Jig's Cell Path

Lecture 1: Cancer 1) Define the words hyperplasia and hypertrophy; give 2 examples of each.

• Hyperplasia – an increase in the size of tissue or organ resulting from an increase in NUMBER of the cells e.g. pregnant uterus; fibrocystic change in breast.

• Hypertrophy – an increase in the size of tissue of organ because of increased SIZE of individual cells (not increase in number) e.g. uterine smooth muscles in pregnancy; cardiac valve problems – atrial muscle against mitral valve stenosis.

2) Explain the difference between metaplasia and dysplasia giving two examples of each.

• Metaplasia – a reversible change in differentiation from ONE FULLY DIFFERENTIATED type to ANTOTHER – usually an adaptive change in reaction to longstanding (chronic) irritation of any kind, or in response to some hormonal stimuli e.g. respiratory to squamous (in smokers), from gastric body to intestinal (occurs in atrophic gastritis – premalignant).

• Dysplasia – an abnormal growth in which some of the histological features of malignancy are present, but at a non- or preinvasive stage (i.e. premalignant). Characterised by: • larger nucleus in relation to cytoplasm • abnormal and increased mitotic figures • abnormal or dys- maturation • e.g. cervical screening for carcinoma of the cervix; fibrous dysplasia – trabecular bone is replaced by fibrous tissue, resulting in aching and a tendency to pathological fracture.

3) Define the words tumour, metastasis, carcinogen.

• Tumour – an abnormal, autonomous proliferation of cells which are unresponsive to normal control mechanisms governing their growth, and which persists even when whatever stimulus started them going has stopped.

• Metastasis – the distant spread of malignant tumour from its site of origin. This occurs by three main routes: 1. through the bloodstream 2. through the lymphatic system 3. across body cavities e.g. through the peritoneum.

• Carcinogen – any substance that, when exposed to living tissue, may cause the production of cancer. They cause damage to the DNA of cells that may persist if the cell divides before the damage is repaired. Damaged cells may subsequently develop into a cancer.

4) List four features which distinguish benign from malignant tumours.

Benign tumours Malignant tumours Slowly growing Fast growing Expansile Invade and infiltrate Capsule No capsule Mitoses normal and few Abnormal/frequent mitoses 5) Define the terms necrosis, ulcer, degenerative, sublethal injury.

• Necrosis – the death of some or all of the cells in an organ or tissue, caused by disease, physical of chemical injury, or interference with blood supply.

• Ulcer – a break in the skin extending to all its layers, or a break in the mucous membrane lining the alimentary tract, that fails to heal and is often accompanied by inflammation.

• Degeneration – the deterioration and loss of specialised function of the cells of a tissue or organ. The changes may be caused by a defective blood supply or by disease. Degeneration may involve the deposition of calcium salts, fat, or fibrous tissue in the affected organ or tissue.

• Sublethal injury – an injury that isn’t lethal.

6) Give two examples each of diseases caused by infection and one example of a disease caused by a chemical agent.

• Infection • syphilis, rubella • Chemical • tobacco contains chemicals which are carcinogenic and tumour promoting.

• NO2 and SO2 are industrial pollutants which cause asthma

Lecture 2: Haemodynamic disorders 1) Describe the causes and consequences of oedema at different sites • Oedema – an abnormal collection of fluid within the interstitial space.

• Causes: increased blood vessel permeability • increased hydrostatic pressure • reduced plasma oncotic pressure • obstruction of lymph drainage • retention of sodium • Subcutaneous – post-radiotherapy, filariasis o Complications – cellulitis, venous eczema, venous ulcer, lipodermatosclerosis (hardening of fatty tissue due to prolonged high venous pressure) • In lungs it can be life threatening if acute and not treated • In the brain it is serious and life threatening, not much spare space intracranially. o Brain stem infarction 2) Explain the term thrombosis and give the cause and potential consequencs of such an event.

• Thrombosis – a condition in which the blood changes from a liquid to a solid state and produces a blood clot (thrombus).

Inappropriate activation of the haemostatic process.

