` • Expresses E6 and E7 proteins • These inhibit p53 and pRB protein function respectively ◦ p53 - activates apoptosis ◦ pRB - causes cell cycle to arrest • Increases risk of cervical carcinomas ```

Answer 532

• Cause chronic liver cell injury and regeneration ◦ Resulting tissue either acts as a: ‣ Promoter - for any pre-existing mutations ‣ Initiator - causes new mutations to form

Answer 533

``` • Causes gastric inflammation ◦ Resulting tissue either acts as a: ‣ Promoter ‣ Initiation • Increases risk of gastric carcinomas ```

Answer 534

• Causes inflammation in bile ducts and bladder mucosa ◦ Resulting tissue either acts as a: ‣ Promoter ‣ Initiator • Increases risk of cholangio- and bladder carcinomas

Answer 535

* Inhibit neoplastic growth | * Both alleles must be inactivated (two hits - one for each allele)

Answer 536

* Oncogenes enhance neoplastic growth * When abnormally activated, become proto-oncogenes * Only one allele of each proto-oncogene needs to be activated

Answer 537

Caretaker genes are a class of tumour suppressor genes * Repair DNA and maintain genetic stability * One or both alleles can be inactivated depending on the cancer syndrome

Answer 538

Oncogene Mutated in approximately 1/3 of all malignant neoplasms • Function: Encodes a small G protein that relays signals into the cell to push the cell past the restriction point Mutation in only one allele required • Mutated version: Mutant RAS encodes a protein that is active all the time, producing a constant signal to pass through the cell cycle's restriction point

Answer 539

Oncogene | Function: encodes transcription factors

Answer 540

Function: encodes growth factor receptors

Answer 541

Oncogene Apoptosis regulator

Answer 542

RAS C-myc HER-2 BCL2

Answer 543

• Function: Restricts cell proliferation by inhibiting passage through the restriction point Both alleles must be inactivated • Mutated version: Allows unrestrained passage through the restriction point

Answer 544

Carcinoma? Colon cancer Inheritance? Autosomal dominant Mutation? • First germ line mutation in caretaker gene - affects of of several DNA mismatch repair genes • Second somatic mutation in tumour suppressor gene/oncogene

Answer 545

Mutation? First germ line mutation in caretaker gene - affects BRCA1 or BRCA2 genes which are important for repairing double strand DNA breaks (these mutations do not have to be inherited- can be found in sporadic malignant neoplasms

Answer 546

Explains differences between tumours occurring in families and those occurring in the general population caused by mutations in the retinoblastoma gene (can occur in other tumour suppressor genes) • Familial cancers ◦ First hit - germline and affected all cells in the body ◦ Second hit - somatic mutation • Sporadic ◦ First hit - somatic mutation ◦ Second hit - somatic mutation

Answer 547

An example of an inherited cancer syndorome that has a germline mutation that causes malignant neoplasms indirectly by affecting DNA repair Carcinoma? Skin cancer at a very young age Inheritance pattern? • Autosomal recessive Mutation • First germ line mutation in caretaker gene - Germ line in one of 7 genes that affect DNA nucleotide excision repair • Second somatic mutation in tumour suppressor gene/oncogene - Patients are very sensitive to UV damage and develop skin cancer at a very young age

Answer 548

Initiation Promotion Progression including the adenoma-carcinoma sequence

Answer 549

* Most malignant tumours require alterations affecting a combination of multiple tumour suppressor genes and proto-oncogenes * Early adenomas, later adenomas, primary carcinomas and metastatic carcinomas have accumulating mutations over a time frame which is typically decades * This steady accumulation of multiple mutations is called cancer progression. The exact number of mutations needed for a fully evolved malignant neoplasm is unknown but thought to be approximately ten or less

Answer 550

- self-sufficient growth signals - resistance to anti-growth signals - grow indefinitely - induce new blood vessels - resistance to apoptosis - invade and produce metastases

Answer 551

HER2 gene amplification (breast cancer)

Answer 552

CDKN2A gene deletion (cyclin dependant kinase inhibitor) - melanoma

Answer 553

Telomeres gene activation (most cancers)

Answer 554

Activation of VEGF expression (many cancers)

Answer 555

BCL2 gene translocation (lymphoma)

Answer 556

E-Cadherin mutation (gastric cancer)

Answer 557

Result of a mutation in an oncogene, tumour suppressor gene or caretaker gene. Accelerated mutation rate found in malignant neoplasms

Answer 558

2-napthylamine (aromatic amine) used in dye industry | Causes bladder carcinoma

Answer 559

All cells have the germ line mutation

Answer 560

A mutation in a proto-oncogene in an embryo would result in the formation of an oncogene which causes neoplastic growth. If this was present in an embryo, embryogenesis would not proceed normally so the foetus would not be viable. A mutation in two tumour-suppressor genes are required for neoplastic growth. If there is a germ-line mutation in one tumour-suppressor gene, it is likely that embryogenesis can proceed as normal and the foetus is viable.

Answer 561

Cells can no longer divide because telomeres have shortened so coding DNA is now lost.

Answer 562

There is wastage of cells: - necrosis - not every cancer cell has equal ability to divide due to terminal differentiation

Answer 563

