Pathology+101 Complete) | Heart Failure | Atherosclerosis



v1.0 For the last 2 weeks we have endured long days and sleepless nights to bring you these notes. Apologies to future dermatologist and orthopaedic surgeons, we didn’t get to starting musculo or skin, look out for them in the second edition (may or may not be released next year, probably not). The main inspiration to keep us going to get these done was that Raj really needed them. v2.0 So its 3wks in now and I’ve got an update, guess next year came quicker than expected. I know the exam is soon but it might help. All the systems are there now and thanks to Tash we now have skin notes. Thanks to Ben for his help with notes on demyelination. The main inspiration to get this done was that Raj said he’d do dentistry if he didn’t get into orthopaedics.

Tareq and Faran Publications, 2008


Heart failure occurs when the heart is unable to pump blood at a rate that meets the metabolic requirements of the peripheral tissue. Compensatory Mechanisms: are triggered during reduced myocardial contractility or increased haemodynamic burden. Pressure vs Volume Overload  Activation of neurohormonal systems: Pressure overload state (eg. hypertension, valve noradrenaline, renin-angiotensin system, ANP. stenosis) causes increased SBP. Results in increased  Frank-starling mechanism: Cardiac failure causes diameter of cardiac muscle (added myofibrils). ↑EDP resulting in increased stretch of cardiac → CONCENTRIC HYPERTROPHY: wall thickening with muscle → fibres contract more forcibly, hence no change in chamber size. ↑CO. Volume overload state (eg. valve regurge, abnormal  Myocardial structural changes (hypertrophy). shunts) causes increased DBP. Results in increased This is an adaptation to chronic ↑ workload and length of muscle fibres (added sarcomeres). since myocytes can’t proliferate, concentric or → ECCENTRIC HYPERTROPHY: chamber enlargement eccentric hypertrophy occurs. with some wall thickening. Adaptive mechanisms eventually aren’t sufficient with sustained worsening of heart → pathologic changes (eg. myocyte apoptosis, cytoskeletal changes, altered ECM synthesis) cause structural and functional disturbances. Classification: resulting failure can be classified by a variety of mechanisms:  Forward failure: diminished cardiac output, reduced tissue perfusion. vs Backward (congestive) failure: back pressure, venous congestion and oedema.     Systolic failure: inability to contract normally and expel blood. vs Diastolic failure: inability to fill ventricles. High output failure: heart is pumping normally, however tissue demands have greatly increased. vs Low output failure: heart cannot keep pace with basic peripheral demands. Acute heart failure: quick onset, usually systolic heart failure and hypotension but no oedema. vs Chronic heart failure: long term, often normal BP but with oedema. Compensated heart failure: if compensatory mechanism produce sufficient CO vs Decompensated heart failure: compensatory mechanisms, especially hypertrophy, increase O2 requirements, eventually leading to insufficient CO and increasing risk of ischaemic injury. Left-Sided Heart Failure
More clinically significant, can be due to IHD, HHD, VHD, CMP (ie. main heart diseases). Can be further classified according to mechanisms above. Symptoms are primarily due to pulmonary congestion, oedema and ventricular dilation:  Dyspnoea, orthopnea  Cough (transudate in airway)  Tachycardia, cardiomegaly, 3rd heart sound

Right-Sided Heart Failure
Usually a consequence of left sided heart failure causing increased pulmonary pressure. Isolated right heart failure is rare but can be due to:  Lung disease with chronic pulmonary hypertension → enlargement of right ventricle (cor pulmonale).  Congenital heart diseases with right to left shunts. Symptoms are mostly due to backward failure (congestion) causing engorgement of systemic and portal venous systems:  Hepatic and splenic enlargement  Peripheral oedema, pleural effusion, ascites

 Fine crepitant rales at lung bases (oedema in alveoli)  Mitral regurgitation (papillary muscle damage)  Atrial fibrillation (irregularly irregular heart beat)

Group of related myocardial ischaemic syndromes caused mostly by coronary artery atherosclerosis. Unstable angina, infarction and sudden cardiac death usually occur when:  Rupture, fissuring, ulceration of plaques exposes thrombogenic constituents or underlying endothelial basement membrane.  Haemorrhage into the core of plaque expands volume, causing vascular occlusion. NB: a minority are due to vasopasm, vasculitis or embolism.

Angina Pectoris
Chest pain due to inadequate perfusion (reversible myocardial ischaemia). Felt as crushing/squeezing substernal chest pain, can radiate to left and jaw.  Stable angina: is predictable, occurring during exacerbation or increase O2 demand. >75% due to fixed atherosclerotic narrowing.  Unstable angina: is erratic, occurring at rest or with low exertion, getting progressively worse (pre-infarct state). Caused by plaque disruption, thrombosis or vasospasms.  Variant (Prinzmetal) angina: occurs at rest due to vasospasm. Artery may be normal. Slow development of atherosclerotic plaque build up allows time for compensation from collateral circulation. Clinically significant plaques are predominantly in the first few cms of left anterior descending, left circumflex or entire length of right coronary artery.

Acute Myocardial Infarction
Necrosis of heart muscle resulting from ischaemia, usually caused by plaque disruption and thrombosis. The left ventricle is always involved:  Transmural infarct when >50% necrosis of myocardial wall thickness in area supplied by a single coronary artery.  Subendocardial infarct circumferential necrosis around chamber involving inner ½ of myocardium, may involve area of multiple arteries.

Transmural Infarct (old and new)

Subendocardial Infarct

Morphology: early changes after vascular obstruction are reversible (angina). Irreversible changes after 20-40min of severe ischaemia → myocyte death (coagulative necrosis).  <12hrs, AMI is not grossly apparent, however Infarcts >3hrs can be seen with vital stains for lactate dehydrogenase which leaks into blood during myocyte damage. Infarct seen as pale zone.  12-24hrs, infarct is grossly identified by a reddish brown discolouration (stagnant, trapped blood). Becomes yellow and soft thereafter.  10-14days, infarcts rimmed with highly vascularised granulation tissue.  Weeks, fibrous scar tissue formation (from border to centre).

Extent of MI: infarction begins in subendocardial zone then spreads outwards to include transmural thickness of chamber. Extent of infarct depends on:  Size, site and degree of obstruction  Rapidity of onset and extent of collateral circulation that was allowed to develop.  Duration of occlusion, reaches full size within 3-6hrs, hence intervention can limit damage.  Associated arterial spasm. Clinical: severe crushing substernal chest pain, can radiate to neck, jaw, epigastrium, left arm. Can be asymptomatic (10-15%), usually due to diabetic neuropathies or in the elderly. Dyspnoea and features of left sided heart failure are also common.  ECG can show pattern of injury. o Changes in Q waves indicate transmural infarcts. o ST segment abnormalities, T wave inversion indicate myocardial repolarisation problem. o Arrhythmias can be detected, indicates conduction pathway damage.  Laboratory tests are important in confirming diagnosis and are based on measuring intracellular macromolecules which leak out of damaged cells. o Myoglobin, troponin T and I, creatine kinase (CK), lactate dehydrogenase (LDH) etc. o Troponins and CK-MB have high specificity and sensitivity for myocardial damage. Treatment: goal is to salvage maximal amount of ischaemic myocardium by reperfusing tissue quickly.  Can use thrombolysis (drugs), balloon angioplasty, coronary artery bypass graft.  Reperfusion injury can occur, mediated by oxygen free radicals from increased leukocyte numbers. Can cause endothelial swelling or haemorrhage. Complications: risk depends on infarct size, site and thickness of damaged heart wall. Sudden death (15%), no complications (10-15%), complications (65-70%).  Contractile dysfunction: severe pump failure (cardiogenic shock) proportional to infarct size.  Arrhythmias: responsible for many sudden deaths due to conduction problems.  Myocardial rupture: due to CT lysis, can occur in ventricular wall (haemopericardium and tamponade), IV septum (shunt formation) or papillary muscle (mitral valve regurgitation).  Pericarditis: fibrous or haemorrhagic. Typically spontaneously resolves.  Mural thrombus ± systemic thromboembolism, pulmonary embolism  Ventricular aneurysm  Progressive late LV congestive heart failure.

Chronic Ischaemic Heart Disease
Progressive heart failure due to ischaemic injury, also known as ischaemic cardiomyopathy.  Usually results from post infarction cardiac decompensation, after exhaustion of hypertrophy.  May be due to diffuse atherosclerotic narrowing of coronary arteries (>¾ obstruction).  Results in severe progressive heart failure, sometimes with episodes of angina or MI.

Sudden Cardiac Death
Unexpected death from cardiac causes either without symptoms or within 1hr of symptom onset.  Coronary artery disease most common cause via lethal arrhythmia, esp. ventricular fibrillation.  Non atherosclerotic causes are more common in younger people eg. congenital abnormalities.  Increased cardiac mass is a risk factor.

Systemic Hypertensive Heart Disease
Systemic hypertensive heart disease is characterised by (basis of diagnosis):  Left ventricular hypertrophy (concentric) without other CVS pathology (eg. valve stenosis).  A history or pathologic evidence of hypertension.  LV thickness >2cm, weigh 4-800gm (2-3x normal).

LV Concentric Hypertrophy

Pathophysiology: Hypertension results in pressure overload on LV, which adapts by depositing myofibrils parallel to the long axes of cells. This results in concentric hypertrophy.  Wall thickening without change in chamber size, hence cavity diameter reduced size.  Hyperplasia cannot occur as myocytes are terminally differentiated. Hypertrophy initially compensatory but if prolonged/excessive eventuates into myocyte contractile failure. This is due to:  ↑ O2 demand due to increased cell size, ↓ blood supply as capillaries don’t grow (ischaemia).  Change in gene expression leading to less functional protein and hence ↓ contractility. Clinical Manifestations: depend on severity, duration and underlying cause of hypertension.  Ischaemia causes fibrous deposition which limits diastolic relaxation, leading to LA enlargement.  Contractile failure leads to CHF, with lung congestion and subsequent wide spread oedema.  Atrial fibrillation is common due to LA enlargement or backward CHF.  Many patients will be asymptomatic (compensated HHD), others will suffer as mentioned above.

Pulmonary Hypertensive Heart Disease (Cor Pulmonale)
Right ventricular enlargement due to pulmonary hypertension (>30mmHg) which has been caused by primary disorders of lung parenchyma or vasculature. Pathology/Classification: cor pulmonale may be acute or chronic.  Acute: commonly after massive pulmonary embolism (>50% occlusion), causing acute right ventricular dilatation.  Chronic: secondary to prolonged pressure overload causing lung vasculature compression. Results in right ventricular hypertrophy. Eventual hepatosplenomegaly, oedema and LV failure. Note: definition excludes congenital heart disease or left ventricular failure that cause right heart enlargement via pulmonary hypertension.

RV Hypertrophy

Risk Factors: disorders predisposing to cor pulmonale include:  Diseases of pulmonary parenchyma (eg. COPD, interstitial fibrosis, cystic fibrosis)  Disease of pulmonary vessels (eg. PE, primary pulmonary HT, arteritis, vascular obstruction or drug/toxin/radiation induced).  Disorders affecting chest movement (eg. kyphoscoliosis, obesity, neuromuscular disease).  Disorders inducing pulmonary artery constriction (eg. metabolic acidosis, hypoxaemia, chronic altitude sickness, obstruction to major airways).

Valvular Stenosis and Incompetence
Valvular disease results in stenosis or insufficiency. These processes can occur in pure form, coexist in same valve or affect multiple valves. Valve abnormalities are either congenital or acquired. Stenosis Failure of valve to open completely, obstructing forward flow. Creates a high pressure gradient across valve causing turbulent flow. Mitral Stenosis -Cause: post inflammatory scarring (RHD). Incompetence (Insufficiency/Regurgitation) Failure of valve to close completely, allowing reverse flow. Creates backward volume overload. Mitral Regurgitation -Causes: o Myxoid degeneration (floppy leaflet that -Clinical: LA pressure increase → pulmonary prolapses into LA due to abnormal ECM). congestion and hypertension → RV o RHD, infective endocarditis. hypertrophy. o Dilatation of valve ring (LV enlargement or -Murmur: diastolic, rumbling with opening calcification of annulus). snap. o Papillary muscle fibrosis or rupture. -Clinical: variable effects o Little effect with prolapse, incompetence usually only if chordae tendinae rupture. o LV hypertrophy if onset is slow. o Acute LV failure if papillary muscle ruptures. -Murmur: systolic, click with prolapse Aortic Valve Disease Aortic Stenosis Aortic Regurgitation -Causes: RHD, degenerative calcification (eg. -Causes: leaflet abnormalities (eg. RHD, IE), aortic old age, congenitally deformed valve) diseases (eg. degenerative aortic dilation, syphilitic aortitis, ankylosing spondylitis, rheumatoid -Clinical: small pulse, LV hypertrophy, angina, arthritis, Marfan syndrome). syncope, LV failure or sudden death. -Clinical: wide pulse pressure, collapsing pulse, LV -Murmur: systolic, ejection murmur hypertrophy, angina, LV failure -Murmur: diastolic, opening snap, 3rd heart sound

Mitral Valve Disease

NB: stenosis of mitral and aortic valves accounting for 2/3 of all valve diseases.

Damage to right side valves (tricuspid and pulmonary) is rarer due to lower pressure.  Rarely isolated, often asymptomatic or symptoms dominated by left valve problems.  Can be caused by portal/pulmonary hypertension, oedema or fatigue.

Rheumatic Heart Disease (RHD)
Cardiac manifestation of rheumatic fever, an acute multisystem autoimmune inflammatory disease.  Pathology: results from formation of anti-streptococcal antibodies that cross react with cardiac tissue. Disease occurs few weeks after S. pyogenes pharyngitis (group A β-haemolytic strep).  Clinical: scarring of valves most commonly causes mitral stenosis/regurgitation with associated cardiac symptoms. Also affects joints, skin, kidneys and CNS. Acute RHD is associated with inflammation of valves, myocardium and pericardium due to cross reacted auto-antibodies.  Endocarditis (valves): focal fibrinoid necrosis and fibrin thrombi along lines of closure.  Myocarditis: Aschoff body formation. May have LV dilatation or failure due to mitral stenosis/incompetence. Aschoff Bodies
Inflammatory lesions in heart consisting of fibrinoid change, lymphocytes, plasma cells and macrophages. Diagnostic. Can be found in any layer of heart, or in all layers (pancarditis).

Pericarditis: fibrinous/serofibrinous exudates, resolves spontaneously.

Chronic RHD results in organisation of acute inflammation and scarring.  Leaflet/cusp thickening, fibrosis, commissural fusion,  Shortening and thickening of chordae tendinae → fish mouth, button hole deformity.

Infective Endocarditis
Infection of valves and endocardium with formation of vegetations. Usually affects abnormal valves (eg. previously damaged, congenitally malformed or artificial valves). Other risk factors include neutropaenia, immunosuppression, IVDU and dental work/surgery. Pathology/Classification: either acute or subacute based on clinical pace and severity.  Acute endocarditis: caused by highly virulent organisms (eg. Staph aureus) which may affect normal or abnormal hearts. o Causes large vegetations, valvular destruction and myocardial abscesses. o Mortality >50% even with surgery and antibiotics.  Subacute endocarditis: caused by less virulent bacteria (eg. viridans Strep). o Grow slowly on pre-damaged valves (eg. post rheumatic fever) o Other pathogens include fungi and Rickettsiae, although less common. Morphology: form bulky, friable vegetations with destructive potential.  Colonies of bacteria embedded in fibrin, mixed with inflammatory cells  Form over areas with high pressure gradient (eg. incompetent valves, PDA, VSD).  May erode into underlying myocardium to produce an abscess cavity.

IE aortic valve

Subacute endocarditis of mitral valve

Clinical: acute febrile illness with swinging temperature.  Changing heart murmur, heart failure, splinter haemorrhages, retinal haemorrhages (Roth’s spots), petechiae, finger clubbing, splenomegaly.  Requires blood culture for diagnosis. Complications: heart valve perforation, incompetence, myocardial abscess formation.  Embolism can occlude artery causing infarct, or may be septic and cause metastatic abscesses.  Glomerulonephritis from microemboli or circulating immune complexes.

Cardiomyopathies are heart diseases due to intrinsic myocardial dysfunction and not secondary to other conditions of the heart. Cause: unknown or unusual aetiology classed as primary or secondary.  Primary: disease solely or predominantly confined to heart muscle. Causes include idiopathic, familial and endomyocardial fibrosis.  Secondary: heart involved as part of a generalised multiorgan disorder that directly affects myocytes. Causes include infection, metabolic disorders, familial storage disease, CT disorders (eg. SLE), infiltrations (eg. amyloidosis), muscular dystrophies and toxic reactions. Classification: various ways of classification.  Aetiological: as above or as either genetic, acquired or idiopathic.  Clinico-pathological: a more clinical and functional classification that divides CMPs into three groups; dilated CMP (90%), hypertrophic CMP and restrictive CMP.

Dilated Cardiomyopathy
Cardiac dilation and systolic dysfunction, usually with hypertrophy, in all four chambers. Characterised by forward failure with reduced CO. Pathology: probably end result of myocardial damage to variety of toxic, metabolic or infectious agents.  Acquired: alcohol, pregnancy (multifactorial), mineral deficiency (eg. selenium, Ca, PO4), thyroid disease, toxic (eg. cocaine, cobalt), chronic tachycardia. Certain forms may be reversible.  Familial: 20% of DCMP, genetically heterogenous. Autosomal dominant, recessive and x-linked forms. Result in abnormalities in myocyte skeleton (eg. dystrophin gene mutations).

Peripartum Cardiomyopathy
CMP during pregnancy due to related hypertension, volume overload, nutritional deficiency, abnormal metabolism and altered immune function. Usually transient and reversible.

Morphology: grossly enlarged heart up to 3x normal  Macroscopic: dilated and flabby heart, possible mural thrombi, patchy fibrous scarring.  Microscopic: hypertrophic myocytes, enlarged nuclei, patchy and interstitial fibrosis. Clinical: most pursue a downhill course, majority die within 3yrs of symptom onset due to heart failure or arrhythmia. Can affect any age, >55yrs worse prognosis.  Progressive CHF (dyspnoea, poor exertion capacity), end stage with ejection fraction <25% (normal 60%).  Secondary mitral incompetence and arrhythmia due to LV dilatation.  Embolism from intracardiac emboli.

Hypertrophic Cardiomyopathy
Characterised by LV hypertrophy of a non-dilated chamber (concentric), without obvious cause such as hypertension or aortic stenosis. Pathology: about 50% of cases due to autosomal dominant mutations in genes coding for myocyte contractile apparatus (eg. B-myosin heavy chain). Marked hypertrophy results, but is asymmetrical (LV).  Abnormal diastolic filling due to increased thickness of ventricular wall.

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Some patients have further dynamic obstruction to LV outflow. This is due to anterior leaflet of mitral valve being displaced by hypertrophy, narrowing the subaortic area. Hypertrophy is accompanied with fibroblast proliferation causing interstitial fibrosis.

Clinical: signs and symptoms related to hypertrophy or resulting diastolic dysfunction.  Dyspnoea, fatigue or syncope due to decreased CO and secondary pulmonary congestion. This is caused by impaired diastolic filling leading to lower stroke volume.  Angina resulting from myocardial ischaemia, due to massive hypertrophy.  Harsh systolic ejection murmur (obstruction), 4th heart sound (reduced LV compliance). Complications: atrial fibrillation with mural thrombus formation, IE of mitral valve, CHF, arrhythmias, and sudden death

Restrictive Cardiomyopathy
Characterised by a primary decrease in ventricular compliance, with an excessively rigid LV wall and impaired diastolic filling. Pathology: can be idiopathic or associated with; hypertrophic CMP, systemic diseases that affect the myocardium (eg. radiation fibrosis, amyloidosis, sarcoidosis) and constrictive pericarditis.  Similar pathology to endomyocardial fibrosis, Loeffler endomyocarditis and endocardial fibroelastosis of infancy.  Mural thrombi are a complication in all these conditions.
Endomyocardial Fibrosis: dense fibrosis of endocardium and subendocardium from apex to AV valves. Seen in young people in Africa. Loeffler Endomyocarditis: endomyocardial fibrosis associated with eosinophilia from any cause. Endocardial Fibroelastosis of Infancy: fibrous thickening of LV.

Inflammation of myocardium with neutrophilic infiltration causing injury (not response to injury).  Secondary to infections (eg. viral, bacterial) or immune reactions (eg. post viral, SLE). Coxsackie A and B most common causes.  Can be asymptomatic or cause serious heart disease (eg. CHF, CMP, sudden death).  Can affect previously well fit persons.

Pericardial Disease

Shaggy Thrombosis

Fibrous Pericarditis

Tuberculous Pericarditis

Pericardial conditions include inflammatory diseases and effusions. Isolated disease is unusual, pericardial lesions are usually associated with heart, surrounding structure or systemic disease. Pathology: may be infectious, non-infectious or immune related. Inflammatory exudates may serous, fibrous, haemorrhagic, suppurative or caseous.  Infectious Pericarditis: virus is most common infectious cause (eg. coxsackie, echovirus, mumps). Bacteria and fungi may be involved. Myocarditis may also be present, especially with viral disease.  Non-Infectious Pericarditis: more commonly secondary to AMI, uraemia, irradiation, neoplasia, myxoedema or trauma.  Hypersensitivity/Autoimmune Pericarditis: rheumatic fever, collagen vascular disease (eg. SLE), drug induced or post cardiac injury.

Clinical: may be acute (<6wks), subacute (<6mnths) or chronic (>6mnths).  Roughened pericardial surface can be heard as ‘pleural rub’.  Effusion present as globular appearance on x-ray.  Healed/chronic cases may result in adhesive pericarditis, adhesive mediastinopericarditis or constrictive pericarditis.

Pericardial Effusions
Effusions <500mL do not interferes greatly with heart function. Rapid accumulation of fluid, often due to catastrophic haemorrhage (eg. AMI, ruptured aneurysm, trauma) can cause cardiac tamponade and restrictive HF.

Usually only an option for dilated CMP and severe IHD in younger patients. Overall prognosis of 80% 1yr survival, 60% 5yr survival depending on two main issues: Rejection is characterised by interstitial lymphocytic inflammation and associated myocyte damage. Diagnosed by endomyocardial biopsy of transplanted heart.  Is reversible in early to moderate stages by immunosuppressive therapy. Treated with cyclosporine, azathioprine and steroids.  Advanced rejection involves necrosis and is irreversible. Graft coronary arteriosclerosis (GCA) is a late stenosing intimal disease of coronary arteries. Very common and leads to silent IHD/MI, HF or sudden cardiac death.

Congenital Heart Disease
Congenital heart diseases consist of defects of cardiac chambers or the great vessels, either resulting in shunting of blood between the right and left circulation or causing outflow obstructions. Left-to-right shunts are most common and typically involve atrial septal defect (ASD), ventricular septal defect (VSD) or patent ductus arteriosus (PDA).  Result in chronic right sided pressure and volume overload.  Eventually causes pulmonary hypertension with reversal of flow and right-to-left shunts with cyanosis (Eisenmenger syndrome). Right-to-left shunts are typically caused by tetralogy of Fallot; VSD, aorta overriding VSD, obstruction to RV and RV hypertrophy. May also be caused by transposition of the great vessels (eg. aorta in RV).  Cyanosis and are associated with polycythaemia, hypertrophic osteoarthropathy, paradoxical emboli. Obstructive lesions include valvular stenosis and aortic coarctaion (constricting or narrowing). Clinical severity of lesion depends on the degree of stenosis and the openness of the ductus arteriosus.