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Thrombosis may occur within a blood vessel when: o endothelial injury – atheromatous plaque, MI, cigarette smoke, vasculitis (inflammation), hypercholesterolaemia o turbulent blood flow or stasis o hypercoagulability – genetic or aquried (smoking, pregnancy, malignancy, oral contraceptive pill (OCP) Thrombosis in an artery obstructs the blood flow to the tissue it supplies: • Obstruction of an artery to the brain is one of the causes of a stroke • Thrombosis in an artery supplying the heart – coronary thrombosis – results in a heart attack.

• Thrombosis can also occur in a vein (deep vein thrombosis) and it may be associated with inflammation.

3) Define embolus and know about the importance of pulmonary embolism in clinical practice.

• Embolus – an abnormal substance (which can be solid, liquid or gas) travelling within the lumen of a blood vessel, and capable of blocking it (causing onward blood flow to stop) – ischaemia/infarction • Spleen – embolus will cause a wedge shaped white infarct. (Spleen has one artery in and one vein out.)

• Kidney – single renal artery. Wedge shaped white infarct.

• Pulmonary embolism - 60% - cor pulmonale or sudden death 4) Describe possible causes of haemorrhage and potential outcomes.

• Extravasation of blood due to vessel rupture o Capillary bleeding – chronic congestion (abnormal accumulation) o Venous/arterial – vascular injury • External vs. enclosed in the tissue • Petechiae – platlet/clotting defects • Subcutaneous haematoma (accumulation of blood that clots) • Aortic aneurysm • Outcome o None o Chronic anaemia o Hypovolaemic shock o Pressure 5) Define shock and identify the possible causes and mechanisms • Cardiovascular collapse -> hypotension, impaired tissue perfusion, cellular hypoxia • Causes - Severe haemorrhage, massive trauma, burns, myocardial infarction, massive pulmonary embolism, sepsis • Types – o Cardiogenic: pump failure, myocardial damage, tamponade, pulmonary embolism o Hypovolaemic: loss of blood/plasma o Septic: systemic microbial infection o Anaphylactic: hypersensitivity o Neurogenic: spinal trauma • Non-progressive - Reflex compensation: tachycardia, peripheral vasoconstriction, renal fluid retention o Hypotensive, cool, clammy, tachycardic, (septic: warm, flushed)

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Progressive Tissue hypoperfusion, circulatory/metabolic imbalance, acidosis, cerebral disturbance, low urine output Consequences – o Brain: ischaemic encephalopathy o Heart: subendocardial ischaemia/necrosis o Kidneys: acute tubular necrosis o GI tract: haemorrhagic enteropathy o Lungs: ARDS Irreversible – severe tissue/ cellular injury, survival not possible Define the term infarct and define possible causes.

Infarct – a small localised area of dead tissue produced as a result of an inadequate blood supply – occlusion of venous/arterial routes 99% - thrombotic or embolic White – end atery occlusion, solid tissue with limited haemorrhage Red – venous occlusion, loose tissues, dual circulation

Lecture 3: Inflammation 1) List 4 causes of acute and 3 of chronic inflammation.

• Inflammation – the directed response of living, vascularised tissue to a sublethal injury.

Acute inflammation Chronic inflammation Mechanical trauma Chronic viral infections Chemical injury Chronic autoimmune diseases Bugs Chronic chemical intoxication UV or X-ray irradiation Chronic nonviral infections Ischaemia 2) State three possible outcomes of acute inflammation due to a pyogenic microorganism.

• Spreads – fibrin, phagocytosis can’t contain infection and spreads through tissue planes or via blood stream.

• Resolves – where not much structural damage has been done and if that tissue’s cells can regenerate.

• Repairs – where damage done, and cells can’t regenerate, so repair by scarring.

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• Goes chronic – with different inflammatory cells and fibrosis usually.

3) Describe briefly how the microscopic features of acute inflammation differ from those of chronic inflammation.

• The character of the cellular exudate changes, with lymphocytes, plasma cells and macrophages replacing the neutrophil polymorphs.

4) Define the terms: ‘resolution’; ‘suppuration’; ‘organisation’.

• Resolution – the complete restoration of the tissues to normal after an episode of acute inflammation.

• Suppuration – the formation of pus, a mixture of living, dying and dead neutrophils and bacteria, cellular debris and sometimes globules of liquid.