Recognition and destruction of a cell with a mutated oncogene

Answer 564

Squamous metaplasia

Answer 565

* Breast * Lung * Prostate * Bowel 65 (small proportion in people up to age 24)

Answer 566

* Leukaemias * Central nervous system tumours * Lymphomas

Answer 567

* Testicular cancer * Malignant melanoma * Breast cancer

Answer 568

* Pancreatic cancer * Lung cancer - biggest cause of cancer related deaths in UK * Oesophageal cancer

Answer 569

* Age * General health status * Tumour site * Tumour type * Grade (differentiation) * Tumour stage

Answer 570

Measure of the malignant neoplasms overall burden. It is a powerful predictor of survival.

Answer 571

Commonest, standardised method for assessing the extent of a tumour Is a powerful predictor of survival • T - refers to size of primary tumour ◦ T1/T2 = small primary, T2/T3 = large primary • N - extent of regional node metastasis ◦ N0 to N3 • M - extent of distant metastatic spread ◦ M0 or M1

Answer 572

T1 or T2 N0 M0 Early local disease

Answer 573

T3 or T4 N0 M0 Advanced local disease

Answer 574

Any T N1 or more M0 Regional metastasis via lymphatics

Answer 575

Any T Any N M1 Advanced disease with distant metastasis via bloodstream

Answer 576

Ann Arbor staging • Stage I - lymphoma in a single node region • Stage II - indicates two seperate regions on one side of the diaphragm • Stage III - spread to both sides of the diaphragm • Stage IV - diffuse or disseminated involvement of one or more extra lymphatic organs such as bone marrow or lungs

Answer 577

Dukes' staging • Dukes' A - invasion into but not through the bowel • Dukes' B - invasion through the bowel wall • Dukes' C - involvement of lymph nodes • Dukes' D - distant metastases

Answer 578

Tumour grade describes the degree of differentiation of a neoplasm.

Answer 579

Grade - describes the degree of differentiation of a neoplasm

Answer 580

* G1 - well-differentiated * G2 - moderately differentiated * G3 - poorly differentiated * G4 - undifferentiated or anaplastic

Answer 581

Bloom-Richardson system

Answer 582

* Tubule formation * Nuclear variation * Number of mitosis

Answer 583

* Soft tissue sarcoma * Primary brain tumours * Lymphomas * Breast cancer * Prostate cancer

Answer 584

X-rays or other types of ionising radiation are used to kill proliferating cells by triggering apoptosis or interfering with mitosis due to damage to DNA (particularly during G2) • Triggering apoptosis - high dosage causes either direct or free-radical induced DNA damage that is detected by the cell cycle check-point during G2, triggering apoptosis before M phase • Interference with mitosis - double stranded DNA breakages cause damaged chromosomes that prevent the M phase from completing correctly

Answer 585

* Radiotherapy is focused on the tumour with shielding of surrounding healthy tissue * Given in fractionated doses

Answer 586

• Antimetabolites mimic normal substrates involved in DNA replication eg. Fluorouracil • Alkylating and platinum-based drugs cross-link the two strands of the DNA helix eg. Cyclophosphamide and cisplatin (testicular cancer) • Antibiotics several methods eg. Doxorubicin - inhibits DNA topoisomerase needed for DNA synthesis Bleomycin - causes double-strand DNA breaks • Plant-derived drugs eg. vincristine - blocks microtubule assembly and interferes with mitotic spindle formation

Answer 587

It is relatively non-toxic (but only available for certain malignant tumours)

Answer 588

Selective oestrogen receptor modulators (SERMs) Eg. Tamoxifen They bind to oestrogen receptors, preventing oestrogen from binding.

Answer 589

Identifying cancer-specific alterations such as oncogene mutations allows drugs to be targeted specifically at cancer cells.

Answer 590

* A quarter of breast cancers have gross over-expression of the HER-2 gene * Herceptin can block HER-2 signalling

Answer 591

* Chronic myeloid leukaemia (CML) shows a chromosomal rearrangement (t9:22) creating an abnormal 'philadelphia' chromosome in which an oncogene gusion protein (BCR-ABL) is encoded * Imatinib inhibits the fusion protein.

Answer 592

Treatment given after surgical removal of a primary tumour to eliminate subclinical disease (used to treat cancers known to have micrometastases)

Answer 593

Treatment given to reduce the size of a primary tumour prior to surgical excision.

Answer 594

Various substances are released by cancer cells into the circulation. Although some have role in diagnosis, in general, they are most useful for monitoring tumour burden during treatment and follow up. They include: - hormones - oncofetal antigens - specific proteins - mucins and glycopeptides

Answer 595

Hormone Testicular tumours

Answer 596

Oncofetal antigen Hepatocellular carcinoma

Answer 597

Prostate carcinoma

Answer 598

Mucins/glycopeptides Ovarian cancer

Answer 599

Attempts to detect cancers as early as possible when the chance of cure is the highest by looking for early signs of disease in healthy people.

Answer 600

• Lead time bias ◦ Although 5-year survival seems to improve, it has not. Cancer has just been detected earlier. • Length time bias • Over diagnosis ◦ Screening picks up slow growing benign tumours that would not have turned malignant and would be asymptomatic so we think we have detected more cases but we haven't

Answer 601

Cervical Breast Colorectal

Answer 602

TNM system is for solid tumours | Leukaemia is a 'liquid tumour'

Answer 603

Blackened lungs