A state of circulatory failure characterised by inadequate tissue perfusion due to a lack of CO/BP. Low blood perfusion to tissues can result in ischaemia and necrosis. Pathology: distinguished by underlying mechanism of shock.  Hypovolaemic shock: occurs when there is inadequate blood volume (↓venous return). Can be due to excessive blood or fluid loss (eg. haemorrhage, burn, dehydration).  Cardiogenic shock: heart is inadequately pumping (↓contractility). Causes include MI, valve failure or arrhythmias.  Obstructive shock: blockage outside heart that impedes flow. Inflow obstructions include pulmonary vein embolism and raised thoracic pressure (↓venous return). Outflow obstructions include aortic and pulmonary artery narrowing (↑afterload).  Distributive shock: increased vascular dilation results in a relative low blood volume (↓venous pressure). Can be caused by spinal cord injury, anaphylaxis, drugs or neurogenics. Clinical: shock is classified according to severity.  Compensated shock: not severe enough to cause own progression. Compensatory mechanisms allow recover; cardiac (sympathetic), endocrine and haematological changes.  Uncompensated shock: shock is progressive and can be fatal if not treated due to multiorgan (renal, cardiac and cerebral) failure.  Irreversible shock: untreatable and will result in death due to extensive cell death and accumulation of waste products.

Abnormal electrical activity within the heart resulting in either an altered impulse generation or conduction (ie. altered beating rhythm).  Are a result of other heart diseases that affect the conductive tissue (eg. MI, CHF).  Either bradyarrhythmias (slow rhythm) or tachyarrhythmias (fast rhythm).  Can be intermittent (alternate), transient (come and go) or permanent/persistent.


Arterial wall thickening and loss of elasticity, 3 different patterns which may coexist.  Arteriolosclerosis: thickening and luminal narrowing of small arteries/arterioles associated with hypertension and diabetes. Has 2 variants; hyaline and hyperplastic.  Monckeberg medial calcific sclerosis: uncommon calcific deposits in media of muscular arteries, while intima and adventitia may appear normal. Usually not clinically significant as arteries are not narrowed. Typically in limbs or uterus of people >50yrs.  Atherosclerosis: an intimal based lesion organised into a fibrous cap and a lipid core (atherosclerotic plaques). Obstruct blood flow and weaken underlying media which may rupture. Most frequent and clinically important.

Pathogenesis of Atherosclerosis
Atherosclerosis mainly affects the elastic arteries (aorta, carotid, iliac) and large-medium sized muscular arteries (coronary, popliteal). Still no single theory that can explain all aspects of atherogenesis, including all the atheromatous lesions described on the right. Response to injury hypothesis: atherosclerosis is a chronic inflammatory response of arterial wall to endothelial injury. 1. Chronic endothelial injury (eg. hyperlipidaemia, hypertension, smoking). 2. Endothelial dysfunction (eg. increase permeability), monocyte adhesion and emigration. 3. Macrophage activation and smooth muscle recruitment. This involves cell signalling and mediator release. 4. Macrophages and smooth muscle cells engulf lipid (mainly LDLs and oxidised forms) → macrophages become foam cells (NB: accumulation of lipid containing macrophages forms ‘fatty streaks’). 5. Smooth muscle proliferation, collagen and other ECM deposition, extracellular lipid accumulation → fibro fatty atheroma (plaque). 6. Excessive thickening of intima → stenosis of lumen → blockage of vascular flow. Macrophage hypothesis: macrophages transport LDL into intima and secrete chemo-attractants and lipases, leads to oxidation of lipid. NB: Gelatinous lesions are expansions of intima by proteoglycan rich ECM, macrophages, SMCs. Unknown relationship to fatty streaks and fibrous plaques.

1. Fatty Streaks
Common lesion found throughout arterial tree at all ages.  Migration of macrophages from blood to intima, uptake of lipid, and transformation into foam cells.  Lipid filled SMC may be a component in advanced fatty streaks.  May progress to fibrous plaques, regress or remain unchanged for life.

2. Fibrous Plaques
Result from SMC proliferation, ECM deposition and extracellular lipid accumulation (fibro-fatty atheromas).  Fibrous cap consists of collagen rich CT matrix, SMCs and macrophages.  Necrotic centre contains foam cells, cholesterol esters, fatty acids and CT matrix.  Capable of regression, usually results in clinical sequelae.

3. Complicated Lesions
Are fibrous plaques complicated by:  Calcification  Ulceration and release of cholesterol athero-emboli  Thrombosis which may become emboli or be incorporated  Haemorrhage into a plaque may expand or rupture it  Aneurysm formation may follow atrophy and fibrosis of media

4. Atrophic Lesions
Plaques that impinge on underlying media causing atrophy.  Weakening of media and destruction of internal elastic lamina.  May lead to lymphocytic reaction in adventitia or cause aneurysm.

Clinical Aspects of Atherosclerosis
Signs and Symptoms: plaques develop slowly over decades but may cause acute symptoms due to rupture, thrombosis, haemorrhage or embolism. IHD, AMI, stroke, aortic aneurysms, PVD, intestinal and renal ischaemia. Epidemiology: Atherosclerosis is responsible for around 50% of deaths in developed countries, half which is due to IHD and AMI. Death rates have been declining in last 30yrs due to recognition of risk factors and subsequent preventative measures.

Early aortic atheromatous lesion

Risk Factors: many are modifiable and related to lifestyle issues.  Non-modifiable: age, males, post menopausal women, family history, genetic abnormalities (eg. familial hypercholesterolaemia).  Modifiable: hyperlipidaemia (specifically hypercholesterolaemia, high LDLs, low HDLs), hypertension, cigarette smoking, diabetes mellitus (also induces hypercholesterolaemia).  Other ‘soft factors’: obesity, physical inactivity, stress (type A personality), high CHO intake, lipoprotein A (altered form of LDL), high homocystine levels, hardened (trans) unsaturated fat intake, postmenopausal oestrogen deficiency. Prevention: can be primary (risk factor identification and modification to delay atheroma formation) or secondary (prevent AMI, stroke etc using drugs).

Hypertension is chronic elevate blood pressure above 140/90mmHg which affects >25% of the population. Typically asymptomatic until late in course, hence increases with age. Classification: aetiologically classified as primary (essential) or secondary.  Essential hypertension: idiopathic, complex, multifactorial disorder (90-95% of cases).  Secondary hypertension: known underlying cause, usually disease of kidney (reduced Na excretion, increased renin secretion) or endocrine gland (thyrotoxicosis, aldosteronism). Risk factors: high dietary salt (Na) intake, stress, obesity, smoking, inactivity and some genetic susceptibility (multifactorial eg. genes coding regulation mechanisms). Complications: atheroma acceleration (MI, strokes) most deadly. Increased risk of LVH, CHF, aortic dissection and renal failure.

Regulation of Hypertension
Blood pressure is regulated by a combination of CO and peripheral resistance (BP α CO x SVR). This is done via neuronal and hormonal mechanisms.  Cardiac output: blood volume (Na, mineralocorticoids, ANP) and cardiac factors (HR, contractility). CO=HR x SV  Peripheral resistance: neural, hormonal and local factors (autoregulation, pH, hypoxia).

Renin-Angiotensin System
Renin is a major regulator of blood pressure, secreted by kidneys in response to decreased afferent arteriole pressure or glomerular Na filtration.  Converts angiotensinogen to angiotensin → ACE converts to angiotensin II  Angiotensin II causes vascular SMC contraction and aldosterone secretion → increased Na (hence water) resorption → increase blood volume/BP.

Vascular Pathology in Hypertension
Vascular changes during hypertension include: atherosclerosis acceleration, degenerative changes in walls of larger arteries, and arteriosclerosis in small vessels (hyaline or hyperplastic). Benign Hypertension (95%) persists slowly over years and is of moderate degree. Is usually idiopathic, although can be due to renal disease.  Small arteries/arterioles undergo hyaline arteriosclerosis. Consists of homogeneous eosinophilic hyaline thickening of media → narrowing of lumen can cause ischaemia.  Small to medium arteries show intimal fibrosis and media SMC hypertrophy.  Large muscular and elastic arteries have accelerated Hyaline arteriosclerosis atherosclerosis. Malignant Hypertension (5%) is rapidly progressive and is of severe degree (DBP>120mmHg). Associated with renal failure, retinal haemorrhages and optic disc swelling.  Arterioles undergo hyperplastic arteriosclerosis. Characterised by concentric proliferation of SMCs with onion skin appearance → narrowing of lumen.  Hyperplastic changes are accompanied by fibrinoid necrosis, particularly in kidney (see renal notes).

Hyperplastic arteriosclerosis

Aneurysm is a localised abnormal dilation of a blood vessel or the heart. Aneurysms are classified by tissue layers involved, shape, size and anatomical position.  True aneurysm: dilation of all three layers of intact arterial wall (intima, media, adventitia). o Saccular aneurysm: round outpouching involving only part of vessel wall, 5-20cm in diameter and often contain thrombi. o Fusiform aneurysm: diffuse dilation of a long segment of vessel, vary in diameter (<20cm) and length. Can involve extensive portions of aorta.  False aneurysm (pseudoaneurysm): breech in vascular wall with blood contained by extravascular tissue (haematoma), eg. ventricular ruptures contained by pericardial adhesion.  Dissecting aneurysm: arise when blood splits the wall of the artery and enters space between its layers. Dilation may be slight, hence dissection is more accurate.

Causes: any cause of damage or weakness of vessel wall.  Atherosclerosis most common cause due to plaque compressing on media.  Cystic medial degeneration of artery.  Trauma (eg. hypertension, post MI).  Congenital defects structural wall.  Infections (mycotic aneurysms), syphilis. Complications: rupture, occlusion (by thrombus or pressure), embolism, mass effect on surrounding structures.

Abdominal Aortic Aneurysms (AAA)
Atherosclerotic aneurysms occur most frequently in abdominal aorta, more frequently in men and elderly. Usually positioned below renal arteries and above aortic bifurcation, saccular or fusiform. Causes: majority of cases result from an altered balance between collagen degradation and synthesis.  Mediated by local inflammatory cells and their proteolytic enzyme release.  Elevated matrix metalloproteases (MMPs), lowered tissue inhibitor of metalloproteases (TIMP) → degrade ECM of arterial wall.  Familial predisposition, hereditary defects in structural components of vessel wall (eg. Marfan's).


Complications: Ruptured  Rupture into peritoneal cavity or extraperitoneal tissue, can be fatal. Risk of Aortic Aneurysm rupture α size of aneurysm, >5cm serious.  Occlusion of a branch vessel (iliac, renal, mesenteric, vertebral arteries) → ischaemic damage.  Embolism from atheroma or mural thrombus.  Impingement on adjacent structure (eg. compression of ureter, erosion of vertebrae).

Syphilitic Aneurysm
Pathogenesis: Vasa Vasorum  Late complication of syphilis, whereby T. pallidum affects the vasa vasorum in the Arterial network aortic adventitia, causing ‘obliterative endarteritis’ (endothelium inflammation). supplying larger  Affected vessels show luminal narrowing and obliteration. Scarring of vessel wall blood vessels. with surrounding inflammation (lymphocytes and plasma cells).  Lumen narrowing of vasa vasorum causes ischaemic injury of aortic media → loss of elastic fibres and muscle cells (destruction and weakening of media) → dilation (aneurysm). Complications:  Contraction of fibrous scarring leads to wrinkling of aortic intima, resembles tree bark.  Associated atherosclerosis of aortic root can obstruct coronary ostia, can cause MI.  Weakening of aortic root dilates valvular annulus → valvular insufficiency → volume overload (eccentric) hypertrophy of LV – “cor bovinum” (cow’s heart).  Most patients with syphilitic aneurysms die of heart failure induced by valvular incompetence.

Aortic Dissection
Blood dissects aortic wall and tracks along luminal planes of the media. Forms a blood-filled channel within the aortic wall. Occur in mainly in men aged 40-60 with hypertension. Pathogenesis: main risk factor is hypertension, but the pathways of how this damages the media is still not known.  Unknown trigger for intimal tearing activated. Intimal tearing then occurs, most frequently in ascending aorta.  Once tear has occurred, blood under high systemic pressure penetrates the media forming a medial haematoma.  Smaller percentage related to CT disorders (Marfan most common). Generally younger patients. Marfan’s Syndrome
An autosomal dominant disease of fibrillin, an ECM scaffolding protein required for normal elastic tissue synthesis. Causes long features, high arch palate, aortic regurge etc.

Morphology: histology commonly shows cystic medial degeneration (CMD) in the media.  cystic spaces filled with proteoglycan rich ECM separating elastic tissue and SMCs in the media  fragmentation and loss of elastic tissue. Classification: dissections classified into two types.  Proximal lesions (type A): associated with dissections from the aortic valve to arch, most common and dangerous.  Distal lesions (type B): not involving ascending part, usually begin distal to subclavian artery. Clinical: typical symptom of sudden onset of pain in anterior chest, radiating to back between scapulae, moving downward as dissection progresses. Can be confused with MI. Complications: depend on the level of aorta affected.  Rupture is most common cause of death from dissection. Can rupture through adventitia causing haemorrhage or haemopericardium (cardiac tamponade).  Extension of dissection to branches of aorta causing vessel obstruction (eg. carotid, spinal, renal and mesenteric arteries).  Other complications depend on tissue deprived of blood (eg. carotid obst. → neuro symptoms).

Vasculitis is inflammation of the vessel wall associated with immune mediated processes (idiopathic).  Known causes include infection, physical and chemical injury (eg. irradiation, drugs, trauma).  Frequent systemic manifestations include fever, malaise, myalgia, athralgia. Specific symptoms depend on which vascular bed is involved. Pathogenesis: vasculitis is generally idiopathic, associated with a variety of immunological mechanisms.  Immune complex deposition: antibody and complement found in vasculitic lesions, although the nature of the antigen responsible for deposition not determined.  Anti-neutrophil cytoplasmic antibody (ANCA): cause either direct injury (to endothelium) or induce neutrophil activation (inflammation). Two types; o Cytoplasmic localisation (c-ANCA): targets proeinase-3 (PR3) eg. Wegener Granulomatosis. o Perinuclear localisation (p-ANCA): targets myeloperoxidase (MPO) eg. polyarteritis nodosa.  Anti endothelial cell antibody: antibodies against ECs may predispose to certain vasculatides eg. Kawasaki disease.

Large Vessel Vasculitis (aorta and large branches)
Giant Cell (Temporal) Arteritis granulomatous inflammation of large arteries, most common form.  Histology: giant cell granulomatous inflammation with lymphocyte and eosinophil infiltrate. Intimal fibrosis (resembling arteriosclerosis) and lumen narrowing. Diagnosis via biopsy.  Clinical: usually >50yrs. Mainly affects aorta and arteries in head eg. temporal (blurring), vertebral (diplopia) and ophthalmic (blindness). Other symptoms include headache and tenderness over affected area. Takayasu Arteritis involves granulomatous inflammation with transmural fibrous thickening of aorta.  Histology: indistinguishable from giant cell arteritis, distinction by age (<40yrs).  Clinical: symptoms depend on aortic branches involved. Possible ocular disturbances, neurological deficits (carotids), pulmonary/systemic hypertension (lung/renal), AMI (coronary). Weak peripheral pulse due to luminal narrowing.

Medium Vessel Vasculitis (main visceral arteries, their branches)
Polyarteritis Nordosa (PAN) is systemic vasculitis of arteries, typically involving visceral vessels.  Histology: transmural necrotising inflammation resulting in fibrous thickening of wall. Scarring with chronic inflammatory cell infiltrate (plasma cells, macrophages). Diagnosed via biopsy.  Clinical: mainly in vessels of kidneys, heart, liver, GI tract with associated symptoms. General symptoms include fever, weight loss, abdominal pain, muscle pain and peripheral neuritis. Primarily disease of young adults (but occurs in all ages), 30% patients have Hep B antigen.  Complications: luminal thrombosis, aneurysms (weak arterial wall), rupture  Treatment: corticosteroids and immunosuppressives (eg. cyclophophamide), fatal if untreated. Kawasaki Disease arteritis of medium sized vessels associated with anti-endothelial/SMC antibodies.  Histology: PAN-like morphology.  Clinical: febrile illness of infancy and childhood. ‘Mucocutaneous lymph node syndrome’ as it presents with inflammation (conjunctival, oral, skin), rash and lymph node enlargement.  Complications: arteritis of coronary arteries can cause aneurysms that rupture or thrombose causing AMI. Leading cause of acquired heart disease in children.

Small Vessel Vasculitis (arterioles, capillaries, venules)
Microscopic Polyangiitis (hypersensitivity vasculitis) is a necrotising (fibrinoid) vasculitis.  Pathology: antibody response to drugs, microorganisms etc. Results in immune complex deposition or triggering secondary immune responses (neutrophil). p-ANCAs present in 80%. May accompany Henoch-Schonlein purpura, essential cryoglobulinaemia, CT disorders.  Histology: fibrinoid necrosis, acute inflammatory cell infiltrate, RBC extravasation, nuclear dust (leukocytoclastic vasculitis). All lesions are of the same age in any given patient.  Clinical: symptoms depend on vascular bed involved eg. purpura (skin), haematuria (kidneys), pain, haematemesis and melena (GIT), pain and weakness (muscle), haemoptysis (lungs). Most patients recover from removal of offending agent. Wegener Granulomatosis is characterised by respiratory, kidney and small vessel involvement.  Pathology: probably a cell mediated hypersensitivity response, possibly to inhaled infectious or environmental agent. c-ANCA present in 95% of cases.  Histology: triad of (i) necrotising granulomas of whole respiratory tract, (ii) focal necrosis of small vessels, and (iii) focal/diffuse necrotising glomerulonephritis.  Clinical: males > females, 40yrs. Persistent pneumonitis, chronic sinusitis, nasopharyngeal mucosal ulcerations, renal disease. Untreated mortality of 80% in 1 yr.  Treatment: immunosuppressive therapy (eg. cyclophophamide). Churg-Strauss Syndrome granulomatous necrosis of respiratory tract with eosinophils in lesions and peripheral blood. Related to Wegener Granulomatosis but distinguished by strong association with allergic rhinitis, asthma, eosinophil involvement and p-ANCA. Thromboangiitis Obliterans (Buerger Disease) segmental, thrombosing inflammation of small-medium arteries in limbs, with secondary vein and nerve involvement.  Pathology: direct toxicity to endothelium by tobacco products, or idiosyncratic immune response to same products.  Clinical: superficial nodular phlebitis, Raynaud’s phenomenon, pain in feet during exercise (in step claudication), severe pain at rest (neural involvement), ulceration of extremities (gangrene).  Occurs in heavy cigarette smokers, usually before 35yrs. Smoking cessation in early stages decreases complications.

Raynaud’s Phenomenon
Extremities change from red (proximal vasodilation), white (central vasoconstriction) and blue (distal cyanosis).  Primary: exaggerated central and local vasomotor responses to cold or emotion. No pathological changes early. Common in young women.  Secondary: vascular insufficiency of extremities due to other disease processes eg. atherosclerosis, SLE, Buerger disease, scleroderma.

Infectious Vasculitis
Important to distinguish between immunologic and infectious mechanisms because immunosuppressive therapy will help the former but exacerbate the latter.  Mainly due to bacteria or fungi (aspergillus and mucor species).  Can weaken arterial walls (mycotic aneurysms) or induce thrombosis and infarction.  Indirect vasculitis can occur from drugs used to treat infection eg. penicillin.


Anaemias are a group of disorders characterized by a decrease in the number of circulating erythrocytes. Classified by erythrocyte morphology and pathogenesis.  Pathogenesis: anaemias may result from (i) blood loss, (ii) haemolysis, or (iii) decreased production of RBCs. Reticulocyte count is a measure of newly synthesised RBCs; compensatory increase after blood loss/haemolysis, low count in hypoproliferative anaemia.  Morphology: RBCs may be normal in size but different shape (normocytic), large (macrocytic) or small (microcytic). Measured in terms of mean cell volume. Hb may be normal (normochromic) or decreased (hypochromic).  Signs and symptoms: palpitations, systolic cardiac murmurs, high output heart failure, pallor, hypotension (decreased volume), tachycardia, fatigue, dizziness, syncope and angina.

Anaemia of Blood Loss
With acute blood loss, immediate threat is hypovolaemic shock rather than anaemia. If patient survives, haemodilution is at full affect within 2-3 days, unmasking affects of RBC loss.  The anaemia is normocytic and normochromic  Recovery is enhanced by a rise in erythropoietin release, which stimulates RBC production within several days. Onset of bone marrow response is marked by reticulocytosis.  With chronic blood loss, iron stores are gradually depleting leading to iron deficiency anaemia.

Haemolytic Anaemia
Group of disorders characterised by premature RBC destruction, Hb breakdown and a compensatory increase in erythropoiesis. Can be intra- or extravascular.  Intravascular causes elevated serum and urinary Hb, jaundice, urinary haemosiderin, and a decrease in circulating haptoglobin (glycoprotein that binds free Hb, allowing removal by liver).  Extravascular haemolysis occurs in the organs of the reticuloendothelial system. Hereditary Spherocytosis membrane defect leads to less deformable spherical RBCs which are vulnerable to splenic sequestration and destruction.  Pathology: autosomal dominant (25% are recessive) gene codes for defective spectrin molecules in erythrocyte membrane. Treated by splenectomy.  Morphology: peripheral smear shows spherical RBCs lacking in central pallor and reticulocytosis. RBCs also have increased osmotic fragility. Normocytic, normochromic. Sickle Cell Disease sickle haemoglobin (HbS) mutation results in deformed RBC, causing increased splenic destruction and microvascular obstruction.  Pathology: hereditary substitution (valine for glutamic acid) in β-chain of Hb, producing HbS molecules. These aggregate and polymerise when deoxygenated, causing sickle shape.  Morphology: RBC assume abnormal, rigid, sickle shape Congestive Splenomegaly (elongated and crescentic). Diagnosis on prep with reducing Occurs mostly in young children due to agent (metabisulfate) of Hb electrophoresis. infarction in spleen from microvascular  Clinical: sickle cells are removed by splenic phagocytes obstruction. Causes scarring, shrinkage and loss of function (autosplenectomy). producing a chronic normocytic anaemia. Widespread Functional asplenia leaves patients microvascular obstruction due to sickle aggregates can vulnerable to infection, most die <30. cause acute pain crisis and tissue infarction.

G6PD Deficiency results in oxidative stress on the RBC, leading to haemolysis.  Pathology: X-linked disorder coding for deficient G6PD (glucose-6-phosphate dehydrogenase). G6PD is needed to generate NADPH which maintains glutathione in reduced state. RBCs normally defend against oxidative injury via reduced glutathione.  Morphology: peripheral smear shows reticulotytosis and Heinz bodies, which are clumps of Hb degradation products seen after staining RBCs with new methylene blue. Thalassaemias an inherited group of disorders characterised by lack of Hb proteins chains, producing a mild anaemia. Require blood transfusion at times of accelerated haemolysis or impaired erythropoiesis.  α-Thalassaemia is decreased or absent synthesis of α-chains of Hb, due to gene deletion. Aggregation of non α-chains → haemolysis.  Β-Thalassaemia (major and minor) is decreased or absent synthesis of β-chain, resulting from mutations of mRNA processing. Results in a hypochromic cell with excess of α-chains that aggregate and become insoluble → haemolysis. NB: major due to 2 abnormal allele mutations, minor only due to 1. Immune Haemolytic Anaemia haemolysis due to anti-RBC antibodies, idiopathic or secondary to malignancy, infection or drug use.  Pathology: antibodies bind and opsonise RBCs. Phagocytosis in spleen or complement fixation with intravascular haemolysis. Warm and cold antibodies, each associated with different underlying diseases/infections.  Diagnosis: Coombs test measures antibodies on RBCs (direct) or antibody in serum (indirect).
Warm antibody: functions at body temperature, is usually IgG. Eg. malignancy (CLL), drugs (penicillin, quinidine), SLE. Cold antibody: functions below body temperature, is usually IgM. Eg. Mycoplasma infection, mononucleosis, B-cell malignancy.