• Organisation – the replacement of tissues by granulation tissue as part of the process of repair.

5) Describe the microscopic features of granulomatous inflammation and give 2 examples.

• Where damage is done, and cells can’t regenerated, area has to be repaired by scarring. Pre-existing capillaries in undamaged area grow new buds into damaged area. This is infiltrated by macrophages, fibroblasts, myofibroblasts. This stuff is called granulation tissue. Fibroblasts/myofibroblasts lay down collagen. This remodels to form a fibrous scar. This all depends on local growth factors from fibroblasts like TNF-α and IL-1.

• Myocardium which has died can be scavenged and replaced by granulation tissue.

• If the defect is larger, repair by granulation tissue and scarring occurs e.g. dermis does not regenerate, haematoma has to be neovascularised and a scar forms, although the epidermis grows over 6) Name two local, and two general causes for a failure of healing or repair.

• Local causes: • implanted foreign bodies • local infection • excessive movement of area if bone/joint • General causes: • nutrition – lack of protein (poor collagen tensile strength) • diabetes • old age

Lecture 4: Cell Injury 1) • • • • • • • • 2) • • •

List the causes of cell injury.

Oxygen deprivation Chemical agents Infectious agents Immunological reactions Genetic defects Nutritional imbalances Physical agents Aging List the mechanisms of cell injury.

The cellular response to injurious stimuli depends on the type of injury, its duration and its severity The consequences of an injurious stimulus depend on the type of cell, its status, its adaptability and its genetic makeup Four intracellular systems are particularly vulnerable cell membrane integrity, ATP generation, protein synthesis and the integrity of the genetic apparatus • Cellular function is lost before cell death occurs which in turn occurs before the morphological changes are seen 3) Define (and give examples of) hyperplasia, hypertrophy, atrophy, metaplasia and dysplasia.

• Atrophy – Shrinkage in the cell (or organ) by the loss of cell substance o Pernicious anaemia (Vitamin B12 deficiency), dementia • Hypertrophy - Increase in the size of cells and consequently an increase in the size of the organ - can be physiological or pathological. It is caused either by increased functional demand or specific hormonal stimulation o Athlete training, ventricular hypertrophy • Hyperplasia - An increase in the number of cells in an organ - Can be physiological or pathological. Physiological hyperplasia can be either hormonal or compensatory. Pathological hyperplasia is usually due to excessive hormonal or growth factor stimulation o Proliferative endometrium, benign tumour • Metaplasia – A reversible change in which one adult cell is replaced by another o Barrett’s (columnar lined) Oesophagus - columnar cells replace squamous cells of the lower oesophagus • Dysplasia – abnormal in form. Precancerous cells which show the genetic and cytological features or malignancy but not invading the underlying tissue o Dysplasia associated with Barrett’s Oesophagus 4) Describe the morphological changes associated with reversible and irreversible injry Reversible • Fatty change • Cellular swelling Irreversible Injury • Nuclear o Karyolysis - fragmented o Pyknosis – Shrunken, smaller and denser o Karyorrhexis – Breaking up and dissolving away • Light Microscopic o Coagulative necrosis – dead but outline still visible - MI – no nucleus

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o Liquefactive necrosis – liquefied – cerebral infact o Caseous necrosis – Pulmonary TB - granular, cheese like appearance o Fat Necrosis – Acute pancreatitis – lipase released, digest own fat – Ca2+ deposits on fat Describe the differences between apoptosis and necrosis •

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Apoptosis may be caused by o Embryogenesis o Deletion of auto-reactive T cells in the thymus o Hormone-dependent physiological involution o Cell deletion in proliferating populations o A variety of mild injurious stimuli that cause irreparable DNA damage that triggers cell suicide pathways Differences: Apoptosis may be physiological Apoptosis is an active energy dependent process Not associated with inflammation

Lecture 5: Autopsy and Forensic Medicine 1) Explain how the need for consent from the deceased’s relatives differs for coroners’ and hospital autopsy.