Other Haemolytic Anaemias  Trauma to RBC can be due to various situations eg. prosthetic valves, microvascular fibrin deposition or turbulence.  Paroxysmal nocturnal haemoglobinuria is an acquired deficiency of a RBC membrane glycoprotein that leads to chronic intravascular haemolysis.

Anaemia of Diminished Erythropoiesis
Megaloblastic Anaemias large immature RBCs in bone marrow due to vit B12 or folate deficiency.  Pathology: deficiencies cause impaired DNA synthesis. Results in destruction of immature RBC within the bone marrow (ineffective erythropoiesis), as well as extra-medullary haemolysis.  Morphology: large, oval, immature RBC (megaloblasts) with large, hypersegmented neutrophils found in peripheral blood.  Vitamin B12 deficiency has profound neurological and Perinicious Anaemia Gastritis where auto-antibodies destroy haematological sequelae. Results from dietary deficiency, gastric parietal cells. Results in absence malabsorption, competitive tapeworm uptake, bacterial of intrinsic factor and hence Vit B12 overgrowth, pregnancy, hyperthyroidism or cancer. impaired absorption. Most common NB: bodies B12 stores are large, takes years to develop cause of adult Vit B12 deficiency. deficiency after absorption stops)  Folate deficiency produces anaemia without neurological changes. Results from deficient intake (poor diet, alcoholism, malabsorption), increased need (pregnancy, malignancy, inc. Haematopoiesis) or impaired use (antimetabolic drugs).

Iron Deficiency Anaemia chronic anaemia exhibiting hypochromic and microcytic cells  Causes: Fe deficiency is very common, caused by blood loss (GIT, genitourinary tract most common), poor diet, malabsorption and pregnancy.  Pathology: inadequate intake of iron results in insufficient haemoglobin synthesis and hypochromic and microcytic red cells.  Clinical: low serum iron and ferritin, low transferrin saturation (high TIBC). Aplastic Anaemia aplasia renders bone marrow incapable of replenishing blood cells.  Causes: multiple causes that lead to bone marrow failure, most cases are idiopathic.  Pathology: multipotent myeloid stem cells are suppressed leading to bone marrow failure and pancytopaenia (anaemia, neutropaenia, thrombocytopaenia ie. myeloid cells).  Clinical: Prognosis is poor, bone marrow transplant may be curative. Hypocellular blood (peripheral smear) and bone marrow (biopsy). RBCs are normocytic and normochromic.

Bone Marrow Failure
Defined as inadequate blood cell production. Has multiple aetiologies, all causing decreased cell production:  Chronic renal failure (low erythropoietin).  Alkylating drugs, radiation, chemotherapy  Infections and other inflammations  Endocrine disorders, liver disease  Congenital abnormalities (Fanconi anaemia)  Invasive neoplasms or granulomas  Myelofibrosis


Sickle Cell


Iron Deficiency

Polycythaemia is an increase in the concentration of circulating erythrocytes. May be relative or absolute (primary and secondary). Relative Polycythaemia is due to loss or sequestration of intravascular volume without loss of RBCs. Can be caused by dehydration, vomiting, diarrhoea, burns, adrenal (aldosterone) insufficiency. Polycythaemia Vera is a primary myeloproliferative syndrome characterised by an increase in erythrocyte mass (ie. absolute).  Clinical: characterised by increased blood volume, vascular stasis/thrombosis, or bleeding tendency. Patients may develop anaemia or acute leukaemia due to ‘bone marrow burnout’. Folate deficiency may develop due to hyperproliferative state.  Pathology: associated with neoplastic myeloid stem cells due to JAK-2 mutation.  Morphology: peripheral smear shows increased RBCs, WBCs and platelets. Erythropoietin levels are low and bone marrow shows erythroid hyperplasia with excess normoblasts.  Treatment: generally managed through therapeutic phlebotomy. Secondary Absolute Polycythaemia is an increase in RBC mass as a result of increased erythropoietin levels. Can be caused by high altitude (low O2), cigarette smoking (high CO2), respiratory disease, cardiac disease (right-left shunts, cardiac failure), renal disease and malignancies.

Platelet Disorders
Decreased Platelet Count Thrombocytopaenia is a decrease in the platelet count. Often causes bleeding from small vessels (skin, GI, genitourinary tract), petechiae (small pin sized haemorrhages in the skin) and purpura (large, red, non-blanching lesions). Classified by cause:  Decreased production eg. drugs, radiation, aplastic anaemia, platelet maturation defect (vit B12 or folate deficiency).  Abnormal sequestration of platelets in the spleen during congestive splenomegaly.  Dilution eg. massive blood transfusion.  Increased destruction eg. DIC, ITP, TTP, drugs or malignancy. Idiopathic/Immune Thrombocytopaenic Purpura (ITP)
Often immune related, caused by antibodies against platelet antigens → IgG coated platelets destroyed in the spleen.  May be primary, or secondary to another disorder (SLE, HIV, haemolytic anaemia).  May be triggered by drugs, infections, lymphomas or be idiopathic.  Long history of bruisability, bleeding (mucous membrane, GIT, genitourinary) and petechiae.

Thrombotic Thrombocytopaenic Purpura (TTP)
Rare disease most commonly caused by deficiencies of ADAMTS13, a plasma metalloprotease which prevents accumulation of multimers of von WF.  Abnormally large von WF → platelet aggregation and development of microthrombi throughout vasculature → microangiopathic haemolytic anaemia  Characterised by purpura, fever, renal failure, neurological changes, anaemia.  Most frequent in young females.

Disorders of Excess Platelets Thrombocytosis is a reactive disorder of increased platelets resulting from bleeding, haemolysis, inflammation, malignancy, iron deficiency, stress or post splenectomy. Essential thrombocythaemia is a primary myeloproliferative disorder associated with JAK-2 mutations. Also a prominent feature of chronic myeloid leukaemia (CML). May lead to diffuse thrombosis. Platelet Function Defects These disorders can be congenital or acquired, resulting in prolongation of bleeding time in the presence of normal platelet count. Classified as follows:  Defects of adhesion (von Willebrand disease, Bernard-Soulier disease).  Defects of primary aggregation (thrombasthenia).  Defects of secondary aggregation and release (aspirin, storage pool disease).

Von Willebrand Disease
Autosomal dominant defect in von Willebrand factor resulting in impaired adhesion of platelets to collagen.  Also results in low factor VIII levels and activity (vWF is carrier molecule for Factor VIII) → prolonged partial thromboplastin time (PTT).  Characterised by spontaneous haemorrhage from mucous membranes, wounds and excessive menstrual bleeding.

Clotting Factor Deficiencies
Acquired Disorders Vitamin K Deficiency a fat soluble vitamin produced by bacterial metabolism of ingested nutrients within the large intestine.  Involved in post translational modification of factors II, VII, IX and X, protein C and S.  Deficiency may result from fat malabsorption, diarrhoea, dietary deficiency, antibiotics, some anticoagulant drugs (warfarin). Liver Disease can result in the failure to synthesis factors II, V, VII, IX, X, XI and XII.

Hereditary Deficiencies Disorders resulting in low factor counts. Include haemophilia A (factor VIII) and B (factor IX).  Signs and symptoms include haemarthrosis (most common), soft tissue haematomas, genitourinary bleeding, bleeding in CNS and neck (life threatening).  Severity related to factor level: <1% severe (spontaneous bleeding), 1-5% moderate (bleeding with mild injury), 5-25% mild (bleeding with surgery or trauma).  Since both Haemophilia A/B have prolonged PTT, must be distinguished by specific factor assays.  Treated by factor replacements (either plasma derived or recombinant).

Factor VIII Deficiency (Haemophilia A)
X-linked recessive disorder resulting in defective Factor VIII or impaired conversion of precursor to Factor VIII. Incidence of 1/10 000 in males.

Factor IX Deficiency (Haemophilia B)
X-linked recessive disorder resulting in inactive or inadequate Factor IX. Affects 1/50 000 males.

Disseminated Intravascular Coagulation (DIC)
Syndrome involving systemic activation of coagulation pathways leading to microthrombi formation. Subsequent consumption of coagulation factors leads to activation of fibrinolysis.  Pathology: widespread endothelial injury causes release of tissue factor, exposure of collagen and vWF. Can be caused by major trauma, sepsis, malignancy, toxins or vascular disorders.  Clinical: can lead to microinfarction (thrombosis formations) or bleeding disorder (consumption of coagulation factors).  Diagnosis: laboratory diagnosis by demonstrating low platelets, low fibrinogen and the presence of fibrin degradation products.  Treatment: directed to the underlying disease. Heparin helps slow consumption of clotting factors. Fresh frozen plasma and platelet concentrate may then be used to replace the deficits.

Laboratory Tests
Platelet counts: determined from anticoagulated blood using an electronic particle counter. Bleeding time: time taken for standard skin puncture to stop bleeding. Assessment of in vivo clotting, normally mins. Prothrombin time (PT): tests the extrinsic and common coagulation pathways. Represents clotting time in the presence of tissue thromboplastin (factor III), normally 12-15 sec. INR=[patient PT/normal PT]ISI. Partial thromboplastin time (PTT): tests factors in the intrinsic and common coagulation pathways, normally 25-35 sec. Thrombin time (TT): measures factor I (fibrinogen).


Hereditary Bleeding Disorders Acquired Bleeding Disorders Haemophilia A and B: X-linked disorders of Liver disease or vit K deficiency: reduced factor
inadequate factors VIII and IX. Von Willebrand's disease: defect in vWF resulting in impaired platelet adhesion. Essential thrombocythaemia: primary disorder of excess platelet production. synthesis/modification. ITP: causes immune platelet destruction. TTP: platelet aggregation due to vWF accumulation. DIC: systemic clotting, followed by factor depletion and bleeding.

White cell disorders, particularly neoplasms, vary widely in presentation and behaviour presenting challenges to classification. Can be classified by cell type:  Lymphoid neoplasm: tumours composed of cells resembling lymphocyte differentiation. Include non-Hodgkin and Hodgkin lymphomas, ALL, CLL and plasma cell myelomas.  Myeloid neoplasm: arise from myeloid stem cells that normally give rise to formed elements of the blood (granulocytes, erythrocytes and platelets). Include AML, CML and myelodysplastic syndromes.  Histiocytic neoplasm: involve proliferative lesions of histiocytes (macrophages). NB: ‘acute disorders’ refers to accumulation of precursor cells due to blocked differentiation, while ‘chronic disorders’ involve cells which retain the capacity for terminal differentiation.

Can be classified by location:  Leukaemias: tumours that primarily involve the bone marrow with spillage of neoplastic cells into the peripheral blood.  Lymphomas: tumours that produce masses in involved lymph nodes/tissue. NB: problem with this classification is that leukaemias can infiltrate lymph tissue, lymphomas can spill over into blood and both can spread to other body tissues (eg. liver, spleen). Despite this, our lectures use this classification (WHO uses cell types).

Benign White Cell Disorders
Leukocytosis is an increase in WBC count. Classified as either primary myeloproliferative disorders or reactive secondary leukocytosis. Meyloproliferative Disorders (Primary)
Overactive marrow, associated with elevated blood counts. Usually involves multiple neoplastic myeloid lines.  Often associated with a mutation in the Jak-Stat signalling pathway which triggers growth signals.  Includes polycythaemia vera and essential thrombocythaemia. Such disorders are rarely benign in WBCs.  Metastatic myeloproliferative WBC disorders include CML and are discussed below.

Reactive Leukocytosis (Secondary)
Infectious or other inflammatory states causing increased WBC counts. Much more common benign causes. Further classified

according to cell line involved.
 Polymorphonuclear (commonest): acute infection/tissue necrosis.  Neutrophilic Leukocytosis: acute bacterial infections.  Monocytosis: chronic infections/inflammation (eg. tuberculosis).  Lymphocytosis: chronic inflammation (accompanies monocytosis), viral infections.  Eosinophilic leukocytosis: allergies, parasite infections.  Basophilic leukocytosis: rare, indicates myeloproliferative disease.

Leukopaenia is a decrease in circulating WBC count. Lack of immune defence (especially neutropaenia) increases susceptibility to overwhelming infection. Need prompt investigation and treatment. Usually secondary to bone marrow disorders causing reduced production:  Myelodysplasia is disordered and ineffective haematopoiesis.  Myelofibrosis, marrow infiltration by fibrous tissue.  Infiltrations of bone marrow, secondary to malignancies.  Infections eg. HIV, hepatitis, dengue, influenza, tuberculosis. NB: pseudo-leukopaenia can occur during infection due to marginalisation of leukocytes.  Drugs eg. chemotherapy, radiotherapy, myelosuppressive agents and alcohol.  Vitamin deficiencies in B12 and folate can lead to abnormal DNA production (megaloblastic anaemia).  Congenital eg. cyclical neutropaenia. Meylodysplasia
Group of myeloid tumours (often benign) characterised by disordered and ineffective haematopoiesis. Bone marrow is still producing cells but patient develops pancytopaenia. Many progress to AML.

Abnormal megakaryocytes release growth factors that stimulate reactive marrow fibroblasts to deposit collagen. Resulting fibrosis slowly replaces the marrow space leading to pancytopaenia and extramedullary haematopoiesis.

Or, less commonly, peripheral disorder of increased destruction:  Splenomegaly/hepatomegaly, increasing sequestration, consumption and destruction.  Associated immune disorders eg. Felty’s syndrome (rheumatoid with splenomegaly and neutropaenia), auto-antibodies or some infections. Non-Specific Lymphadenitis is non-neoplastic inflammation and/or enlargement of lymph nodes. May be caused by infections, drugs, toxins or other inflammatory stimuli.

Chronic Myeloid Leukaemia (CML) arises from mutation in a pluripotent myeloid CML stem cell, resulting in overproduction and accumulation in blood. Present in multiple myeloid lineages.  Pathology: acquired genetic translocation (9;22), producing a BCR-ABL fusion gene that codes for a tyrosine kinase protein. o This protein activates transduction pathways to uncontrolled cell growth, whereas the original ABL gene switches itself off. o Effects granulocyte precursors most, retain capacity for terminal differentiation resulting in elevated granulocytes in blood.  Clinical: chronic phase (slow with non specific symptoms), accelerated phase (symptoms become severe) and blastic phase (>30% myeloblasts in blood or marrow).  Diagnosis: bone marrow biopsy with FISH probes to identify BCR-ABL gene. Quantitative PCR.  Treatment: chemotherapy, drugs (imantinib mesylate), bone marrow transplant.
AML with pallor of

Acute Myeloid Leukaemia (AML) neoplasm comprised of immature myeloid cells. renal substance.  Pathology: diverse genetic lesions express abnormal transcription factors that block myeloid cell differentiation. This results in replacement of normal marrow elements by leukaemic blasts. o Abnormal cytogenetics found in 60-80% of AMLs. o Most common is the t(15;17) translocation in Acute Promyelocytic Leukaemia (APML) resulting in abnormal vitamin A receptors (Tx with vit A analogue).

 

Clinical: makes up 90% of adult and 15% of childhood acute leukaemias. Present with pallor, purpura and petechiae. Diagnosis: chromosome testing most definitive.

Chronic Lymphocytic Leukaemia (CLL) formation of neoplastic B-cells that suppress normal B-cell function.  Pathology: >95% involve B-cell linage, DNA changes associated with apoptosis (90% have increased bcl-2 levels). o Auto antibody production by normal B-cells indicates breakdown in immune regulation. o Cell surface characteristics include CD19+ (pan-B marker) (pancreas) CLL of Coeliac LNs, and CD5+ (pan-T marker).  Clinical: most common leukaemia in adults, may be asymptomatic early. Non-specific symptoms with lymphadenopathy and hepatosplenomegaly occur. Progressive rise in WCC, low blood counts in advanced disease (may be aggressive late). Acute Lymphoblastic Leukaemia (ALL) aggressive tumours composed of immature lymphocytes (blasts).  Pathology: malignant change, usually in pre-B-lymphoblast causes block in differentiation. o Leads to accumulation of immature lymphoblasts in bone marrow, which suppresses normal haematopoietic stem cells. o Mutation is often an oncogene translocation to an active DNA transcription site.  Clinical: 80% of childhood leukaemias. Is a rapid growing disease involving blood, marrow, spleen and other sites (CSF, testes, lymph nodes).

Non-Hodgkin Lymphomas most often involve malignant B-cells (>85%). Malignancy develops at a point in normal development– specific markers present on cell at specific points. Change usually due to oncogene translocation during DNA transcription. Non-Hodgkins  Small lymphocytic lymphoma (4%) is similar to CLL, only with no or limited Lymphadenopathy peripheral blood involvement.  Follicular lymphomas (40%) are lymph node tumours with a nodular appearance. 95% of cases have a t(14;18) translocation leading to increased bcl-2 expression (anti-apoptotic).  Burkitt’s lymphoma is associated with t(8;14) translocation and EBV infection. Need for intensive therapy, including CNS prophylaxis.  MALT lymphoma is usually a localised, indolent disease. >95% of GIT cases associated with H. pylori infection, eradication often allows remission.  Multiple myeloma is malignant growth of mature B-lymphoid cells (plasma cells) which are normally secretory. Can cause anaemia, infections, bone pains or fractures, and abnormal monoclonal antibody production (paraprotein). Hodgkin Lymphomas are neoplasms that arise in a single lymph node and spread in an anatomical stepwise fashion.  Characterised by malignant Reed-Sternberg (RS) cells which are derived from B-cells. These are greatly outnumbered by reactive lymphocytes, macrophages and stromal cells.  Associated with distinctive clinical features, including systemic features eg. fever.  Predictable spread allows for localised treatment if detected early, unlike NHLs.


Atelectasis (collapse) is loss of lung volume caused by inadequate expansion of air spaces.  Results in pathological shunting of deoxygenated blood from arteries to veins (↓ VA/Q ratio).  Is classed by underlying mechanism and distribution of collapse. Resorption Atelectasis when obstruction prevents air from reaching distal airways.  Air present gets absorbed, leading to collapse.  Can be entire lung, lobe or segment depending on obstruction.  Most commonly due to mucopurulent (mucous) plug. This can be postoperative complication or due to obstructive lung disease. Compression Atelectasis when fluid, blood or air accumulates in pleural cavity and mechanically collapses adjacent lung. Can be due to:  Pleural effusion from congestive heart failure. Pneumothorax (air).  Elevated diaphragm causes basal atelectasis, commonly in bedridden or ascites patients. Contraction atelectasis when local/generalised fibrotic changes in lung or pleura hamper expansion and increase elastic recoil during expiration (interstitial disease).  Highly compromised lung function.  Non-reversible (others can be treated). Microatelectasis loss of surfactant, lung cannot expand equally resulting in collapse.

A group of disorders characterised by increased resistance to airflow during inspiration and/or expiration due to airway obstruction (anywhere from trachea to terminal bronchioles).  TLC and FVC are normal or increased (air trapping)  FEV1 (expiratory flow) is decreased, hence [FEV1/FVC] % is decreased.

Abnormal permanent distension of airspaces in acinus (distal to terminal bronchioles) with destruction of alveolar septae. Obstruction results due to loss of elastic recoil. NB: several conditions have enlargement of acini with no destruction eg. compensatory overinflation of lung after pneumonectomy. Not considered emphysema. Pathogenesis: emphysema results from the destructive effects of high protease activity in subjects with low antiprotease activity (protease-antiprotease imbalance). ↑Proteases: 1. Neutrophils (protease source) are normally sequestered capillary periphery. 2. Smoking induces accumulation of neutrophils and macrophages in alveoli via nicotine (chemoattractant) and ROS (induce IL-8, LT-B4, TNF). 3. Accumulated neutrophils/macrophages are activated and release variety of protease granules (eg. elastin). Results in tissue breakdown. ↓Antiprotease: 1. Tobacco smoke contains abundant ROS which deplete antioxidant mechanisms in the lung (oxidant-antioxidant imbalance). 2. This elicits direct tissue damage but also inactivates antiproteases, causing a ‘functional α1-antitrypsin deficiency’ → further protease tissue damage.

Classification: defined by morphological changes, unlike chronic bronchitis (clinical). 1. Centriacinar Emphysema involves only the respiratory bronchioles, distal alveoli are spared.  More common in upper lobes, particularly apical segments.  Distal alveoli may become involved in severe form making differentiation difficult.  Common consequence of cigarette smoking, without α1-antitrypsin deficiency. 2. Panacinar Emphysema involves uniform enlargement of entire acini (resp bronchiole → alveolar sac).  More common in the lower lobes.  Occurs in hereditary α1antitrypsin deficiency. α1-Antitrypsin Deficiency
Hereditary disorder of defective α1-antitrypsin secretion by liver. α1-antitrypsin inhibits the destruction of elastin by elastase, a proteolytic enzyme within inflammatory cells. Elastase acts on alveolar and hepatocyte walls, hence α1-antitrypsin deficiency results in panacinar emphysema and hepatic cirrhosis.

3. Distal Acinar Emphysema involves the distal part of the acinus, sparing the respiratory bronchioles.  More prominent adjacent to pleura, septae and the lobular edge.  More severe in upper lung, esp. following previous injury (adjacent to fibrosis or atelectasis).  Characteristic enlarged subplueral, cystic air spaces (0.5-2cm) called bullae. Can rupture and cause pneumothorax (common cause in young people). Not exclusive to distal emphysema. 4. Irregular Emphysema involves non uniform parts of the acinus, often with scarring.  Often results from healed inflammatory disease (scarring).  Usually asymptomatic, may be most common form.

Clinical: rarely occurs in pure form, usually as part of COPD with chronic bronchitis. Signs and symptoms of predominantly emphysema:  Older patient (>50 yrs), severe dyspnoea and less sputum.  Weight loss, barrel-chest (hyperinflation), purse-lip breathing, prolonged expiratory time (FEV1).  ‘Pink puffers’ as hyperventilation may maintain blood oxygenation till late in the disease.  ↑ Air spaces causes hyper-resonant percussion and low density on X-ray. Complications may include:  Respiratory failure with acidosis and coma.  Right sided heart failure (cor pulmonale). This is due to obliteration of alveolar septal capillaries/vessels resulting in increased resistance (↑ pulmonary BP).  Pneumothorax, leading to compression atelectasis.

Chronic Bronchitis
A clinical diagnosis of persistent productive cough for at least 3 months in 2 consecutive years. Pathogenesis: characterised by chronic irritation causing hypersecretion of mucous (~75mL sputum/day). Usually due to cigarette smoke, but also SO2, NO2, resulting in:  Damage to conducting airways with mucous gland hypertrophy in trachea/bronchi.  Inflammation (CD8+ Tcells, macrophages and neutrophils) with scarring and fibrosis. Actual airway obstruction occurs in more peripheral airways as a result of:  Bronchiolitis (small airways disease) induced by Goblet cell metaplasia with mucous plugging of bronchiolar lumen.  Coexistent emphysema or bronchospasm (asthmatic bronchitis). Clinical: affects 10-20% of urban population, even higher in cigarette smokers. Many have COPD. Signs and symptoms of predominantly chronic bronchitis:  Younger patient (40-45yrs), milder dyspnoea and plentiful sputum.  Barrel-chested, hypercapnia, hypoxia (respiratory failure).  ‘Blue bloaters’ as compensation is rarer resulting in cyanosis in skin and lips. Complications may include:  Cor pulmonale (right heart failure due to pulmonary hypertension).  Infections don’t usually initiate bronchitis but perpetuate it. Can result in acute infective episodes, causing pneumonia or respiratory failure.  Eventual malignant change in epithelium due to squamous metaplasia.  May lead to Bronchiolitis obliterans Bronchiolitis Obliterans
Mucous plugs are permanently fibrosed which results in complete obliteration of the bronchiolar lumen.

Intermittent, reversible airway obstruction due to enhanced reactivity to a variety of stimuli. Classification: may be extrinsic or intrinsic. Extrinsic Asthmas (70%) are due to IgE and TH2 mediated immune responses.  Atopic (allergic) asthma involves type I (IgE) immune reactions to certain antigens (allergens). Runs in families, begins in childhood, associated with hay fever and eczema.  Occupational asthma also involves type I (IgE) immune reactions; to fumes, organic/chemical dust etc. associated with the workplace.  Allergic bronchiopulmonary aspergillosis is due to aspergillus in airways causing type I and III reaction. Intrinsic Asthmas (30%) are triggered by non-immune, usually idiosyncratic, stimuli.  Non-atopic asthmas are thought to be caused by viral respiratory tract infections, some chronic bronchitis, air pollution, exercise or stress → mechanism unknown.  Pharmacological asthma eg. aspirin may cause asthma due to excessive leukotriene production via inhibition of the cyclooxygenase pathway. Pathogenesis: atopic asthma is caused by IgE mediated immune response to environmental stimuli. 1. Person sensitised to common allergen (eg. dust, pollen, animal hair) via TH2 activation. IL-4, activates IgE production by B cells → specific IgE sensitised mast cells. TH2 IL-5, eosinophil recruitment (priming or sensitisation). IL-13, increased mucous production.

2. Re-exposure results in IgE-mast cell release of mediators (immediate phase, minutes). o Induce bronchospasm, ↑ vascular permeability, mucous production. o Mediator effect can be direct or via neuronal reflexes. 3. Mast cell release recruits additional mediator-releasing cells from blood (late phase, hours). o Eosinophils, neutrophils, basophils and TH2 cells are recruited. o Release LT-C4/D4/E4, PG-D2, PAF, TNF etc. resulting in further inflammation. o Eosinophilic major basic protein A can cause epithelial cell damage and bronchoconstriction. Morphology: histological changes are more diagnostic. Macroscopic changes: patchy hyperinflation of lungs with small areas of atelectasis  Due to occlusion of bronchi/bronchioles by thick mucus plugs. Microscopic changes: mucous plugging of bronchi with airway remodelling*.  Charcot-Leyden crystals; eosinophils and membrane protein form crystalloid collections.  Curschmann spirals; mucus plugs containing shed epithelium in a spiral configuration.  Thickening of bronchial basement membrane*.  Oedema and inflammatory infiltrate in bronchial walls*.  Hypertrophy of mucous glands and smooth muscle in bronchial wall*. Clinical: main difficulty in asthma lies in expiration.  Severe dyspnoea with wheezing upon trigger.  Hyperinflation due to air trapping.  Lasts for hours or more until subsides naturally or with treatment (use bronchodilators or corticosteroids).  Intervals between attacks usually asymptomatic. Outcomes of Asthma
-50% childhood cases resolve, mortality 0.2% p.a. -Status asthmaticus; failure of acute attack to subside for days or weeks. Can cause resp failure and death. -Chronic complications in long standing cases (eg. COPD, pneumonia, cor pulmonale etc.)

Abnormal, permanent dilation of the bronchi and bronchioles due to destruction of their walls. Results in cough and purulent sputum. Caused or predisposed by:  Bronchial obstruction (eg. tumour, foreign body, mucus plugs, asthma/bronchitis).  Infection, esp. if suppurative and virulent pneumonia (eg. S. aureus, klebsiella).  Congenital disorders (eg. cystic fibrosis, Kartagener syndrome, bronchial defects).

Bronchiectasis (with emphysema)

Pathogenesis: requires obstruction and chronic persistent infection, in any order. 1. Obstruction hampers normal clearance, can cause superimposed infection (20), or could have been caused by an infection (10). 2. Chronic infection leads to inflammation, accumulation of secretion and bronchial wall damage. 3. Combination of wall weakening and scar contraction (if necrosis occurs) causes irreversible dilation. Process is exacerbated and repeated during subsequent infections.

Clinical Symptoms are a result of constant infection with dilated bronchi.  Characteristic severe cough with mucopurulent sputum (foul smelling).  Sometimes haemoptysis, cough tends to be paroxysmal on awakening.  Possible dyspnoea, finger clubbing. Complications include lung abscesses, pneumonia, empyema, septic emboli.

Morphology Macroscopic changes: dilation of airways, predominantly in lower lobes.  Purulent material accumulation. Microscopic changes: bronchi are severely inflamed and often ulcerated.  Peribronchiolar fibrosis and lymphoid follicle formation distal to dilation.  Neuroendocrine cells adjacent to scarring.

A group of disorders characterised by decreased lung compliance (ie. stiff lungs).  Result in small lung volumes, TLC and FVC are reduced (↓compliance, hence ↓expansion).  Expiratory flow rate (FEV1) is reduced proportionately or normal, hence [FEV1/FVC] % is normal or slightly increased.

Adult Respiratory Distress Syndrome (ARDS)
Clinical syndrome caused by severe, diffuse lung damage resulting in respiratory insufficiency.  Caused by a variety of stimuli (eg. sepsis, shock, burns, trauma, drugs, toxin inhalation).  Final common pathway of ‘acute diffuse alveolar damage’ Pathology: alveolar membrane damage (epithelial and endothelial) allows fluid, protein, cellular debris to enter alveoli → neutrophils and macrophages damage alveoli further by generating ROS and digestive enzymes as part of the inflammatory process. Histology: alveolar oedema, epithelial necrosis, accumulation of neutrophils, presence of hyaline cartilage in ducts. Clinical: 90% develop ARDS within 72hrs of injury, mortality 60100%. Fibrosis of lung is common in survivors. Neonatal Resp. Distress Syndrome
Occurs in premature infants with surfactant deficiency due to inadequate lecithin synthesis by immature type II pneumocytes. Alveoli collapse with resulting hypoxia → endothelial/epithelial damage → oedema and fibrin exudation → hyaline membrane formation. Increased risks; <2.5kg, <36wks, maternal diabetes, caesarean section.

Fibrosing Diseases
Disorders with diffuse chronic involvement of pulmonary CT, principally in the alveolar wall.  Hallmark of these diseases is reduced compliance → lower capacity and dyspnoea.  Diagnosed clinically or histologically, many have unknown cause. Pathology: all disorders thought to begin with alveolitis. Interactions of inflammatory cells result in parenchymal injury and progressive fibrosis. 1. Lung injury from inhaled agents, dust, blood borne toxins, unknown antigens etc. 2. Activation of macrophages which recruit neutrophils (via IL-8, LT-B4). 3. Macrophages/neutrophils release oxidants and proteases which damage type I pneumocytes. 4. Macrophage and type II pneumocyte cytokines lead to fibroblast proliferation → fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is an interstitial pneumonitis of unknown aetiology which leads to interstitial fibrosis (process above). Also called cytogenic fibrosing alveolitis (CFA).  Histology: patchy interstitial fibrosis with cystic spaces forming honeycomb lung. This pattern is known as usual interstitial pneumonitis (UIP).  Clinical: presents with non-productive cough, progressive dyspnoea and inspiratory crackle. Cyanosis, cor pulmonale and peripheral oedema in later stages (median survival <5yrs).

Other Diffuse Fibrosing Diseases
May have similarities with IPF, but can be distinguished histologically and/or clinically.  Non-specific interstitial pneumonia (NIP) diagnosis of elimination, similar to IPF but without heterogeneity (existence of early and late lesions).  Cryptogenic organising pneumonia (COP) unknown aetiology, polypoid plugs of CT in alveoli and bronchioles.  Acute-, desquamative-, lymphocytic- interstitial pneumonitis (AIP, DIP, LIP).  Pulmonary involvement in CT disorder eg. rheumatoid arthritis, SLE, collagen diseases.

Pneumoconiosis is pulmonary fibrosis due to inhaled particulates, most commonly mineral dust.  Also involve macrophages activating inflammatory response leading to fibrotic change (above).  Can all cause extensive fibrosis with increasing pulmonary dysfunction, pulmonary hypertension and cor pulmonale (PMF).  Smoking increases risk/severity of disease and cancer in all exposure, esp. asbestos.  Classified according to causative particulate (may be organic or non-organic). Coal Workers Pneumoconiosis
Results from repeated exposure to coal. Can range from: → Asymptomatic anthracosis → Simple CWP (coal macules with emphysema) → Progressive massive fibrosis (PMF).

Anthro -Silicosis

Comes in two forms; stiff amphilobe exposure (↑ disease) or serpantile chrysotyle exposure. Exposure is linked with six diseases; (i) Interstitial fibrosis (asbestosis) (ii) Localised fibrous plaques (sometimes pleural) (iii) Pleural effusions (iv) Lung carcinoma (v) Mesothelioma (vi) Laryngeal or colonic carcinoma.

The most common pneumoconiosis in the world, usually due to crystalline silica. Ranges from: → Asymptomatic silicotic nodules → Progressive massive fibrosis (PMF).

Granulomatous Diseases
Sarcoidosis multisystem (disseminated) granulomatous disease that can cause restrictive disease in the lung. Characterised by non-caseating granulomas in many tissues and organs.  Pathology: idiopathic, likely to be disorder of immune regulation. Antigens, including infectious agents, with T cell involvement are hypothesised. Diagnosis of elimination.  Clinical: lung is involved in 90% of patients → granulomas replaced by diffuse interstitial fibrosis (honeycomb lung) in 5-15%. Additional lymphadenopathy, eye involvement and skin lesions. Hypersensitivity Pneumonitis is an immune mediated lung disease that primarily affects alveoli (ie. allergic alveolitis). Restrictive, not obstructive like bronchitic asthma, since in alveoli.  Pathology: caused by exposure to organic dusts and other antigens. Chronic reaction of type IV hypersensitivity.  Clinical: two types, (i) Farmers lung, caused by actinomycetes growing on hay, and (ii) Byssinosis, caused by cotton, linen or hemp exposure.

Pulmonary Oedema
Pulmonary oedema/congestion is the build up fluid and blood in lung tissue. Oedema refers to fluid build up while congestion refers more specifically to blood.  Pathology: initial transudate (↓protein) escapes into the alveolar space → hypoxia increases capillary permeability → exudate (↑protein) then leaks.  Histology: lungs become heavy with frothy fluid from cut surface. Pink staining alveoli due to protein leak (exudate).  Causes: may be passive or active. o Passive causes are due to altered hydrostatic pressure/high blood pressure. Includes LHF (backward failure resulting in ↑ pulmonary BP), renal failure (salt/water overload, hypoproteinaemia) or lymphatic blockage. o Active causes are due to direct microvascular damage. Includes infections, inhaled gas or particulates, drugs, shock or ARDS. Acute Congestion of lung
Acute= emergency, subacute= infection.  Fluid in alveolar space (oedema) prevents inspired air reaching capillary wall → hypoxic damage.  Red cell extravasation → interstitial/ intraalveolar haemorrhage (pink tinged, frothy sputum).  Red cells broken down → haemosiderin laden macrophages (heart failure cells) may be present. NB: predisposes to infection.

Chronic Passive Venous Congestion
Severe LHF, congestion marked most when due to mitral stenosis.  Blood congestion → oedema → same process as acute congestion but over long period.  Haemosiderin laden macrophages become abundant causing fibrous reaction.  Iron laid down on elastic fibres eliciting foreign body giant cell reaction (‘brown induration’ grossly).

Pulmonary Embolism
Venous emboli travel via IVC into right heart, then impact in pulmonary arterial tree.  95% arise from the deep veins of the legs eg. femoral, popliteal.  Can be thrombus (mostly), fat, air, amniotic fluid, tumour, foreign body.  Cause pathological shunting (↓ VA/Q ratio) and increase RV pressure. Pathology: severity depends on level of impaction/type.  60-80% are clinically silent since only small branches affected and fibrinolytic activity eventually dissolving embolism.  10% impact end arteries resulting in infarction; infarction rare in other cases due to bronchial artery and direct alveolar oxygen supply.  5% result in major block (>60% block eg. saddle embolism) causing instant death by reflex vasoconstriction, acute RHF (acute cor pulmonale) or cardiogenic shock.  <3% have multiple, recurrent small emboli → chronic cor pulmonale. NB: 30% of pulmonary embolism sufferers experience recurrences. Clinical: risk factor prevention important.  Prolonged bed rest; leg exercises for the immobilised.  Surgery (esp. lower leg), parturition; early ambulation.  CHF, hypercoagulable state; anticoagulants.
Massive Pulmonary Embolism

Pulmonary Infarction
Deep red in colour at periphery of lung. Wedge shaped and firm. Inflammation of overlying pleura (pleurisy) ± effusion. Healing by fibrosis is rapid, only small scarring.

Paradoxical Emboli
When a patient has foramen ovale/septal defect resulting in emboli passing from right to left side of heart and into systemic circulation.

Pulmonary Hypertension
Classification: is aetiological, split into primary and secondary. Secondary pulmonary hypertension is most common, caused by other disease:  Obstructive/interstitial lung disease: destruction of lung parenchyma/capillaries (↑ resistance).  Pulmonary vascular diseases: reduction in functional vascular bed (↑ resistance) eg. emboli.  Acquired heart disease: increased back pressure from LV damage eg. mitral stenosis.  Congenital heart disease: increased blood flow eg. septal defect, ductus arteriosus. Primary pulmonary hypertension is idiopathic, diagnosis by exclusion of known disease. Pathology: changes leading to hypertension depend on cause. Basic mechanisms include:  Damage to vascular endothelial cells via shear and mechanical stress.  Smooth muscle and ECM hypertrophy from increased growth factors/cytokine production.  Decreased vasodilators and anticoagulants.  Familial mutations uncommon (6% of primary have mutation in BMPR2 receptor). Morphology: vascular alterations involve the whole arterial tree.  Main elastic arteries: atheroma development.  Medium muscular arteries: thickening of muscular wall, smaller lumen.  Smaller arteries/arterioles: medial hypertrophy, thickening of elastic membrane, intimal fibrosis. NB: all increase resistance and progressing hypertension. Plexiform Lesions
Different morphology in primary and shunting hypertensions called plexiform lesions. Vessel wall is thinned and network of capillary like channels replaces part of arterial wall. Fibrinoid necrosis of walls occurs resulting in irreversible hypertension.

Clinical: can develop at any age usually due to underlying pulmonary or cardiac disease.  Symptoms include fatigue, dyspnoea, syncope (esp. during exercise), and cyanosis.  Can result in respiratory failure, RHF (cor pulmonale), pneumonia, embolism and even death.

Community Acquired Pneumonia
Mostly acute bacterial pneumonias that can present as one of two patterns (lobar or bronchopneumonia). Lobar pneumonia: airspaces in a lobe are homogenously filled with exudate consolidation. S. pneumoniae causes 90% of adult cases. Typically evolve through 4 stages that can be altered or halted by antibiotic treatment. 1. Congestion: vascular congestion with proteinaceous fluid, neutrophils and bacteria in alveoli, affected lobes are heavy, red, boggy (24hrs). 2. Red hepatisation: RBCs/ fibrin in alveoli give lobe liver like consistency (solid, airless) (2-4days). 3. Grey hepatisation: lung is dry, grey and firm. Due to red cell lysis, while fibrosuppurative exudate persists in alveoli (4-8days). 4. Resolution: exudates within alveoli are enzymatically digested. Debris is reabsorbed, ingested by macrophages, or coughed up (begins after 8days).
Lobar Pneumonia NB: consolidation = exudate Bronchopneumonia: foci of inflammatory consolidation in patches throughout one or more lobes. combining into a firm dense mass.

    

Most frequently bilateral, affecting basal areas. Intervening areas between isolated consolidation foci are normal. Initial infection centred on bronchi and surrounding alveoli, well developed lesion (3-4cms) → can coalesce in severe cases, producing the appearance of lobar consolidation. Usually secondary infection accompanying other illness (eg. cancer, heart failure, stroke). More common at extremes of age. Lobar vs Bronchopneumonia
The distinction between lobar and bronchopneumonia is blurry because (i) many organisms present with either of the two patterns, and (ii) confluent bronchopneumonia is hard to distinguish from lobar pneumonia. Hence, pneumonias are best classified by either the specific aetiological agent or by the clinical setting in which the infection occurs.

Clinical: abrupt onset with fever, chills, productive chest pain, productive mucopurulent cough, haemoptysis (occasionally).  Lobar: severe fever and rigors, cough with rusty sputum, dyspnoea, possible pleurisy.  Bronchopneumonia: septicaemic, high temperature, crackles at affected areas. Pathogens: S. pneumoniae most common cause, usually via aspiration of pharyngeal flora (oropharyngeal commensal in 20% of adults).  Affects young healthy adults, hence usually 10.  More frequent in those with chronic diseases, immune defects or decreased splenic function.  Gram +ve, lancet shaped diplococci on sputum gram stain. Blood S. Pneumoniae [sputum sample] cultures more specific, as may be commensal flora in sputum sample. Other organisms cause acute pneumonia in particular settings.  H. influenzae, M. catarrhalis; COPD.  S. aureus; usually 20 to viral infections.  K. Pneumonia; chronic alcoholics, diabetics, COPD. S. Pneumoniae [blood sample]  P. aeruginosa; cystic fibrosis, burns patients.  L. pneumophila; organ transplant patients. Complications:  Abscess formation due to tissue destruction and necrosis.  Empyema, suppurative material accumulating in pleural cavity.  Fibrosis of lung tissue, due to organisation of intraalveolar exudate.  Bacteraemic dissemination leading to meningitis, septic arthritis, infective endocarditis. Lung Abscesses
Localised area of suppurative necrosis within the pulmonary parenchyma. Will drain (usually into bronchus) leaving a cavity with a rough ragged wall.  Usually a result of necrotising bacterial pneumonia (S. aureus, S. pyogenes, K. pneumoniae). Additional anaerobic bacteria are almost always present (Prevotella, Bacteroides).  Organisms usually introduced by aspiration (more common on right side).  Clinical: fever, cough, foul smelling sputum, clubbing.  Complications: rupture (pneumothorax and empyema), embolisation to brain (meningitis).

Atypical Community Acquired Pneumonias
Acute non-bacterial infections characterised by patchy inflammatory changes in lungs. “Atypical” due to moderated amounts of sputum, absence of physical findings of consolidation, moderate elevation of WBCs and lack of alveolar exudates. Morphology: patchy, largely confined to the alveolar septa and interstitium.  Affected areas are reddish-blue and congested. Can be whole lobe, unilateral, bilateral.  Septa are widened and oedematous, usually containing a mononuclear infiltrate.  Alveoli spaces are remarkably free of cellular exudate (instead in interstitial space). Pathogens: Mycoplasma pneumoniae (most common), viruses (influenza A/B, RSV, adenovirus, rhinovirus, rubeola, varicella) and Chlamydia spp (pneumoniae, psittaci). Pathogen not known in third of cases. Clinical: acute, nonspecific febrile illness characterised by fever, headache, malaise, cough with minimal sputum.  Course can vary from a severe URTI that goes undiagnosed as pneumonia, or may present as fulminant, life threatening infection in the immunocompromised.  “Walking pneumonia” since lungs with extensive infection may look normal under X-ray.  Septal alveolocapillary block may cause respiratory distress out of proportion to clinical findings.

NB: chronic pneumonia can be suppurative (actinomycetes, nocardiosis), fungal (aspergillus, crytpococcus) or granulomatous (tuberculosis, other mycobacteria, histoplasma). Not necessarily community acquired either.

Nosocomial and Immunocompromised Pneumonia
Nosocomial pneumonias are infections acquired during hospital stay. Common in patients with severe underlying disease, immune suppression, prolonged antibiotic treatment or on mechanical ventilation.  Most common pathogens are Enterobacteriaceae, Pseudomonas spp and S. aureus. Pneumonias in the immunocompromised are caused by opportunistic organisms.  Cytomegalovirus pneumonia is usually serious pneumonitis, which can progress to full blown acute respiratory distress syndrome (ARDS). Typical in organ transplant, AIDS patients.  Pneumocystic pneumonia (PCP); caused by reactivation of P. jiroveci (formally P. carinii). Pneumonia with intra-alveolar exudate that is foamy and pink staining. Typical in AIDS (60% of deaths), severely malnourished infants, chemotherapy.

Non-Infectious Pneumonia
Aspiration pneumonia occurs following aspiration of gastric contents, fluid or food.  Resultant chemical pneumonia (irritant effects) followed by infection.  Overall similar picture to bronchopneumonia  If severe can lead to necrosis, abscess formation and even death.  Often in debilitated patients with abnormal gag and swallowing reflexes (eg. comatose). Lipoid pneumonia is due to obstruction or aspiration of lipid material.  Lipid laden foamy macrophages predominate in inflammatory exudate.  Multinucleate giant cells and interstitial fibrosis.

Bronchial epithelium is the site of origin of carcinomas, causing 95% of primary lung tumours.  Commonest cancer worldwide (18% of cancer deaths), peak incidence in 50s and 60s.  More common among men (3:1), but women are increasingly affected. Pathogenesis: stepwise accumulation of genetic abnormalities resulting in transformation from benign bronchial epithelium to neoplastic tissue.  Large areas of respiratory mucosa are mutagenesed after exposure to carcinogens (eg. smoking) → provides fertile ground for more cellular mutations that lead to cancer.  Genetic changes may include; 3p tumour suppressor deletion, p53 mutations, p16 mutations (NSCLC) and RB mutations (SCLC). Cigarette Smoke and Other Carcinogens
Genetic mutations result from cigarette smoking and other environmental stimuli. Smoking: 90% of lung cancers occur in active smokers, with a linear correlation between lung cancer frequency and pack-years of cigarette smoking (10-20x risk).  Cessation of smoking decreases risk of lung cancer over time.  Females are more susceptible to tobacco carcinogens than men.  Passive smoking increases risk 20%. Other environmental stimuli: asbestos (5-90x risk), radioactive ores, arsenic, chromium, uranium, nickel, vinyl, chloride and mustard gas. Ie. occupational exposure and air pollution.

Morphology: four main histological types that begin as small mucosal lesions. As they develop may undergo cavitation (necrosis), haemorrhage or dissemination. Adenocarcinomas (35%) arise from submucosal glands or epithelium, often preceded by ‘atypical adenomatous hyperplasia’. Usually peripheral tumours (bronchioles/alveoli).  Most cases are smokers, but is commonest type in nonsmokers (also women, <45 groups).  Grow slowly, form smaller masses, but metastasise widely at an earlier stage.  Tumours form well circumscribed, grey-white masses that rarely cavitate.  Histologically classified as acinar, papillary or solid. o Acinar; well differentiated gland forming structures, produce mucin. o Papillary/solid; poorly differentiated, no mucin. Atypical Adenomatous Hyperplasia
Precursor lesion with well demarcated foci of epithelial proliferation, demonstrating cytologic change (pleomorphism).

Broncioalveolar Carcinomas
Subtype of adenocarcinomas, only grow along pre-existing structures and preserve the alveolar architecture.  Mucinous and non-mucinous types.  Can project out into alveolar spaces in papillary formations.  Well differentiated, tall, columnar-cuboidal cells.