Hospital • Consent must be obtained from next of kin • With consent, any material can be taken Coroner • No consent from next of kin needed (but their wishes should be considered) • Material can only be taken if it bears upon the cause of death (with coroners permission) 2) List four types of death that must be reported the coroner • Sudden unexpected death • Industrial accidents • Domestic accidents • Drug abuse, poisoning • Deaths during/soon after operations (24 hrs, or up to 1 yr if never wake up) • Where relatives not happy with treatment • Industrial diseases • Infant deaths • Vehicular accidents • Deaths following abortions • Where GP not sure about the cause of death or has not seen patient for 2/52 • Suicides • Deaths in prison or mental custody • Murder • People receiving industrial or war pensions Basically any reason where there are even slight suspious grounds 3) List two reasons for conducting hospital (non-Coroner’s) autopsies.

• Allows a very thorough examination of the deceased, the extent of their disease, their treatment and its effects • Audit – Major discrepancies between stated cause of death and actual cause of death • Monitoring effectiveness of new treatment • Teaching • Research e.g. knowledge of variant CJD relies heavily on study of post mortem brain tissue 4) List four natural unexpected causes of sudden death.

• 1. Coronary ischaemia • 2. Aortic valve disease (stenosis) may often have a bicuspid valve, lowers perfusion pressure in aorta, sudden death.

• 3. Ruptured aneurysm • 4. Cerebral haemorrhage 5) What is a bruise? Give an example of a mechanism of injury that would lead to a bruise.

• A blunt trauma injury - occurs alone (skin intact) or is associated with other injuries • An extraversated collection of blood which has leaked from damaged small arteries, venules and veins but not capillaries • Occur more easily where skin is lax • Fragility of vessels, coagulation state etc all effect bruising 6) What is an abrasion? Give an example of a mechanism of injury that would lead to an abrasion.

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• A graze or scratch - the most superficial of blunt trauma injuries • Confined to the epidermis (strict definition) but may actually extend into the superficial dermis due to skin anatomy) • Due tangential force – may have a distal skin tag Eg Friction burn • Or vertical force Eg Stamp – no distal skin tag • Friction burn, car radiator, flooring, whip, stamp 7) What is a laceration? Give an example of a mechanism of injury that would lead to a laceration.

• A split to the skin • The result of blunt force overstretching the skin • Usually pass through the full thickness of the skin • They are deep and will bleed • Margins ragged with crushing and bruising and “Bridging fibres” arch across the skin defect • Common where skin can be compressed between the force and underlying bone 8) What is the difference between a cut and a stab? Other than a knife, what may cause such a wound?

• Cut - the length of the injury is longer than its depth • Stab (or penetrating injury) - the depth of the wound is greater than the width • Causes by an object with a sharp or cutting edge • Usually a knife but can be anything eg a broken glass or bottle or a piece of metal • Edges are clean and well demarcated - minimal injury to surrounding tissue 9) What is the best generic term to use when describing physical damage to a patient?

• Injury or wound

Lecture 6: Clinical Case Study 1)

Using the example of Helicobacter pylori infection of the stomach, discuss the varied outcomes of the infection and why these occur, and how inflammation can lead to cancer of lymphoma in this organ.

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Helicobacter associated gastritis chronic inflammation o lymphocytes acute inflammation o neutrophils D cells of the antrum produce somatostatin Somatostatin - inhibits gastrin – in antral gastritis D cells reduced The principal cause of duodenitis and duodenal ulcer is acid

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With age, infection spreads – pangastritis (coexisting antral gland gastritis and fundic gland gastritis), atrophy of body mucosa, acid decreases, gastric ulcers Intestinal Metaplasia o Intestinal Metaplasia in gastric mucosa is a response to long term damage o bile, H. pylori o Cancer risk Gastric dysplasia o an abnormal pattern of growth in which some of the histological features of malignancy are present o pre-invasive stage o Intact BM List 2 major complication of peptic ulcers and describe the consequences of these Complications – perforation, haemorrhage Using the example of a case of atherosclerosis, list 3 major outcomes of this arterial disease.

Occludes arteries slowly (angina, myocardial scarring, dementia, claudication,) Occludes arteries suddenly plaque rupture (thrombosis, atheroembolization) or haemorrhages into plaques (MI, stroke, gangrene of the bowel) Weakens artery walls (aneurysms)

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