Squamous Cell Carcinomas (30%) malignant tumour of squamous epithelium, often preceded by squamous metaplasia/dysplasia. Typically central in major bronchi.  Closely related to cigarette smoking (>90%), hence more common in men than women.  Aggressive local spread to hilar lymph nodes but disseminate outside thorax later than other types. Due to lymphatic > blood spread.  Large lesions are prone to necrosis and cavitation.  Histologically, often well differentiated squamous cells with keratin pearls and intercellular bridges. May be poorly differentiated with minimal features.

Small Cell Carcinomas (25%) neuroendocrine tumours, most often forming centrally located masses.  Rapid growth and early metastasis via lymphatics/blood. Usually metastasised at diagnosis.  Can narrow bronchi by extraluminal tumour bulk (expansion within lung parenchyma).  Ectopic hormone production common resulting in paraneoplastic syndromes.  Histologically, fusiform to round cells approx 2x size of lymphocytes (classic ‘oat cell carcinoma’ presentation). Large Cell Carcinomas (10%) form peripheral, undifferentiated lesions that can become quite large and active. Central or peripheral, poor prognosis.  Lack cytologic features of small cell, glandular or squamous differentiation.  Probably represent squamous cell or adenocarcinomas that are so undifferentiated that they can no longer be recognised by light microscopy.


Squamous Cell Carcinoma

Small Cell Carcinoma

Large Cell Carcinoma

Clinical: staging is by size of the tumour, number of affected nodes, and distant metastases (TNM). Lung cancers are silent, insidious lesions that commonly spread before producing symptoms.  Early stages: can have chronic cough, sputum or haemoptysis before spread due to intrabronchial lesions.  Later stages: of disease can include a wide range of presentations: a) Nonspecific symptoms only; weight loss, anorexia, Intrathoracic Dissemination fatigue, weakness, nausea. Intrathoracic spread can cause: b) Intrathoracic spread; invasion/compression of o Apical neoplasms that invade the brachial nerves can cause related symptoms, can also (ulnar nerve pain) or cervical (Horner’s obstruct blood vessels or oesophagus. syndrome) sympathetic plexuses. Known as c) Extrathoracic spread; to lymph nodes (mediastinal, ‘Pancoast syndrome’. clavicular, scalene, Virchow’s nodes), liver, brain, o Phrenic nerve → diaphragmatic damage. adrenal and bone metastases (most common). o Recurrent laryngeal nerve → hoarseness. o Obstruction in SVC → dilation of head/neck d) Paraneoplastic syndromes; systemic syndromes veins, facial swelling, cyanosis. due to ectopic substance (hormone, cytokine) o Oesophageal obstruction → dysphagia. production. Occurs in 3-10% of lung carcinomas. Paraneoplastic Syndromes
Ectopic hormone production can cause: o Hypercalcaemia; PTH secretion (most common in squamous cell carcinomas). o Cushing syndrome; ACTH production leading to ↑ cortisol from adrenals. o Syndrome of inappropriate ADH (SIADH) secretion, resulting in fluid overload. o Neuromuscular syndromes; myasthenia, peripheral neuropathy, poliomyelitis. o Haematologic/vascular syndromes; anaemia, coagulopathy, DIC, non infectious endocarditis, embolism (most common with adenocarcinomas). o Dermatologic signs; dermatomyositis, hyperpigmentation, acanthosis nigricans. o Skeletal /CT syndromes; hypertrophic pulmonary osteoarthropathy. NB: apart from hypercalcaemia and haematologic syndromes, most are more common with SCLCs

Treatment: practically split into SCLC/NSCLC for treatment distinctions. 5 year survival around 15%.  Small Cell Lung Cancers (SMLC) have all metastasised by the time of diagnosis, hence not curable by surgery, and best treated with chemotherapy ± radiotherapy. o Median survival with treatment is 1 year.  Non-Small Cell Lung Cancers (NSCLC) respond poorly to chemotherapy, better treated with surgery (lobectomy or pneumonectomy) if detected before spread. Better prognosis than SCLCs. o At diagnosis, 75% have metastasised, inoperable. o Includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Other Pulmonary Tumours
Remaining 5% primary lung tumours consist of carcinoids, mesenchymal malignancies, lymphomas and some benign lesions. Secondary lung tumours are much more common. Carcinoids arise from neuroendocrine (Kulchitsky) cells that line bronchial mucosa. Contain dense neurosecretory granules but rarely release hormonally active peptides.  Slow growing malignant tumours that rarely Typical Carcinoid; small rounded cells with metastasis (<10%). diffuse chromatin granules, absent/rare mitoses,  Either obstructs lumen or penetrates bronchiolar little pleomorphism. 80% 10yr survival. wall, can be central or peripheral. Atypical Carcinoid; higher mitotic rate, increased  Histologically, can be typical or atypical. pleomorphism, necrosis. 50% 5 yr survival.  Affects genders similarly, often <40 yrs. Malignant Mesotheliomas rare cancer of mesothelial cells usually arising in parietal or visceral pleura.  Cause: related to asbestos exposure (not smoking) with long latent period (25-40yrs). Asbestos not removed/metabolised → generates ROS → DNA damage → oncogenic mutations.  Morphology: diffuse lesion, invasion of thoracic structures. Lung is encased by thick layer of grey-pink tumour. Epithelial, sarcomatoid and biphasic histological types.  Clinical: chest pain, dyspnoea, pleural effusion. Prognosis is poor (12-14mnths). Secondary Lung Cancers result from blood-borne metastasis of tumours from other sites. Most often from breast, colon, stomach, pancreas, kidney (in relative order).

Upper Respiratory Tract Tumours don’t bother
Nose and Sinus Tumours Benign: haemangioma, squamous papilloma, juvenile angiofibroma, inflammatory polyps. Malignant (sinonasal carcinoma): SCC, transitional, adenocarcinoma Other: salivary, melanoma, lymphoma

Squamous carcinoma with lymphoid infiltrate o Leading cause of death in SE Asia Nasopharyngeal o Associated with EBV, other genetic and environmental links. Carcinoma o Keratinising (worse) and non-keratinising forms. o Metastasise to LN, can stimulate large cell carcinoma. Laryngeal Tumours Benign: papilloma (HPV), cysts, laryngeal nodules, amyloidosis. Malignant: squamous cell carcinoma (SCC) most common. o 2% of all male cancers, associated with smoking, alcohol o Glottic, trans-, supra- and infra- glottic forms


Liver functions include:  Filtering blood.  Detoxification.  Metabolism of nutrients, production of bile.  Protein manufacturing. When the liver dysfunctions, pathology include:  Abnormal filter: portal hypertension (esophageal varices, ascites).  Abnormal detoxification: hepatic failure (encephalopathy, multi-organ failure, death).  Abnormal gastrointestinal function: malabsorption.  Abnormal protein manufacturing: bleeding disorders, oedema, ascites.

Hepatic Investigations
 Liver Function Tests o Enzymes: hepatocellular (AST/ALT) and cholagiocellular (GGT/Alk Ph) o Bilirubin o Synthetic function (albumin and prothrombin)  Infective agents HAV, HBV, HCV, delta virus etc o Antibodies to the virus or PCR for viral DNA/RNA  Serology: auto-immune markers antiMA, antiSmM, antiDNA  Tumour marker: alpha feto protein (levels may go up with hepatocellular carcinoma)  Imaging: Xray, Ultrasound, CT scan, MRI  ERCP cholangiogram, MRI cholangiogram, PTC  Fine Needle Aspiration  Liver biopsy histology: diagnosis and grading/staging of disease  Iron and copper studies

Clinical Syndromes
Jaundice (Icterus) is excess bilirubin accumulation in the skin and sclerae, producing a yellow discolouration of these tissues. Bilirubin is the end product of haem degradation and is in excess when >2mg/dl (hyperbilirubinaemia).  Unconjugated bilirubin has not yet been made soluble by liver. Jaundice Hereditary Usually due to excessive haemolysis (haemolytic jaundice). Can be Syndromes due to ↓hepatic uptake or impaired conjugation. Not excreted in Dubin-Johnson Syndrome kidneys, stool still contains pigment (no obstruction). impaired transport of anions.  Conjugated bilirubin is soluble due to conjugation with glucoronic Gilber Syndrome- relatively common mild conjucgation acid. Usually due to impaired bile flow (obstructive jaundice). Can be disorder. due to hepatocellular damage. Dark urine (soluble so excreted in kidneys), stool is pale as no pigments can reach intestine. Cirrhosis is a consequence of chronic hepatocellular injury, associated with diffuse fibrosis and nodular regeneration of the liver. Is usually either alcohol, inflammatory/necrosis, biliary or haemochromatosis related cirrhosis. Cirrhosis can result from chronic infection, chronic drug reactions, autoimmune reactions, and metabolic abnormalities. Clinical features include:  Portal Hypertension → ascites (fluid accumulation in the peritoneal cavity), portocaval shunts forming haemorrhoids, oesophageal varices (can cause haematemesis), periumbilical (caput medusa) and retroperitoneal dilations, splenomegaly.  Impaired Oestrogen Metabolism → gynaecomastia, spider naevi, palmar erythema.  Other features: dupuytren’s contracture, hypoalbuminemia (peripheral oedema), decreased clotting factor synthesis (bleeding diathesis), hepatic encephalopathy. Post-Necrotic Cirrhosis
Is associated with the formation of macronodules composed of regenerating hepatocytes separated by fibrous scars and an inflammatory infiltrate. Most cases are secondary to chronic active viral hepatitis, others are due to exposure to hepatotoxins or autoimmune disorders (eg. lupoid).

Cirrhosis with Portal Thrombosis

Hepatic Failure is due to sustained hepatic damage (loss of function of 80-90% of liver cells).  Caused by acute or chronic hepatic disease (eg. chronic hepatitis or alcoholic cirrhosis).  Clinical presentation varies greatly; jaundice, fetor hepaticus, encephalopathy, renal failure (hepatorenal syndrome), palmar erythema, spider naevi, gynaecomastia (impaired oestrogen degradation), prolonged prothrombin time (impaired synthesis of coagulation factors), weight loss, muscle wasting, malabsorption, anaemia.

Inflammation of the liver which can be acute (lasts less than 6 months) or chronic (lasts more than 6 months). It can be caused by infectious agents, toxins (eg: alcohol), or autoimmune reactions. Acute Viral Hepatitis is viral induced inflammation of the liver which usually lasts 4-6 weeks.  Pathogens: associated with infection by Hepatitis Viruses A-E. o HAV: a self limiting hepatitis. Fecal-oral transmission. o HBV: can cause acute or chronic hepatitis. Associated with hepatocellular carcinoma (200x increased risk). Parental or sexual transmission. o HCV: most progress to chronic hepatitis, and is associated with hepatocellular carcinoma. Transmission via blood. o HDV: in associated with HBV. Parental and sexual transmission. o HEV: a self limiting hepatitis. Fecal-oral transmission.  Morphology: enlarged liver with tense capsule. Microscopically involves coagulative necrosis of liver cells with increased eosinophilia.  Clinical: symptoms include U/A pain, hepatomegaly, jaundice, malaise, anorexia, fever, nausea. o Blood test: elevated serum bilirubin (if icteric), elevated transaminases (ASL/ATL) and alkaline phosphatate. Serology tests for specific viruses/antibodies.
Other Inflammatory/Infectious Diseases Pyogenic Liver Abscess The formation of abscesses commonly involves infection with E.coli, Klebsiella, Streptococcus, Staphylococcus, Pseudomonas, and Fungi. Abscess formation can result from either:  Ascending cholangitis (inflammation of bile ducts, most common cause).  Seeding of the liver due to bacteraemia. Parasitic Infections  Schistosomiasis: associated with the formation of giant cell granulomas in the liver parenchyma surrounding the ova of parasites. This inflammatory process leads to diffuse fibrosis and nodular regeneration.  Amebiasis: caused by Entamoeba histolytica.

Multiple Hepatic Abscesses

Amoebic Abscess

Chronic Hepatitis is chronic inflammation of the liver associated with hepatocyte destruction, cirrhosis and liver failure. It is more likely to occur in the very young, very old, males, immunocompromised, and dialysis patients.  Pathology: characterised by portal infiltrate, necrosis and fibrosis. o Excessive portal lymphocytic infiltrate that spreads to adjacent parenchyma. o Piecemeal necrosis: a condensation, fragmentation and phagocytosis of hepatocytes. o Bridging necrosis: destruction of adjacent hepatocyte lobules. o Progressive fibrosis → cirrhosis.  Causes: HBV, HCV, HDV, drug toxicity, alcohol and autoimmune reactions.

Fulminant Hepatitis involves massive hepatic necrosis, progressive hepatic dysfunction and acute liver failure (mortality 25-90%).  Cause: hepatitis viruses (A-E), carbon tetrachloride, chloroform, other drugs.  Morphology: progressive shrinkage of the liver as parenchyma is destroyed. Histologically get coagulation necrosis followed by liquefactive necrosis → macronodular cirrhosis (if patient survives).

Alcoholic/Drug Induced Liver Disease
Fatty Liver (Steatosis) is a reversible asymptomatic condition resulting from alcoholism. It is an abnormal accumulation of lipids in cells, resulting in a yellow, greasy, enlarged liver.  Pathogenesis: the metabolic breakdown of ethanol produces energy in the form of NADH → inhibits β-oxidation (breakdown) of fatty acids and increase fatty acid synthesis → steatosis.  Histology: fatty vacuoles displacing hepatocellular nuclei in periphery, Steatosis swollen mitochondria and endoplasmic reticulum. NB: steatosis → steatohepatitis (alcoholic hepatitis) → cirrhosis → liver failure. Alcoholic Hepatitis is inflammation of the liver resulting from prolonged alcohol abuse, characterised by swelling of hepatocytes.  Followed by necrosis and polymorphonuclear inflammation, formation of alcoholic hyaline (Mallory bodies) in swollen hepatocytes, cholestasis, and the beginning of fibrosis. Alcoholic Cirrhosis fibrous tissue replaces fatty swelling, resulting in nodule formation.  Early stages of disease: enlarged liver with micronodular formation.  Later stages: small, macronodular liver with a ‘hobnail’ appearance on its surface. Drug Induced Liver Damage

Different drugs can damage liver cells through different mechanisms: 1) Hepatotoxins (carbon tetrachloride, methotrexIschaemic Atrophy: due to atherosclerosis of pancreatic arteries, usually asymptomatic. 2) Obstruction of pancreatic duct: affects only exocrine pancreas, which becomes small, fibrous and nodular. Haemodynamic and Vascular Abnormalities  ate, anabolic steroids). Portal Hypertension is increased resistance to portal blood flow that may  Hypersensitivity (drugs can act as haptens). develop form pre-, intra- or post- hepatic causes. Most dominant cause is  Metabolic response to drugs (paracetamol, cirrhosis (intrahepatic). May manifest as ascites (fluid/lymph in peritoneal phenothiazines, methyldopa, halothane).

cavity), splenomegaly, oesophageal varices and/or hepatic encephalopathy.

Passive Congestion and Central Necrosis are associated with right heart failure, characterised by congestion of central veins and centrilobular hepatic sinusoids (‘nutmeg liver’). Clinically manifests as milf hepatomegaly, a pulsatile liver tender to palpation. Atrophy and necrosis are secondary to hypoxia and hypoperfusion. Liver Infarcts are rare due to double blood supply to the liver. Interuption of the main hepatic artery can be compensated by retrograde accessory vessels and the portal venous system.

Hepatic-Biliary Tract Disorders
Cholestasis is inability of bile to flow from the liver to the duodenum. Results in retention of bilirubin, bile acids and cholesterol. Hence get pale stools, dark urine, itching, increased serum lipids.  Intrahepatic causes: hepatocellular cholestasis seen in viral hepatitis, cirrhosis, drug toxicity.  Extrahepatic causes: gallstones, cholangitis, cancer of bile ducts and head of the pancreas. Cholangitis is inflammation of the bile ducts. Usually associated with biliary duct obstruction (gall stones, carcinoma), which leads to infection with enteric organisms → purulent exudation within the bile ducts, bile stasis. Clinically manifests as jaundice, fever and upper right quadrant pain (“Charcot Triad”). Biliary Cirrhosis is the inflammation and fibrosis of bile ducts.  Primary Biliary Cirrhosis: results from an autoimmune reaction with anti-mitochondrial antibodies, can cause sclerosing cholangitis (below). Early stages of disease involve inflammation around small portal bile ducts. Late stages involve fibrosis causing small bile ducts to disappear. There is a female predominance (middle aged).  Sclerosing Cholangitis: a chronic fibrosing inflammatory disease of extrahepatic and larger intrahepatic bile ducts. Progressive stenosis of larger bile ducts → secondary biliary cirrhosis. This condition predisposes individuals to cholangiocarcinoma. Secondary Biliary Cirrhosis: caused by longstanding large bile duct obstruction → stasis of bile → inflammation, infection and scarring. It presents with jaundice. Histologically, there is dilation of larger bile ducts ± inflammation.

Metabolic Liver Disease
Haemochromatosis an autosomal recessive disorder characterised by excessive absorption of iron. Is the result of uncontrolled gut transporters.  Iron is stored as ferritin, excess ferritin accumulates as haemosiderin (yellow-brown). Deposits occur in the liver, pancreas, heart and other organs.  Haemosiderin accumulates over decades resulting in haemochromatosis with multiorgan dysfunction. It causes micronodular cirrhosis and ‘brick red’ pigmentation of the liver.  ↑ Hepatocellular carcinoma risk, treatment by phlebotomy.

Haemochromatosis of Liver

Wilson’s Disease (hepatolenticular degeneration) autosomal recessive disease, characterised by inadequate hepatic excretion of copper. Is due to mutations in Wilson’s disease protein (ATP7B) gene.  Causes hepatitis or macronodular cirrhosis, degenerative changes in the lenticular nuclei of the brain, and deposition of copper in the corneal limbus (Kayser-Fleischer rings).  Associated with increased risk of hepatocellular carcinoma. Other metabolic disorders include non-alcoholic fatty liver disease (acquired), α1-antitrypsin deficiency (see pulmonary section), cystic fibrosis, neonatal cholestasis and Reye syndrome.

Hepatic Tumours
Benign Tumours: may be asymptomatic (incidental finding on imaging), a palpable mass, cause liver dysfunction due to mass effect, or occasionally haemorrhage or rupture.  Include nodular hyperplasia, hepatocellular adenoma, haemangioma, bile duct adenomas and cysts.


Hepato- Adenoma

Malignant Tumours: most commonly secondary metastases, but primary tumours do occur.  Metastatic Tumours are much more common than primary neoplasms, most commonly arising from the breast, lung and colon. Characterised by multiple, well circumscribed nodules in a markedly enlarged liver. Hepatocellular Carcinoma cancer of hepatocytes, causing 90% of primary liver neoplasms. Associated with cirrhosis, HBV infection, anabolic steroids, and aflatoxin B (fungal toxin). o Causes liver enlargement (unifocal, multifocal, or infiltrative). o Often bile strained and invades vessels. Metastases generally first occurs in the lungs. o Alpha-feto protein present in 50-90% of patient’s serum. o Death due to GI bleed or hepatic failure. Hepatoblastoma a rare, malignant neoplasm in children and infants. Composed of epithelial and/or mesenchymal tissue. Mixed type often shows calcification. Angiosarcoma malignant neoplasm of vascular stromal tissue. It is associated with exposure to vinyl chloride and arsenic. Tumours produce spongy, haemorrhagic nodules.

Multiple Metastatic Tumours

Hepato- Carcinoma

Cholelithiasis (Gall Stones)
Gall stones can result from (i) supersaturation of bile pigment or cholesterol, and/or (ii) decreased amounts of phospholipid or bile salts, in the gall bladder. Classification: based on composition of the stones.  Cholesterol Stones pure cholesterol stones are radiolucent, solitary, yellow and smooth (1-5cm). o A typical patient is fat, female, fertile, over forty years of age (4 F’s) o Exogenous oestrogens, high calorie diet, clofibrate, obesity, diabetes, pregnancy, celiac disease and increasing age all predispose to cholesterol stones. Mixed Cholelithiasis  Pigment Stones small, black, multiple, radiolucent clumps of pigment. Derived (mostly pigment) from unconjugated bilirubin. Associated with chronic (not acute) haemolytic disease (eg. hereditary spherocytosis).  Mixed Stones comprises 80% of all stones and are associated with chronic cholecystitis. o Composed of cholesterol and calcium bilirubinate. o Composition determines colour (yellow → black). o Those with high calcium are radiopaque. Clinical: most stones remain in the gall bladder and are asymptomatic. Obstruction of:  The gall bladder or cystic duct → biliary colic, acute cholecystitis, and mucocele formation.  Common bile duct → obstructive jaundice, ascending cholangitis.  Ampulla of Vater (→ pancreatitis) or distal small bowel (→ gallstone ileus).

Acute Calculous Cholecystitis is inflammation of the gall bladder, caused by obstruction of the gallbladder neck/cystic duct by gallstones. Calculus obstruction is followed by secondary bacterial infection in 75% of cases, and by chemical irritation.  Morphology: enlarged, erythematous and tense gall bladder. Thickened wall Acute Calculous with oedema and fibrosis. Microscopically, has acute inflammatory infiltrate Cholecystitis with mucosal ulceration, erosion and necrosis/haemorrhage.  Clinical: typically acute onset upper right quadrant pain, fever, tenderness and leukocytosis. Most resolve with medical management.  Complications: secondary bacterial infection. Can progress to empyema (lumen filled with pus), gangrenous necrosis, or rupture. These cases require cholecystectomy. Acute Non-Calculous Cholecystitis cholecystitis without gallstones. It is associated with congenital anomalies, diabetes, infections, polyarteritis nordosa, burns, trauma and surgery. Chronic Cholecystitis is chronic inflammation of the gallbladder of unknown aetiology. It is probably due to chemical injury from supersaturated bile, and not due to irritation by stones.  Gallbladder wall is thickened by fibrosis.  Rokitansky-Aschoff’ sinuses; penetrations of the mucosa through the muscularis, with chronic inflammation.

Gallbladder Tumours
Benign Tumours: Papillomas, Adenenomas and Adenomyomas. Malignant Tumours: typically adenocarcinomas with variable differentiation. Usually asymptomatic adenocarcinomas until advanced stages, poor prognosis (3% 5 yr survival).  Gallbladder Carcinoma rare tumours, typically involve the fundus and neck of the gallbladder. o Risk factors include cholelithiasis, cholecystitis, and porcelain gallbladder (due to calcium deposition in the wall). o Serum alpha feto protein raised in 60-75% of cases. o Pre-metastatic diagnosis depends on detection of co-existent Gallbladder Carcinoma abnormalities eg. gallstones.  Cholangiocarcinoma adenocarcinoma of the bile ducts, either extra or intra hepatic. Tumours are usually small, with papillary, fungating, nodular, or infiltrative lesions. o Often presents with obstructive jaundice, upper right quadrant pain and sometimes symptoms of pancreatitis due to obstruction of the pancreatic duct. o Half metastasise via ducts/lymph/blood to lungs, bones, adrenals and brain. o Associated with primary sclerosing cholangitis, liver fluke infection.

Acute Pancreatitis

[Note: disorders of endocrine pancreas discussed in Endocrine Pathology]

Diffuse necrosis of the pancreas caused by the release of activated pancreatic enzymes. It is associated with alcoholism and biliary tract disease. Pathology: there are four theories describing its pathogenesis:  Obstruction of the pancreatic duct causes ↑ intraductal pressure → leakage of enzymes from the ducts (eg. gallstones at Ampulla of Vater or oedema due to chronic alcohol ingestion).  Hypercalcaemia may cause activation of trypsinogen (unclear mechanism).  Direct damage to acinar cells (eg. trauma, ischaemia, viruses, drugs)  Hyperlipidaemia Morphology: grey (parenchyma destruction), yellow/white (fat necrosis) and red (haemorrhage) areas.  Proteolysis of parenchyma → necrosis of acini with surrounding inflammatory infiltrate.  Necrosis of fat by lipases → FA combine with calcium to form insoluble white salts.  Destruction of blood vessels → haemorrhage with Acute Pancreatitis microvascular leakage (oedema). Clinical: full-blown acute pancreatitis is a medical emergency.  Symptoms: painful rigid abdomen radiating to upper back due to digestive enzymes. DIC, shock and multiorgan failure due to response (inflammatory, clotting).  Signs: ‘Grey Turner Sign’ (bluish discolouration of the flanks) and the ‘Cullen Sign’ (periumbilical discolouration) indicate extensive damage.  Treatment: supportive, no oral intake, nasogastric suction, IV fluids.  Complications: infection, abscess formation, pseudocysts and obstruction of the duodenum.

These lesions are sequelae of pancreatitis or trauma, formed by the localisation of fluid which can be suppurative, haemorrhagic, or necrotic debris.  Usually 5-10cm in diameter with fibrous capsule, but no epithelial lining.  Present as abdominal mass, often with pain  Rupture causes peritonitis.

Chronic Pancreatitis
This condition involves remitting and relapsing episodes of mild pancreatitis, causing progressive pancreatic damage. Pathology: is unclear, possibly, excess protein secretion by the pancreas leads to ductal obstruction.  Chronic Calcifying Pancreatitis (associated with alcoholism): hardened organ with multiple calcifications. Involves acinar atrophy, fibrous and inflammation in a lobar distribution. Occasional squamous metaplasia of ductal epithelium.  Chronic Obstructive Pancreatitis (associated with gallstones): lesions more common in the head of the pancreas, with no lobular distribution. Clinical: manifests with upper abdominal pain, fever and jaundice. Calcification of pancreas presents on X-ray. May result in pseudocyst formation, diabetes or steatorrhea.
Chronic Calcifying Pancreatitis

Pancreatic Carcinoma
Pathology: most are adenocarcinomas arising in the ductal epithelium. Associated with smoking, high fat diet and chemical exposure.  Carcinomas of the head (60%): produce small, white, fibrous, infiltrating lesions. Frequently invade the wall of the common bile duct → obstructive jaundice and ductal spread.  Carcinoma of the body (20%) and tail (5%): produce large, hard Carcinoma of pancreas, masses that spread widely to the liver and regional lymph nodes. spread to humerus  Diffuse pancreatic carcinoma (5%) Clinical: usually asymptomatic until late in its course, prognosis very poor.  If resectable, <5% 5yr survival, death usually within 6 months of symptoms.  Jaundice in half with carcinomas of head of pancreas. Painless jaundice with a palpable gall bladder is suggestive of pancreatic cancer. Cystic Fibrosis in Pancreas
This is an autosomal recessive systemic disorder of exocrine gland secretion, associated with a defect in the Cystic Fibrosis Transporter Gene (CFTG) on Ch 7. Defective chloride channels → secretion of very thick mucus → mucous plugging of the pancreatic ducts → cystic dilations, fibrous proliferation and obstructive atrophy of the pancreas.

Pancreatic Atrophy
 Ischaemic Atrophy: due to atherosclerosis of pancreatic

arteries, usually asymptomatic.  Obstruction of pancreatic duct: affects only exocrine pancreas, which becomes small, fibrous and nodular.


Non-Neoplastic Disorders
Various problems include: • Infections – HSV, candida • Inflammation – glossitis, xerostoma, aphthous ulcers • Leukoplakia • Odontogenic cysts and tumours • Calculi in salivary ducts

Mouth Tumours
Squamous cell carcinoma (SCC) is the most common malignant tumour of the oral cavity involving the tongue, floor of mouth, palate and buccal mucosa (lower lip is the most common site). Lesions can be papillary or ulcerative. Peak incidence is 40-70. Predisposing factors include: 1. Physical and chemical irritants: chewing and smoking tobacco products, alcohol abuse, chewing betel nuts, UV radiation, poor oral hygiene. 2. Iron deficiency in the form of Plummer-Vinson syndrome with angular stomatitis. 3. Infection with certain strains of Human Papilloma Virus. The precursor lesion has dysplasia which progresses to Squamous Cell Carcinoma In-Situ, and then to invasive SCC. Precursor lesions present as white or red thickenings/plaques called leukoplakia with atypia (although leukoplakia can also be simple hyperplasia without atypia. Invasive carcinoma has variable differentiation, with poorly differentiated tumours being more infiltrative and metastasize to regional lymph nodes. Treatment: complete excision of tumour ± removal of regional lymph nodes ± radiation therapy,

Salivary Gland Tumours
Tumours can arise in the parotid, submandibular and submental glands (including other minor glands, although most involve the parotid glands (75%). Can be benign (parotid) or malignant (mostly submandibular and sublingual), arising from epithelial and stromal elements. Pleomorphic adenoma (most common) is a benign neoplasm composed of glandular and stromal elements. • Arises in superficial love of parotid as a slow growing painless smooth mass • More commonly in the middle aged and women • Diagnosis made by Fine Needle Aspiration cytology • Treatment is by surgery which is usually curative as long as an adequate clear margin is obtained. “Shelling out” the tumour usually leaves behind small extentions of tumour which will recur. • Complications due to cranial nerve VII (facial nerve) involvement (bell’s palsy). • Occasionally undergo malignant transformation, usually to a carcinoma. Mucoepidermoid, Adenoid cystic and Acinic Cell Carcinoma are malignant epithelial tumours, associated with rapid growth and acute onset of pain due to nerve involvement. Local invasion, particular along nerves. Metastasize to regional lymph nodes and beyond. They show characteristic cytological and histological features enabling diagnosis. Prognosis depends on the grade and stage of the tumour and adequacy of excision.


Various problems include: • Congenital - tracheo-oesophageal fistula, achalasia • Infection – HSV, candida • Varices secondary to liver cirrhosis

Reflux Oesophagitis (Gastro-oesophageal reflux disease or GORD) A condition associated with chronic symptoms or mucosal damage produced by abnormal reflux of gastric content into the esophagus. This can be due to a defective gastroesophageal sphincter, transient gastroesophageal sphincter relaxation, impaired removal of gastric reflux, pr a hiatus hernia. This can result in persistent reflux (mild, moderate or severe) causing: • Inflammation • Hyperplasia of the squamous epithelial lining and • Erosion/ulceration of the epithelium Complications of reflux oesophagitis include: 1. Barrett's oesophagus, dysplasia and malignancy (see below). 2. Stricture (due to fibrosis) 3. Perforation (due to erosion) Barrett’s Oesophagus
Barrett's oesophagus is generally defined as intestinal metaplasia (the replacement of one adult cell type by another adult or mature cell) of the squamous epithelium lining the oesophagus. This process is reversible, and represents adaptive substitution of squamous epithelial cells that are sensitive to stress (ie: acid reflux) by secretory columnar epithelium with Goblet cells that are more stress resistant. In some patients, Barrett's oesophagus progresses through low and high grade dysplasia to adenocarcinoma. Dysplasia: A premalignant state involving disordered cell characteristics or abnormal cell growth. This usually occurs in epithelium and is characterised by cytological (pleomorphism, enlarged hyperchromatic nuclei, abnormal mitotic activity) and/or architectural changes (loss of nuclear polarity, nuclear stratification, gland crowding and cribiform arrangements). Regular surveillance by endoscopy and biopsy is recommended for patients with Barrett's oesophagus. Patients with low grade dysplasia are followed by short interval surveillance and treated with acid suppressing agents. The finding of high grade dysplasia is an indication for oesophagectomy. .

Corrosive Oesophagitis Caused by ingestion of acid or alkaline material. This leads to mucosal injury of the mouth, pharynx, oesophagus and stomach. Severity is dose dependent and in severe forms leads to full thickness mucosal necrosis, ulceration and even perforation. It heals by fibrous stricture formation. Infectious Oesophagitis Rare in immunocompetent individuals, but is more common in the immunocompromised (eg: AIDS and transplant patients). Common infectious agents include: 1. Candida species – colonise the squamous epithelium, giving rise to white plaques and hyperkeratosis with an inflammatory infiltrate. 2. Herpes Simplex Virus – infects squamous epithelial cells resulting in blisters and superficial ulcers. Infected cells are typically multinucleated with intranuclear viral inclusions which have a glassy basophilic appearance.

3. Cytomegalovirus (CMV-. Infects both endothelial and squamous epithelial cells. Infected cells appear enlarged with prominent intranuclear inclusions, with or without basophilic intracytoplasmic inclusions.

Oesophageal Tumours
• • • • • Commonly occurs after the age of 50, male incidence 3x greater. Clinical features include dysphagia, retrosternal pain, anorexia, weight loss, melena, systemic symptoms of metastases. Locations: 50% middle third of esophagus, 30% lower and 20% upper. Prognosis generally poor , with the average 5 year survival being less than 10% due to late diagnosis. Common sites of metastases include the liver and lungs.

Oesophageal Squamous Cell Carcinoma Squamous cell carcinoma is most common worldwide but its incidence is decreasing in western countries. Iran, Central China and South Africa have the highest incidence. Blacks are at higher risk than whites. Adenocarcinoma is showing comparable incidence rate. Aetiology: involves a combination of dietary, genetic and environmental factors: • Dietary factors: vitamin deficiencies (Vit A, C, Thiamine etc), deficiencies in trace elements (zinc) and fungal contamination of food. • Life style: Smoking and tobacco use, alcohol, hot beverages • Oesophageal disorders: long standing oesophagitis, Plummer-Vinson syndrome, achalasia • Racial and genetic predisposition: coeliac disease, ectodermal dysplasia Oesophageal adenocarcinoma Usually arises in the distal oesophagus is often reflux induced. • Acid reflux causes intestinal metaplasia (Barrett’s oesophagus) • Further genetic alteration of the metaplastic mucosa may lead to low-grade dysplasia, high-grade dysplasia and in-situ and invasive carcinoma The life time risk of developing adenocarcinoma from Barrett's oesophagus is approximately 10%.

Various problems include: • Menetriers disease • Pernicious anaemia/ atrophic gastritis • Pyloric stenosis (congenital)

Acute Gastritis (acute gastric ulceration, erosive gastritis). These lesions are complications of NSAIDs or severe physiological stress (eg. severe trauma/head injury, burns, shock, sepsis).

Pathogenesis: poorly understood, but is associated with decreased prostaglandins, acid hypersecretion (vagal nerve stimulation), impaired oxygenation secondary to vasoconstriction and systemic acidosis. Morphology:  Macroscopic: Multiple, small (<1cm), round, superficial defects with a blood stained base. Adjacent mucosa is normal with no thickening or scarring.  Microscopic: Superficial erosion of surface epithelium which may extend deeper to become full thickness mucosal ulceration. Chronic Gastritis (Helicobacter Gastritis) Chronic gastritis is associated with infection of the stomach by the bacillus Helicobacter Pylori. The organism is a curvi-linear gram negative rod measuring 3.5 x 0.5um. It is transmitted by oral-faecal, oral-oral and environmental spread. The prevalence of Helicobacter infection is very high and in some countries reaches 80% of adult population. The infection is usually acquired during childhood and persists for decades. In Australia, 20% are infected by age 30, and 50% are affected at age 60. Symptoms: most people have no symptoms. • Symptoms include indigestion, abdominal pain, nausea, bloating and burping. • At the time of initial infection there may be acute symptoms of nausea, vomiting and indigestion. • Later, when the inflammation becomes chronic, symptoms may be mild or nonexistent. • Symptoms usually disappear if the infection is successfully treated. Pathology: H.pylori is able to withstand the acidic gastric environment due to: • Flagella enabling motility through viscous mucous • Production of urease which breaks down urea (which is normally secreted into the stomach) to carbon dioxide and ammonia (which neutralizes gastric acid). • Expression of bacterial adhesins that allow the organism to bind to cells bearing blood group O antigen. • Expression of bacteria toxins. H. pylori damages gastric epithelial cells via the production of ammonia, proteases, vacuolating cytotoxin A (VacA) and phospholipases. Gastric and Duodenal Ulcers (Peptic Ulcer Disease)
Peptic ulcers are deep mucosal lesions occuring within the duodenal or gastric mucosa that is exposed to gastric acid. This is caused when there is imbalance between mucosal defence mechanisms and the damaging forces (NB: hyperacidity is not a pre-requisite for peptic ulceration). Helicobacter infection is a major factor in the pathogenesis of peptic ulcer disease and is present in almost all duodenal ulcers and up to 70% of gastric ulcers.  The majority of duodenal ulcers occur in the proximal region of the duodenum  Gastric ulcers often occur in the lesser curvature and around the transition zone between antrum and body. Complications include bleeding, perforation and stricture formation/obstruction.

Complications: gastric and duodenal ulcers, gastric carcinoma, gastric lymphoma. Treatment: combination of antibiotics and suppression of gastric acid production (via Proton Pump Inhibitors) • Omeprazole 20mg twice/day • Amoxacillin 1000mg twice/day • Clarithromycin 500mg twice/day

Gastric Tumours
Gastric Adenocarcinoma (>90%) Most common primary malignancy in the stomach (90-95%). 50% arise in the antrum and pylorus, 25% in the gastric cardia. Metastases is frequently present at the time of diagnoses (symptoms develop late). Very high

incidence in Japan, Chile, China and Russia, with relatively lower incidence include Australia, New Zealand, US, UK, and Canada. Predisposing factors: • Helicobacter infection causing chronic gastritis, gland atrophy and intestinal metaplasia. This may evolve to dysplasia and carcinoma. • Autoimmune gastritis, which often is associated with gland atrophy and intestinal metaplasia, can progress to gastric carcinoma. • Diet (eg: preservatives, salted and smoked foods) • Genetic alterations and susceptibility. Types of gastric carcinoma • Diffuse type (Signet Ring Cell Type)- not associated with chronic gastritis. Composed of gastric type mucous cells that doesn’t form glands but permeates the mucosa as signet cells. Diffuse infiltration of the gastric wall causes the stomach to have a gross leather bottle appearance, also known as “linitis plastic”. Female predominance at a younger age. • Intestinal type- associated with chronic gastritis caused by H.pylori infection, with gastric atrophy and intestinal metaplasia. Composed of malignant cells forming glands. Male predominance, usually >50. Clinical:  Spread; penetration of serosa lymph nodes (Virchow’s node), and in females spread to ovaries (Krukenberg tumours).  Prognosis; depends on the depth of invasion. Early gastric cancer has better prognosis and those advanced (invasion beyond submucosa) have poor prognosis with five year survival rate less than 15%. Gastric Lymphoma Lymphoma accounts for less than 5% of gastric tumours. Nearly all gastric lymphomas arise from B-cells. The most common type of gastric lymphoma is MALT (Mucosa Associated Lymphoid Tissue) lymphoma. • Majority are associated with chronic Helicobacter gastritis (NB: some MALT lymphomas regress after H.pylori eradication). • Characterised by atypical lymphoid cell infiltration of the mucosa. • If not treated, progression to a higher-grade diffuse large B-cell lymphoma is possible. Gastrointestinal Stromal Tumours (GISTs) (1-3%) • Majority occur in the stomach (70%) 20% in small intestine and 10% in the esophagus. • Patients present with dysphagia, GI harmorrage and metastases to liver. • They arise from the interstitial cells of Cajal • Arise beneath the mucosa and usually protrude into the lumen • The overlying mucosa either remains intact or focally ulcerates causing blood loss. • Histology: spectrum of appearances, with cells characteristically overexpressing a c-kit oncogene (CD117) (also a useful diagnostic test). • Most have low malignant potential (however, size, necrosis, cellularity, mitotic rate and pleomorphism may indicate malignant behaviour). • Treatment: Surgical resection, presence of the c-kit oncogene overexpression indicates likely tumour response to Glivec.

Various problems include: • Peptic ulcer disease of duodenum • Malabsorption • Tropical sprue (postinfectious) • Whipples disease • Meckels diverticulum in ileum • Crohn’s disease (Inflammatory bowel disease) in the terminal ileum

Coeliac Disease
Coeliac disease (Gluten-sensitive enteropathy)- an autoimmune disorder occurring in genetically predisposed people. It is characterised by an immune reaction to gliaden, a gluten protein found in wheat (including oats, barley and rye). This leads to flattening of the small bowel lining (villous atrophy), interfering with nutrient absorption. Pathogenesis: Upon exposure to gliaden, the enzyme transglutaminase within enterocytes modifies the protein, causing a T lymphocytes to cross react with the epithelial cells. It is familial with a strong association with HLA-DQ2 or HLA DQ8. Found predominantly in Caucasians and has a prevalence of 1:100 – 1:200 Morphology:  Macroscopic: mucosa has a scalloped or flattened appearance as the villi are shortened or absent.  Microscopic: loss of normal villous architecture, intra-epithelial T lymphocytes, inflammation within lamina propria, regenerative changes in the crypts. Diagnosis: Detection in the blood of raised levels of antibodies to gliadin, endomysium or tissue transglutaminase is useful in establishing the diagnosis. Clinical: symptoms of diarrhoea, loss of weight, anaemia, fatigue, flatulence, and possibly associated with extra-intestinal features.  Treatment involves gluten-free diet.  Complications of long term risk of lymphoma

Small Intestine Tumours
These are uncommon in comparison to the rest of the GIT. Benign and malignant epithelial neoplasms do occur, particularly in the periampullary region of the duodenum. They may be associated with multiple polyp syndromes such as familial adenomatous polyposis (FAP). Carcinoid (Neuroendocrine) Tumours These tumours arise in the mucosa from neuroendocrine cells (Enterochromaffin Cells) located amongst the glandular epithelium. These tumours have variable malignant potential, but those within the small bowel (ileum)are generally more aggressive and metastasize to mesenteric lymph nodes and liver.

Morphology:  Macroscopic: yellow, nodular, 1-2cm diameter causing mucosal elevation. Mucosa is usually intact until the tumour enlarges, causing ulceration. The tumour infiltrates outward into the serosa where the accompanying fibrosis may cause kinking and obstruction.  Microscopically: nest, cords and rosettes of small round cells with a uniform and characteristic appearance.

Clinical effects: These tumours can secrete a variety of substances which have clinical effects.  Carcinoid syndrome where over secretion of serotonin causes diarrhoea, episodic flushing, brochospasm, cyanosis, telangiectasia and skin lesions.  Endocardial fibrosis and damage to the tricuspid and pulmonary valves are more serious long term effects that do not regress with removal of the tumour. Primary Lymphoma Lymphoma occurs in the small bowel in two clinical settings (both involve abdominal pain and diarrhoea: 1. Western-type intestinal lymphoma: affects children <10 and adults >40. Most common in the ileum and can manifest as multiple plaques, diffuse thickenings or as a tumour mass. It can present as obstruction, intussusception or perforation as well as occult bleeding. The sub-type of lymphoma is variable although in the setting of coeliac disease it is usually a T cell lymphoma. It is thought that the persistent activation to T lymphocytes is a predisposing factor although a decrease in the inflammatory response, does not remove the risk of lymphoma. The prognosis is poor. 2. Mediterranean Lymphoma- occurs in young men of low socio-economic status in poor countries, possibly due to an environmental factor. Arise from B lymphocytes and is associated with α-heavy chain disease under the label immunoproliferative small intestinal disease (IPSID). It predominantly involves the duodenum and proximal jejunum affecting a long segment. Diffuse inflammatory infiltrate within the mucosa can result in malabsorption. Gastrointestinal Stromal Tumours (GISTs) Typically arise in the jejunum, where they can rarely cause obstruction, intussusception or low grade blood loss resulting in anaemia.

Inflammation of the appendix usually associated with obstruction of the lumen by a faecolith (firm rounded aggregate of faeces). This predisposes to bacterial overgrowth and infiltration into the wall. On-going secretion of mucus into the blocked lumen causes increased luminal pressure and compromises venous outflow resulting in ischaemia and possibly causing infarction (gangrene perforation and peritonitis). Acute appendicitis usually occurs in children and young adults but can occur at any age. Signs and symptoms include pain (first periumbilical, followed by right iliac fossa), nausea and vomiting, abdominal tenderness and guarding, mild fever. Note: these signs and symptoms are non specific and seen in a range of other pathologies (eg: mesenteric lymphadenitis, systemic viral infection, acute salpingitis, ectopic pregnancy, Meckel’s diverticulum). Treatment is resection ( open surgery or laparoscopy).

Tumours of the Appendix
Benign: Mucinous Cystadenoma Malignant: Mucinous Aystadenocarcinoma: involves penetration of bowel wall by malignant cells, forming peritoneal impants  peritoneal cavity filled with mucin (Pseudomyxoma peritoneii) produced by malignant cells . The appendix is prone to blockage by a tumour with the resultant accumulation of mucin, forming a mucocele which can rupture. Carcinoid Tumours (most common, but rare)

Most common problems include: • Angiodysplasia • Hirschprungs (congenital aganglionic megacolon) • Colitis

Colitis (“Inflammation of the colon”) comprises of many different types/causes of inflammation- infectious, tuberculosis, pseudomembranous, ischaemic, idiopathic inflammatory bowel disease, Crohn’s disease, Ulcerative colitis, microscopic, collagenous/lymphocytic, obstructive, graft vs host disease, and allergic colitis. Symptoms and signs can be acute or chronic, persistent or intermittent. They include: abdominal pain, diarrhoea, haemorrhage (overt leading to per rectum bleeding, or occult leading to anaemia), fever, dehydration, malabsorption, perforation info the peritoneal cavity and sepsis. Investigations  Stool culture  Radiology: Plain abdominal X ray, barium enema, angiography  Colonoscopy/sigmoidoscopy  Biopsy (random vs targeted)  Surgical resection Infectious Colitis (acute self-limited) Organisms are usually ingested. They have to adhere to the mucosa, replicate and either secrete an enterotoxin or invade the mucosa. Causative organisms include:  Secretory (enterotoxin): Vibrio cholera, E coli, Bacillus cereus, Clostridium Perfringens  Exudative (damage to mucosal epithelium): Shigela, Salmonella, Campylobacter, Entamoeba histolytica Morphology:  Macroscopic: mucosa can be congested, harmorragic, or ulcerated.  Microscopic: Inflammatory infiltrate (particularly neutrophils) in the lamina propria with congestion and oedema +/- haemorrhage, erosion with ulceration, cryptitis and crypt abcesses, architecture is preserved, organisms rarely identified (need microbiology) Pseudomembranous Colitis Caused by the exotoxins of Clostridium Difficile (a normal gut commensal). Overgrowth is associated with antibiotic therapy (clindamycin/lincomycin). It is characterised by the formation of an adherent inflammatory exudate overlying the site of mucosal damage. Can present as acute abdominal pain with diarrhoea, and diagnosis involves detection of Clostridium Difficile cytotoxin in stool.

Morphology:  Macroscopic: Fibrino-purulent necrotic debris and mucus form a plaque-like exudate attached to the mucosa  Microscopic: Surface epithelium is shed with a layer of mucous and acute inflammation over the surface. Neutrophils and capillary thrombi in lamina propria, crypts distended by mucopurulent material, and a layer of mucous and acute inflammation over the surface. Differential diagnosis: Inflammatory bowel disease. Treatment: Antibiotics (vancomycin) and occasionally surgery (sometimes due to misdiagnosis). Ischaemic Bowel Disease This can involve three main arteries (celiac, superior and inferior mesentetic) with the classic site of pathology being the splenic flexure. Usually occurs in older people (>50 years) with cardiovascular disease and diabetes. The pathology depends on site of occlusion, acute or gradual occlusion, duration of occlusion and collateral circulation. Chronic ischaemia can lead to transmural fibrosis and stricture formation. Aetiologies  Thrombosis: arterial (severe atherosclerosis, vasculitis, hypercoagulable state) and venous (hypercoagulable state, intra abdominal sepsis, invasive neoplasms (HCC), cirrhosis, abdominal trauma).  Embolus - athero-emboli, cardiac vegetations, angiography/vascular surgery  Hypotension - cardiac failure, shock, dehydration, vasoconstrictive drugs  Others - radiation, volvulus, external stricture, herniation Symptoms/Signs Acute Subacute • Severe acute abdominal pain and tenderness • Non-specific symptoms, episodes of bloody • Nausea & vomiting diarrhoea blood loss, sepsis • Bloody diarrhoea • Loss of bowel sounds, abdominal rigidity Chronic • Shock, vascular collapse • episodes of bloody diarrhoea Morphology:  Macroscopic: Variably demarcated, congested (purple/red), haemorrhagic (due to blood reflow into damaged area), edema (thick rubbery wall), thinning of the wall and perforation.  Microscopic: Exudate (neutrophils and fibrin), mucosal infarction/necrosis and sloughing, oedema, haemorrhage, ulceration with granulation tissue, vascular thrombi with haemosiderin, fading of muscle details. Treatment: Surgery Idiopathic Inflammatory Bowel Disease A group of inflammatory conditions including Crohn’s Disease and Ulcerative Colitis. It is associated with immune-mediated inflammation and tissue destruction. Both have unknown aetiology (infectious and autoimmune causes have been proposed) although there is a genetic predisposition. Extraintestinal manifestations indicates that IBD is a systemic illness (eg: U/C predominantly colonic but may also cause liver or biliary tract disease, arthritis, uveitis, pyoderma gangrenosum, and Wegeners granulomatosis).

Crohn’s Disease (Regional enteritis)
Any age after late childhood (20-40yo) Symptoms/Signs ♦ Abdominal pain ♦ Diarrhoea ♦ Rectal bleeding, less common than U/C ♦ Abdominal mass Pathology ♦ Any part of the intestine to anus (terminal ileum 40% or colon 30% or both 30%) ♦ Preferentially right sided (rectal sparing) ♦ High incidence of anal lesions ♦ Sharp demarcation, continuous or skip lesions Macroscopic ♦ Mucosal cobblestone appearance ♦ Deep fissuring linear ulceration- fistula formation ♦ Transmural inflammation ♦ Intestinal wall thickened - oedema, inflammation, fibrosis, muscle hypertrophy ♦ Stricturing Microscopic • Variable between fragments and sites • Transmural changes • Mucosal inflammation • mainly chronic, some acute • Ulceration – classically “rose thorn” • Non-caseating granulomas (40-60% of cases) • Architectural distortion - cycles of destruction and regeneration, paneth cell metaplasia • Retention of mucus production • Submucosal fibrosis • Hypertrophy of the muscularis • Serosal thickening due to fibrosis, creeping fat Complications • Toxic megacolon with perforation • Stricture with obstruction • Fistula - bowel, bladder vagina, peritoneal cavity, perianal skin • Iliitis - malabsorption, protein losing enteropathy, pernicious anaemia (vitamin B12), steatorrhoea (bile salts) • Carcinoma colon Treatment ♦ Supportive therapy ♦ Immunosuppression – local/systemic ♦ Surgery – total colectomy, reconnection depends on the presence of perianal disease ♦ Surveillance for malignancy

Ulcerative Colitis
Any age, peaks at 20-30 and 70-80 years (M=F) Symptoms/Signs ♦ Pain and cramps relieved by defecation ♦ Episodic if mild, continuous if severe, can be fulminant ♦ Attacks of bloody mucoid diarrhoea days/months ♦ Occasionally constipation ♦ Abate with or without treatment ♦ Flare ups precipitated by stress Pathology ♦ Characteristically left sided disease (rectosigmoid) but extends proximally (pancolitis in 40%) ♦ Continuous – no skip lesions Macroscopic ♦ Blood and mucus in lumen ♦ Hyperaemia, granularity, friability ♦ Broad based ulceration (not linear) with pseudopolyps of regenerating mucosa ♦ Muscularis propria and serosa normal Microscopic • Continuous and relatively uniform • Mucosa and submucosa • Lymphoplasmacytic inflammation in the lamina propria • Ulceration (flask shaped) confined to the mucosa/submucosa with granulation tissue • No granulomas • Mucosal acute inflammation with cyptitis and crypt abcesses • Goblet cell depletion • Pseudopolyps of granulation tissue • Architectural damage - regeneration, fibrosis, gland disarray/atrophy, paneth cell metaplasia Complications • Toxic megacolon – perforation – peritonitis/abcess • Strictures rarely • Loss of blood or fluid and electrolytes – anaemia, malnutrition • Carcinoma (20-30x risk in pancolitis for 10+ years) Treatment • Supportive therapy • Immunosuppression – local/systemic • Surgery – total colectomy • Surveillance for malignancy

Large Intestine Tumours
Investigations: - Clinical examination, faecal occult blood test (FOBT) - Imaging (plain films, barium studies) - Endoscopy, Colonoscopy - Pathology: cytology, fine needle aspiration, brushings, fluids, biopsy, resection. Polyps (Adenomas) Polyps are abnormal epithelial growths projecting from the mucosa (smooth, discrete and round elevations). Two main types of polyps are: 1) Hyperplastic polyps (90%)- non-neoplastic lesions, occurring mostly in the rectosigmoid colon. 2) Adenomatous polyps- true neoplasms, which are precursor lesions for adenocarcinoma. There is a higher incidence of cancer in higher grade, larger polyps, and those containing a greater proportion of villous growth: Familial Adenomatous Polyposis a. Tubular adenomas (pedunculated)- 75%. A genetically inherited (autosomal dominant) Can be sporadic of familial. Male to condition associated with a mutation in the APC female ratio of 2:1. Average age is 60. gene on chromosome 5. This predisposes to Mostly occur in the left colon. multiple (hundreds) of colonic adenomas starting in b. Villous adenomas (usually sessile)the rectosigmoid area, and eventually covering the largest, least common polyp. 33% are entire colon. This occurs during adolescence and cancerous. Characteristic “cauliflowerearly adulthood. Benign polyps undergo malignant like” growth (1-10cm diameter). transformation usually in the 30s and 40s. c. Tubulovillous adenomas Treatment is by total colectomy. Morphology: The mucosal lining of adenomatous polyps show increasing architectural complexity and cytologic atypia (ie: low and high grade dysplasia). Adenocarcinoma This malignancy accounts for 98% of all colon cancers. There is a high incidence in urban, Western societies. It is the 3rd most common tumour in men and women. Most colorectal adenocarcinomas appear to arise from villous adenomas, but are also associated with ulcerative colitis, Crohn’s disease, and familial polyposis. Risk factors include: age, prior colorectal carcinoma, familial/genetic predisposition and diet (low dietary fibre, high fat and red meat). Morphology:  Macroscopic: tumours can be polypoid (protruding into the lumen), ulcerating (eroding into surrounding structures) or infiltrative (spread within colonic wall). 75% occur in the rectum or sigmoid colon.  Microscopic: variable differentiation. Usually irregular glandular structures lined by atypical columnar epithelium. Spread:  Direct invasion is usually into the mesentery and if the surface is breached, can involve adjacent structures (small bowel, female genital tract, bladder)  Lymphovascular invasion is common with metastasis to mesenteric lymph nodes followed by the liver, lungs and bones.

Clinical features:  May be clinically silent and rarely presents as an abdominal mass  Rectal bleeding  Change in bowel habits (constipation/diarrhoea)  Obstruction - more common with left sided tumours; lumen is smaller and faeces more solid  Perforation with peritonitis  Fistula formation (eg: rectovaginal)  Systemic symptoms related to malignancy – anorexia, malaise, weight loss, weakness. Screening: Faecal Occult Blood Testing (FOBT) and subsequent colonoscopy/biopsy with patients that test positive. This allows for early detection of precursor adenomas or early stage adenocarcinomas, possibly improving the overall outcome. Treatment:  Surgical excision.  Chemotherapy and radiotherapy: have a role to play, either before surgery to down size the tumour or after surgery to decrease the likelihood of or palliate any recurrence.

Various problems include:  Haemorrhoids  Fissure/ fistula (Crohn’s disease) Squamous cell carcinomas (most common anal tumour) Often associated with Human Papilloma Virus (HPV) infection, as well as chronic anal fissures or trauma. Other factors include poor hygiene and anal sex. There is an increase in incidence in homosexual males with HIV.  Clinical: tumours present with pain, bleeding or a mass (although the tumour may be infiltrative  rather than exophytic).  Spread: The tumours infiltrate the surrounding tissues involving the rectal sphincters, prostate and vagina.  Treatment: Combined chemo- and radiotherapy is the treatment of choice but sometimes abdominal-perineal resection is required.


Glomerulonephritis (GN) is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys. It may present with isolated haematuria and/or proteinuria , as a clinical syndrome outlined below, or as acute/chronic renal failure. Nephrotic Syndrome is a clinical complex characterised by proteinuria, resulting in hypoalbuminaemia and oedema. Podocyte injury is an underlying mechanism of proteinuria, and may be the result of either non immune diseases (MCD, FSGS) or immune mechanisms (MGN).  Minimal Change Disease (MCD): effacement of podocyte foot processes without antibody deposits, unknown pathogenesis. Most frequent cause in children.   Focal and Segmental Glomerulosclerosis (FSGS): sclerosis of segments of glomeruli (focal; only some glomeruli affected). May be primary (idiopathic) or secondary (eg. hypertension). Membranous Glomerulonephritis (MGN): loss of foot processes caused by an autoimmune response against an unknown renal antigen (can be viral).

Nephritic Syndrome is a clinical complex characterised by haematuria, proteinuria, oliguria with uraemia, and hypertension. Most common cases are immune mediated glomerular injury, characterised by proliferative changes and leukocyte infiltration.  Acute Post Infectious Glomerulonephritis: glomerular inflammation due to deposition of immune complexes, typically post S. pyogenes infection in the young.   IgA Nephropathy: characterised by deposits of IgA-containing immune complexes due to abnormal production/clearance. Most common cause worldwide. Hereditary Nephritis; caused by mutations in the genes coding for collagen in the glomerular basement membrane (GBM). Slow progressing, glomeruli appear normal until late in course.

Rapidly Progressing Glomerulonephritis (RPGN) is a clinical entity with rapid loss of renal function and features of nephritic syndrome. Regardless of cause, distinctive histologically due to crescents.  RPGN is associated with severe glomerular injury and necrosis of the GBM. Results in proliferation of parietal epithelium (crescents).  Usually immune mediated eg. anti-GBM antibody disease, immune complex deposition.

Renal Failure
Inability of the kidneys to function, including blood filtration and urine concentration. Morphologically, usually involves obliteration of glomeruli and significant interstitial necrosis. Acute Renal Failure, urine flow falls within 24hrs to less than 400mL/day (oliguria). Can result from all acute glomerular, tubular, interstitial or vascular injury. Most common glomerular disease is RPGN. Chronic Renal Failure, characterised by prolonged symptoms of uraemia, is the end result of all chronic renal disease. Chronic glomerulonephritis is an important cause of endstage renal disease, probably represents the endstage of a variety of entities (eg. FSGS, MGN, IgA nephropathy).

Tubulointerstitial nephritis includes a group of inflammatory diseases of the kidneys that involve the tubules and interstitium. May be bacterial (pyelonephritis) or nonbacterial (interstitial nephritis).

Acute Pyelonephritis
Suppurative inflammation of the kidney and renal pelvis, caused by bacterial infection. A manifestation of UTIs; lower (cystitis, prostatitis, urethritis) and/or upper (pyelonephritis) UTI. Pathogens: main causative organisms are the gram –ve rods with E. coli most common by far. Proteus, Klebsiella, Enterobacter, Pseudomonas species are other causes, associated with recurrent infection. Pathogenesis: bacteria can reach the kidney via the blood or from the lower urinary tract. 1. Bloodstream (haematogenous): involves bacterial seeding of kidneys during septicaemia or infective endocarditis. Less common, typically involves S. aureus or E. coli. 2. Ascending infection from lower urinary tract: most common and important route. a. Adhesion of bacteria to mucosal surfaces → colonisation of distal urethra. b. Organisms gain access to bladder via urethral instrumentation (eg. catheter ) or direct colonisation (women more common due to shorter urethra, closer to rectum and trauma during sex). c. Outflow obstruction or bladder dysfunction (diabetes ↑susceptibility) → urinary stasis → bacteria multiply. d. Vesicoureteral reflux (VUR); reflux of urine up the ureter due to defective vesicoureteral orifice (normally only allows unidirectional flow). e. Urine propelled up to renal pelvis and farther into renal parenchyma through open ducts at the tip of the papillae (intrarenal reflux). Morphology: Pyelonephritis  Macroscopic: kidneys have discrete yellowish and raised abscesses on their surfaces. Often hyperaemic, usually unilateral.  Microscopic: suppurative necrosis or abscess formation within the renal parenchyma. Large masses of intratubular neutrophils.
Acute Pyogenic

Clinical: typical sudden onset pain at costovertebral angle. Chills, fever, malaise.  Pyuria and bacteriuria, urethral irritation causes dysuria, frequency, urgency.  Disease tends to be benign and self limiting even without antibiotic treatment.  Predisposed by: obstruction, instrumentation, pre-existing lesion or VUR, females, pregnancy, older males (prostatitis), immunosuppression.  Diagnosis: finding leukocytes by urinalysis and urine culture.

Chronic Pyelonephritis
A clinical entity whereby interstitial inflammation leads to grossly visible scarring and deformity of renal parenchyma and the pelvicalyceal system. Associated with urinary obstruction or reflux. Pathology: divided into two forms based on cause.  Chronic Obstructive Pyelonephritis: obstruction predisposes to recurrent infections → recurrent bouts of inflammation and scarring → chronic pyelonephritis. Can be bilateral (eg. congenital anomalies of urethra) or unilateral (eg. obstructive lesions such as calculi).  Chronic Reflux Associated Pyelonephritis (reflux nephropathy): results from superimposition of a UTI on congenital vesicoureteral reflux (VUR) and intrarenal reflux. Is more common, can be unilateral or bilateral. Morphology: uneven scarring, can be patchy or diffuse. Scarring involves the pelvis and/or calyces → calyceal deformities. Since can involve one or both kidneys, they are not equally contracted. Clinical: results in gradual renal insufficiency.  Many people are diagnosed late in the course of disease because of gradual onset of renal insufficiency or because signs of kidney disease are not noticed on routine lab tests.  If bilateral, tubular dysfunction → loss of concentrating ability → polyuria, nocturia.  Some develop glomerular sclerosis and secondary FSGS → proteinuria and chronic renal failure.

Chronic Pyelonephritis

Non-Infectious Nephritis
Drug Induced Interstitial Nephritis is reaction to a drug, characterised with interstitial inflammation, often with abundant eosinophils and oedema.  Pathology: drugs act as haptens that, during secretion by tubules, covalently bind to cytoplasmic or extracellular components of tubular cells and become immunogenic. o most frequently occurs with synthetic penicillins (methicillins, ampicillin), rifampicins, diuretics (thiazides), NSAIDs.  Clinical: disease begins ~15days after exposure to drug and is characterised by fever, oesinophilia, rash and renal abnormalities. Associated haematuria and leukocyturia. o Can cause drug induced renal failure (withdrawal of offending agent → recovery). Analgesic Nephropathy is the result of consumption of large quantities of certain analgesics (NSAIDs, paracetamol), which results in the development of chronic interstitial nephritis. Often associated with renal papillary necrosis.  Pathology: not clear, varies. Paracetamol injures cells by covalent binding and oxidative damage. Aspirin inhibits prostaglandin synthesis (vasodilator), predisposing to ischaemia. o ‘triple whammy’; ACE-I (↓glomerular filtration) + NSAIDs (↓blood to glomeruli) + diuretics → net effect is loss of haemostatic control in glomeruli.  Clinical: common clinical features of renal failure, hypertension and anaemia. Cessation of analgesic intake may stabilise or improve renal function. o Although renal disease can occur in healthy individuals, pre-existing renal disease seems to be a necessary precursor to analgesic induced renal failure. o ↑ Incidence of transitional cell carcinoma in those that survive renal failure.

Acute Tubular Necrosis
Acute tubular necrosis (ATN) is characterised by damaged tubular epithelial cells and acute suppression of renal function. It is the most common cause of acute renal failure. Pathology: associated with intrarenal vasoconstriction resulting in reduced GFR and diminished delivery of oxygen/nutrients to tubular epithelial cells. Subsequent cellular and basement membrane necrosis.  Ischaemic ATN (vasomotor nephropathy) results from ischaemic injury; eg. during shock, sepsis, severe haemoglobinuria, metabolic disorders.  Nephrotoxic ATN results from toxic injury to renal tubules; eg. poisons, heavy metals, organic solvents, gentamycin.

Multifocal Renal Infarction

Morphology: characterised by necrosis of segments of the tubules (typically the proximal tubules), proteinaceous casts in distal tubules, and interstitial oedema. Clinical: manifestations are oliguria, uraemia and signs of fluid overload.  Initiation phase (36hrs); is usually dominated by the inciting medical, surgical or obstetric even in the ischaemic form of ATN.  Maintenance phase (2-6days); significant oliguria, uraemia and fluid overload.  Recovery phase; steady ↑ in urine volume (up to 3L/day). Tubular function still deranged → 25% of deaths occur in this phase due to electrolyte imbalance and infection.

Hypertensive Diseases
[see cardiovascular notes]

Benign Nephrosclerosis is progressive, chronic renal damage associated with benign hypertension.  Pathology: slow progressing hypertension, resulting in gradual organ damage, usually over years. Mostly idiopathic. o Frequency and severity of lesions are increased with age, hypertension and diabetes.  Morphology: characterised by hyaline arteriosclerosis and narrowing of vascular lumens with resultant cortical atrophy.  Clinical: rarely causes severe damage in the kidney, mild degree of proteinuria. o Some functional impairment, such as loss of concentrating ability or diminished GFR. Malignant Nephrosclerosis acute renal injury associated with malignant hypertension.  Pathology: malignant hypertension occurs in 5% of people with elevated BP. Causes and is caused by renal disease. o Long standing benign hypertension → fibrinoid necrosis and hyperplastic arteriosclerosis → narrowing of vessel lumen → ischaemia of kidneys. o Activation of renin-angiotensin system → further vasoconstriction and ischaemia (self perpetuating cycle). Also exacerbated by aldosterone release (↑ Na and fluid retention).  Morphology: arterioles undergo fibrinoid necrosis and hyperplasia of SMCs, narrowing the vessels to the point of obliteration. Petechial haemorrhage on the renal cortical surface from arteriole rupture.  Clinical: malignant hypertension is characterised by diastolic pressure >120mmHg, papilloedema, encephalopathy, cardiovascular abnormalities and renal failure. o 90% deaths cause by uraemia, other 10% by vascular disease. 50% 5yr survival.

Thrombotic Microangiopathies
Disorders characterised by fibrin thrombi in glomeruli and small vessels resulting in renal failure. Common diseases causing these lesions include; childhood/classic haemolytic uraemic syndrome (HUS), adult HUS (various forms), and thrombotic thrombocytopaenic purpura (TTP). TTP
Caused by defects in von Willebrand factor (vWF) leading to excessive thrombosis with platelet production (see cardio notes). Multiple thrombi throughout vasculature, including kidney, result.

caused by endothelial injury by an E. coli toxin → activation and intravascular thrombosis.  This disease is one the main causes of acute renal failure in children.  25% of children eventually develop renal insufficiency due to 20 scarring.

Simple Cysts
Generally innocuous lesions occur, as single or multiple cystic spaces. Dialysis Associated Cysts Morphology: 1-5 cm in diameter translucent cysts. Lined by a grey smooth membrane, and filled with a clear fluid. Usually confined to the cortex. Clinical: these cysts are common with no clinical significance. The main importance lies in their differentiation from kidney tumours. In contrast to renal tumours, renal cysts have smooth contours, are almost always avascular, and give fluid rather than solid signals in ultrasound.
Occur in patients with end stage renal disease who have undergone prolonged dialysis. Present in the cortex and medulla, may bleed causing haematuria. Renal adenomas and adenocarcinomas occasionally arise from the walls of these cysts.

Autosomal Dominant (Adult) Polycystic Kidney Disease
Autosomal dominant disease characterised by multiple cysts in both kidneys that ultimately destroy the intervening parenchyma. Accounts for 10% of chronic renal failure. Pathology: mutations in polycystin molecule which is involved in cell-cell and cell-matrix adhesion. It is thought that defects in cell-matrix interactions may lead to alterations in tubular epithelial cells, and to cyst formation.  Polycystin 1; PKD1 on Ch 16, accounts for 85-90% of mutations.  Polycystin 2; PKD2 gene on Ch 4, implicated in 10-15% of cases. Morphology: kidneys increase in size and are palpable abdominally.  Cysts may arise at any level of the nephron, from tubules to the collecting ducts.  Cysts are filled with fluid, which may be clear, cloudy or haemorrhagic.


Clinical: small cysts start to develop during adolescence, asymptomatic until around age 40yr.  Most common presenting complaint is flank pain or a heavy dragging sensation.  Typically leads to intermittent haematuria, hypertension and urinary infection.  Complications: saccular aneurysms in Circle of Willis (10-30%), end stage renal failure (50yrs), death usually results from uraemia or hypertensive complications.

Autosomal Recessive (Childhood) Polycystic Kidney Disease
Rare developmental defect of the kidney that is autosomal recessive.  Pathology: caused by mutations in the PKHD1 gene coding for a membrane receptor protein called fibrocystin.  Morphology: many small cysts in the cortex and medulla giving the kidney a spongelike appearance. Cysts originate from the collective tubules, nearly always accompanied by cysts in the liver.  Clinical: serious manifestations usually present at birth. Infants can due quickly from hepatic and renal failure. Survivors develop liver cirrhosis.


Medullary Cystic Disease
Increasingly recognised as a cause of chronic renal failure in children and young adults.  Pathology: complex inheritance, associated with mutations in several genes that encode epithelial cell proteins called nephrocystins (may be involved in ciliary function).  Morphology: Small, contracted kidneys. Many small cysts typically in the corticomedullary junction.  Clinical: Polyuria and polydipsia (due to diminished tubular function). End stage failure occurs over a 5-10 year period. Disease difficult to diagnose (no serological markers, cysts may be too small to be seen with radiological imaginary). Medullary Cystic Disease

Urolithiasis (Renal Stones)
Urolithiasis is calculus (stone plaque) formation at any level in the urinary tract, most often occurring in the kidney. Often multiple, more common in males, familial tendency has been recognised. Pathology: the most important cause is increased urine concentration of various constituents, so that it exceeds their solubility in urine (supersaturation). May also occur from the lack of substances that normally inhibit mineral precipitation.  Calcium Stones (Oxalate/Phosphate/Mixed) (75%) mostly caused Causes of Calcium Stones by hypercalciuria but can be due to other metabolic abnormality, Hypercalcuria (60%); ↑ gut absorption, or even idiopathic. Favoured by ↑pH. ↓ renal reabsorption, hypercalcaemia  Struvite (Magnesium Ammonium Phosphate) (15%) occur in (↑PTH, vit D etc). persons with persistently alkaline urine due to UTIs. Urea splitting Hyperuricosuria (20%); ↑ uric acid in bacteria (eg. P. Vulgaris, Staph) predisposes persons to stones. urine, promoting Ca deposition.  Uric Acid Stones (6%) gout and diseases involving rapid cell Hyperoxaluria (5%); hereditary ↑ in turnover (eg. leukemia) lead to high uric acid levels in the urine oxalate in urine. and the possibility of the uric acid stones. Favoured by ↓pH. No known metabolic problem (15%)  Cystine stones (1-2%) genetic defect in the renal transport of cystine (AA) forming yellow, soft stone. Favoured by ↓pH. Morphology: unilateral in 80% of cases, commonly in the renal pelvis, calyces, and bladder.  Usually small (2-3mm), however progressive accretion of salts can lead to branching.  Staghorn calculi; development of branching structures which create a cast of the renal pelvicalyceal system.
Staghorn Calculi

Clinical: stones can exist without producing symptoms or renal damage. Smaller stones may pass into the ureter producing paroxysms of intense flank pain, radiating to the groin.  Complications; gross haematuria, bacterial infection.  Diagnosis; radiological, calcium stones are radiopaque.

Dilation of the renal pelvis and calyces, with accompanying atrophy of the renal parenchyma. Caused by obstruction to the outflow of urine. Causes: may be congenital or acquired.  Congenital: atresia of urethra, valve formations in the ureter or urethra, renal artery compressing ureter, kinking of ureter.  Acquired: foreign bodies (calculi), tumours (prostate, bladder), inflammation (prostatitis, ureteritis, urethritis), neurogenic (spinal cord damage and paralysis of bladder), pregnancy. Pathology: obstruction may occur at any level of the urinary tract.  Affected pelvis and calyces dilate with urine → high pressure transmitted back to the collecting ducts, compressing vasculature → atrophy of renal parenchyma.  Bilateral if obstruction below ureters, unilateral if above. Morphology: general dilation of structure due to fluid overload.  Macroscopic; enlarged kidneys beginning at pelvis, later in cortex. Papillae exposed to greatest pressure, are affected most.  Microscopic; dilated nephrons, flattened epithelium. Later atrophy and fibrosis. Clinical: impairment of renal concentrating ability and GFR.  Anuria (no urine) in bilateral complete obstruction. Hydronephrosis  Polyuria (rather than oliguria) in bilateral incomplete obstruction due to defects in tubular concentrating mechanisms.  Return of normal function if obstruction is removed within a few weeks.

Renal Cell Carcinoma
Malignant neoplasms derived from renal tubular epithelium, hence located predominantly in the cortex.  Represent 80-85% of all primary tumours of the kidney, 2-3% of cancer deaths.  More common in 60-70yrs, men 2x risk.  Higher risks for smokers, hypertensive or obese patients, and those exposed to cadmium Pathology: previous classification was morphological, is now genetic.  Clear Cell Carcinomas (70-80%) solitary, large tumours arising in cortex. o Most cases are sporadic, familial association loss of VHL tumour suppressor protein. Severe in individuals with von Hippel-Lindau (VHL) disease (autosomal dominant). o Yellow-orange-grey, large (3-15cms), distinct margins in cortex.

Papillary Renal Carcinomas (10-15%) arise in proximal tubules with papilla formation. o Associated with activation mutations in the MET oncogenes → abnormal growth in epithelial cell precursors → papillary carcinomas. o Frequently multifocal and bilateral, yellow-orange (less vibrant), fibrovascular cores. Chromophobe Renal Carcinomas (5%) arise from the intercalated cells of collecting ducts. o Tan-brown, histologically clear cytoplasm and distinct cell membrane. o Cells have multiple losses of entire chromosomes (7 total), extreme hypodiploidy.

Renal Cell Carcinoma

Clinical: characteristic triad of painless haematuria, palpable abdominal mass, and dull flank pain but may present in many fashions. Fever due to necrosis. Mortality rate of 40%.  Paraneoplastic syndromes result in polycythaemia (erythropoietin release), gynacomastia (gonadotrophin release) and hypercalcemia (PTH release).  These tumours frequently invade the renal vein metastasise to bone, lungs and liver.

Nephroblastoma (Wilms Tumour)
Congenital malignant neoplasm derived from the mesoderm, 5% of renal cancers, major in children. Pathology: involves mutations in Wilm’s tumour (WT) 1 and 2 genes on chromosome 7.  Familial associations include WAGR syndrome (WT1), Denys-Drash Syndrome (WT1) and Beckwith-Wiedemann Syndrome (WT2).  Sporadic mutations in WT1 causes around 5% of Wilm’s tumours. Morphology: begins in renal cortex and replaces entire kidney.  Macroscopic: tan-grey, large and soft. Usually solitary well circumscribed mass.  Microscopic: classic triphasic combination of blastema (small round blue cells), epithelial cells and stromal/SM cells. Clinical: palpable asymptomatic abdominal mass.  Prognosis generally good with combination of nephrectomy and chemotherapy.  If anaplasia is diffuse with extrarenal spread, prognosis is less favourable.

Other Renal Tumours
Urothelial Carcinoma of Renal Pelvis located in renal pelvis, 5-10% of renal cancers. May be multiple, increased incidence with analgesic nephropathy. High grade infiltrative tumours (5 year survival of 10%). Secondary kidney tumours have metastasised from other sites. Most common primary sites are lung, skin, contralateral kidney, GIT and gonadal tumours. Benign Kidney Tumours present in 25-50% of patients with tuberous sclerosis. May include renal papillary adenoma, renal fibroma/hamartoma or angiomyolipoma.

Cystitis is inflammation of the urinary bladder, usually due to bacterial infection. It is extremely common, especially in females. Bacterial Cystitis is most often caused by gram negative bacilli from the GIT, especially E. coli. It is often associated with, and precedes, pyelonephritis.  Pathogens: mainly E. coli, also Proteus, Klebsiella, Enterobacter and Mycobacteria species.  Pathology: similar to acute pyelonephritis. Ascending infection after colonisation of distal urethra is by coliform organisms most common (women more susceptible). Haematogenous infection is less common.  Morphology: nonspecific acute/chronic inflammation, varies with cause. Typically; ulceration on bladder mucosal surface, congested blood vessels, oedema, and neutrophilic infiltrate in bladder wall. Histiocytes are seen in chronic form.  Clinical: can be acute or chronic, symptomatic or asymptomatic. Urinary symptoms include frequency, dysuria, abdominal pain and haematuria. Nonbacterial Cystitis can be due to fungi, viruses and protozoa (eg. Candida, Mycoplasma, adenovirus).  Cystitis cystica is a chronic cystitis glandularis (glandular metaplasia) with cyst formation.  Granulomatous forms can be cause by TB or intravesical BCG, following instrumentation.  Iatrogenic (radiation or chemotherapy)  Others: Malakoplakia, Schistosomal, Eosinophilic (protozoa), Interstitial Cystitis (idiopathic)

Bladder Neoplasms
More than 90% of bladder neoplasms arise from transitional epithelium. Most are malignant, frequently multifocal, and may involve other urothelial lined surfaces (eg. ureter, renal pelvis). Morphology: basis of classification of benign and malignant tumours. Transitional Cell Papillomas (2-3%) benign epithelial tumour with finger like projections (fonds). Lesions may be single or multiple.  Patients present with painless haematuria, as projecting papillary fronds bleed easily.  Histologically, epithelium <7 cells thick with no dysplasia.  Commonly arise in 60-80yrs, affect males 3x more. Urothelial (Transitional Cell) Carcinomas (90%) can range from papillary to flat.  May also range from invasive to non-invasive, and low to high grade. Those with ‘low malignant potential’ are labelled PUNLMP (papillary urothelial neoplasm of low malignant potential).  Previously known as papillary carcinoma (has early papillary projections).  Mean age 60yrs, males 3x more, greater in urban pop, ↑ Egypt (↑ Schistosomiasis infection). Other bladder carcinomas other 10% of tumours are Carcinoma In-Situ, Squamous Cell Carcinoma, Adenocarcinoma, Sarcoma, Small Cell Carcinoma and secondary metastases.

Transitional Cell Carcinoma

Pathology: various associated causes/risk factors.  Occupational exposure eg. textile, chemical, rubber, plastic industries. Carcinogen exposure (eg. Beta-Napthyl-Amine) is associated to 50x greater incidence, with 20yr latent period.  Smoking directly by carcinogens in cigarette smoke or indirectly by abnormal tryptophan metabolism producing toxic metabolites in urine.  Others include analgesic abuse, drugs causing cystitis, diets high in fat and protein, Schistosomiasis and genetic/congenital abnormalities (eg. bladder extrophy). Clinical: painless haematuria mainly. Frequency, urgency, dysuria and pyelonephritic complications may or may not manifest.  Diagnosis; cystoscopy, contrast radiography, CT scans (and others), urine cytology and biopsy.  Metastases; direct to nearby structures (prostate, vagina, GIT), lymphatic (pelvic LN) or haematogenous (later to liver, lungs, bone marrow).  Outcome; generally all have tendency to recur with greater anaplasia, may be at different site. Survival rate depends on prognostic factors, death from renal failure or dissemination. Important Prognostic Factors
Growth Pattern:  Papillary (better prognosis) vs flat  Non-infiltrating (better prognosis) vs infiltrating  Carcinoma In-situ are very likely to progress to carcinoma. Histological Grade: WHO (grade I,II,III) or ISUP (low and high grade). Staging: (Ta, Tis, T1, T2, T3a/b, T4) Mode of spread: tentacular/pushing invasion, lymphatic or blood.


Non-Neoplastic Penile Lesions
The penis may be affected by many congenital and acquired disorders. Benign problems include malformations and inflammatory conditions. Congenital Lesions Hypospadias The urethral opening develops on the underside of the penis, most commonly on the inferior aspect of the glans. o Due to failure of fusion of urethral folds over the urogenital sinus. o Commonest congenital abnormality of male urethra (1 in 250 births). Epispadias Urethra opens onto dorsum of penis, usually at base of the shaft, near pubis. o Results in urinary incontinence and infections. o Is much less common. Non-Infections Inflammations Balanoposthitis Inflammation of inner surface of prepuce (posthitis) usually accompanied by (balanitis) inflammation of adjacent surface of glans penis (balanitis). o Often associated with a tight prepuce (phimosis). o Due to secondary infection of smegma by pyogenic bacteria. NB: smegma is cheesy substance (exfoliatd epithelial cells, skin oils and moisture) that can accumulate under male foreskin (prepuce) or vulva in females. Phimosis Prepuce unable to be retracted, tightening up. o Commonest medical indication for male circumcision. Paraphimosis Tight prepuce retracted behind glans. o Obstructs venous return → oedema Balantis Involves thickened white plaques and fissures on glans and prepuce. Xerotica o Non retractile prepuce or discharge. Obliterans o Treated with circumcision. (BXO) o Histology similar to lichen sclerosus of vulval skin. o Usually 30-50yrs Infections Genital Herpes Is caused by HSV types 1 and 2, most genital tract lesions due to type 2 as STI. o Itching followed by appearance of closely grouped vesicles surrounded by erythema. o Becomes latent for life and reactivates intermittently. Genital warts Condyloma acuminatum lesion is caused by HPV. o Commonest urogenital lesion. o Infection with HPV types 6 and 11 (unlike warts types 1, 2 and 4 in other parts of body) o Histology: epidermis shows papillomatous hyperplasia. Cytoplasmic vacuolation and kiolocytes (keratinocyte squamous cell with irregular and enlarged nuclei). Cytoplasmic Condyloma Acuminatum clearing at the periphery. NB: condyloma acuminatum is wart like growth with stalk base (planum is flat). Found around anus, vulva, glans penis. Syphilis Is caused by T. pallidum, with three distinct stages. o Primary stage: chancre on penis, a painless ulcerated nodule with firm raised boarders. Endarteritis with lymphocytes and associated lymphadenitis. o Secondary stage: condyloma lata, generalised lymphadenitis. o Tertiary stage: gumma (destructive granulomatous lesions), often in testis. NB: second/tertiary stages not commonly seen due to antibiotic treatments when detected.

Tumours of the Penis
Intraepidermal Carcinoma is full thickness dysplasia of epidermis with no stromal invasion.  Carcinoma in situ with strong association with HPV infection.  A sharply delineated red patch with moist keratotic patch (“erythroplasia of Queyrat” on glans).  Significant risk of progression to invasive SCC. Invasive Squamous Cell Carcinoma is a well differentiated, invasive tumour.  Usually in the glans or inner aspect of prepuce → forms indurated nodule/plaque that later ulcerates. Rarely develops on the outer surface of prepuce or shaft.  Alost exclusively in uncircumcised men, HPV infection important cause.  Rare in western countries, common in Africa/Eastern Asia.  Invades corpus cavernosum, metastasises to inguinal lymph nodes. NB: genitals drain to inguinal nodes, testis to para-aortic nodes

Non-Neoplastic Testicular Lesions
Congenital Abnormalities Cryptorchidism When one or both testes fail to descend into scrotum. o Instead, may be found in inguinal canal, upper scrotum or abdomen. o Increased risk of germ cell tumours (4-10x). o Risk of torsion and infarction. NB: orchidopexy is to retrieve undescended testes into scrotum. Anorchidism Absecnce of both testes. Polyorchidism More than 2 testes (extremely rare).

Acquired Abnormalities Testicular Torsion Occurs when the spermatic cord is twisted, cutting off blood supply to testes. This may result in testicular infarction, in the form of coagulative necrosis. o Orchialgia (testicular pain) is common. o Outline of seminiferous tubules consists of inflammatory cells. o Predisposed by congenital factors (eg. abscence of scrotal ligament, shortened peritoneal ligaments, cryptorchidism, atrophy of testes). o Needs treatment within 6-8hrs of onset to prevent loss of testes. Hydrocele Accumulation of serious fluid within tunica vaginalis of testis (can occur in any body cavity). o Smooth, pear shaped swelling (commonest intrascrotal swelling). Tense testicles but usually fluctuant (swelling changes). o Transilluminable upon exposure to light and testis not palpable due to transparent surrounding fluid. o Can be acute inflammatory hydrocele (accumulates rapidly, often painful) or chronic hydrocele (involves gradual stretching of tunica, dragging sensation). Congenital hydrocele appears first few weeks of life. o Due to patent processus vaginalis, an embryonic outpouching of peritoneum (forms tunica vaginalis) that doesn’t close → peritoneal fluid drains under gravity causing hydrocele.

Secondary hydrocele may be associated with underlying lesion of testis or epididymis. o This can be caused by inflammation (eg. mumps, gonococcal infection)or neoplasms. Varicocele Abnormal dilation and tortion of pampiniform plexus veins (combine to form gonadal veins) in spermatic cord. o Due to insufficiency of venous valves. o 90% left sided (gonadal vein drains into renal vein first on left, not straight to IVC like on right), 10% bilateral. o Associated with infertility due to ↑ temperature during blood stasis. Orchidoepididymitis Inflammation of the testes and epididymitis, often due to infection. o Viral orchidoepididymitis; mumps, coxsackie B. Bilateral involvement results in infertility. o Bacterial orchidoepididymitis; most commonly due to C. trachomatis, N. gonorrhoea (young) or E. coli from UTI (older). Other species can cause infection via haematolymphatic spread. o Granulomatous, fungal, syphilitic orchidoepididymitis.

Germ Cell Tumours
Germ cell tumours are the most common type of neoplasm in the testis, with peak incidence between 25-50 yrs. It is widely believed that these tumours arise from intratubular germ cell neoplasias (IGCN). Are considered to be seminomas, non-seminomatous or mixed. Intratubular Germ Cell Neoplasia (IGCN) In situ Lesions Lesions of seminiferous tubules which gives rise to most testicular tumours, known as unclassified type (IGNCU). Is a precursor for the invasive germ cell tumours below. o Identical in morphology to seminoma cells, except non-invasive. Involvement is patchy but 2x3mm biopsies will identify the major parts with IGNC. 40% of cases are bilateral. o Identified in almost all testis with invasive germ cell tumours except spermatocytic seminoma. o 70% with IGCN develop an invasive germ cell tumour within 7yrs. o Risk factors include cryptochidism, prior testicular tumour, primary relative with GCT o Treated by orchidectomy Seminomas Large cell tumours that arise from IGCNs, with classic and spermatocytic types. Classic Characteristic classic triad of large tumour cells (with Seminomas cytoplasmic clearing), fibrous tissue and lymphocytes o The most common germ cell tumours (50% of all cases). o May present with painless mass, 15% normal on examination. o 30% have metastasised at presentation, but rarely have symptoms from these metastases. o Serum AFP (alpha fetoprotein) normal, 10-20% have ↑ β-HCG (human chorionic gonadotropin). Spermatocytic Occur only in testes (2% of germ cell tumours). Seminomas o Consist of small, intermediate and large cells. o Patients in their 50s and present with a mass. o Very rarely metastasise. o Usually cured with orchidectomy.

Non-Seminomatous Germ Cell Tumours (NSGCT) Group of tumours which may arise from IGCN or seminomas. Embryonal Ill-defined invasive masses with foci of haemorrhage and Carcinoma necrosis. o Second most common germ cell tumour (20% of cases) and present in the majority of mixed GCT. o Mostly 20-30yr men with testicular mass, very rare in children and older men. o >2/3 have metastasis, but only 10% symptomatic. o Serum AFP normal, 60% have ↑ β-HCG. Yolk Sac Tumour ‘Endodermal sinus tumour’ with multitude of histological patterns. o Children: most common testicular cancer in children where it occurs in pure form. Is usually diagnosed before 24months age. o Adults: pure form rare, but found in 50% of mixed GCT. o Usually presents with a mass, ↑ Serum AFP o In children orchidectomy alone is curative in 90%. Teratoma Tumour of all three embryonic layers (endo-, ecto-, meso- derms). o Adults and children present with a testicular mass. o Children: 2nd most common GCT in children, occurs in pure form, diagnosed around 20months. Metastases don’t occur in children. o Adults: component of mixed GCT, is identified in >50% of mixed tumours, however still treated like a pure NSGCT. Metastasis occurs in adults. Choriocarcinoma Very unusual pure form (<1% of germ cell tumours) which is bright red tumour (highly vascular) and contains trophoblastic cells with nuclear atypia. o Found in 15% of mixed GCT. o Many patients present with symptoms related to metastases to lungs or brain. ↑ serum β-HCG o Does not develop in children. o Poorer prognosis but tumour is chemosensitive. Mixed Germ Cell Tumours (Mixed GCT) Lesions composed of two or more germ cell tumour types. Comprises 33% of all GCT. Often consists of seminoma and non-seminomatous components. NB: Non-germ cell tumours are uncommon but include sex-cord stromal tumours (sertoli or leydig cell), mixed tumours, haematopoietic tumours and secondary (metastasised) tumours. Testicular Cancer Staging and Treatment
Staging is by common TNM classification, especially metastases; stage 1 (no lymph nodes), stage 2 (lymph nodes), stage 3 (distant metastases). Those with extratesticular extension are considered bulky (16% of cases, mostly at hilum). Treatment depends on type and staging of tumours. All involve orchidectomy.  Seminoma S1, non-bulky S2→ LN radiation. 90-95% cure rate. Seminoma bulky S2, S3→ radiation, chemotherapy. 80% survival rate.  NSGCT S1→ LN dissection. 90-95% survive, 10% relapse. NSGCT S2 non-bulky→ LN dissection, chemo. Cure 90%. NSGCT S2 bulky→ chemo and resection residual masses. Cure 70-80%.

Bacterial Prostatitis is most commonly due to E.coli and other gram –ves.  Pathology: intraprostatic uterine reflux. Get culture positive urine and/or prostatic secretions.  Histology: inflammatory infiltrate with neutrophils.  Clinical: tender prostate, can be acute (febrile illness) or chronic (pelvic pain, recurrent UTI). Non-Bacterial Prostatitis is more common than bacterial.  Leukocytes in secretions but negative culture (not associated with UTI).  STD association; C. trachomatis, U. urealyticum, M. hominis, T. vaginalis.  Can be refractory and difficult to treat.

Benign Prostatic Hyperplasia
Benign enlargement of the prostate gland due to hyperplasia of glandular and/or fibromuscular tissue. Very common in older men. Pathology: is dependent on action of androgenic hormones.  Dihydrotestosterone (DHT) derived from testosterone and mediates growth. Accumulates in prostate, binds to receptors and promotes growth.  Relative increase in oestrogens (oestradiol) in elderly may sensitise prostate to DHT by inducing androgen receptor.  Hence senescence in old men is a strong risk factor.

CZ/TZ- Hyperplasia, PZ- Carcinomas

Morphology: most common in the central and transitional zones (ie. inner part) of the prostate.  Macroscopic: firm rubbery enlargement up to 200g (normal 2g). Benign Prostatic Hypertension o Begins in periurethral glands, compresses them. o Multinodular proliferation surrounded by compressed prostatic tissue (psuedocapsule). o Nodules vary in appearance according to composition (often cystic).  Microscopic: hyperplasia may be glandular, muscular, fibrous or mixed. o Cystic dilation often prominent, containing secretions ± corpora amylacea (calcified amyloid material in ducts). o Often secondary inflammation, infarction (25%) or squamous metaplasia. o Glands have double epithelial lining; in carcinoma it’s single. Clinical: prostatism which involves poor urinary stream, dribbling, frequency, nocturia etc.  Rectal examination shows enlarged, nodular, soft, boggy gland.  Late manifestations relate to urethral obstruction with urinary retention and infection.  Very common, esp >50 (80% at 80 yrs). Common in Australia, USA, Europe but not in Asian countries.

Tumours of the Prostate
Nearly all prostatic neoplasms are adenocarcinomas. Others are very rare, including transition cell carcinomas, squamous cell carcinomas, sarcomas and lymphomas.  Mostly >50yrs (average 75, 10-80% by 80 depending on definition).  Incidence and death rate increasing (aging population, better diagnosis). Over 1000 new cases/yr in WA. 2nd highest cause of cancer death in men.  Common in developed countries, low in Asia. Pathology:  Sporadic Adenocarcinoma (95-97%) begin as carcinoma in situ (usually high grade ± invasion). o Predisposed to by premalignant conditions eg. atypical hyperplasia, duct-acinar dysplasia, prostatic intraepithelial neoplasia. o Other risk factors include; age, race, endogenous hormones and environmental factors.  Hereditary Adenocarcinoma (3-5%), autosomal dominant inheritance. Usually early onset <50yrs and multifocal.

Prostatic Adenocarcinoma

Morphology: 95% in peripheral (outer) zone, most in posterior lobe.  Macroscopic: variable size, often hard pale/yellow fibrous areas, can be multifocal.  Microscopic: usually adenocarcinoma (single epithelial lining) with accompanying hyperplasia (since in elderly men). Perineural invasion very common. Clinical: great variation between clinical significance depending on how adenocarcinoma is defined.  Symptoms: often asymptomatic early, initial symptoms like hyperplasia (prostatism). Back pain and anaemia due to bone metastases in later stages.  Complications: renal complications if urinary obstruction occurs, metastatic complications.  Prognosis: depends on size (volume), grade (Gleason, score), TNM staging. New prognostic factors include; PSA and genetic alterations.  Treatment: nil, surgery, radiation, hormonal (oestrogens, anti-GnRH). Prostatic Cancer Staging
T1- incidental, unsuspected clinically . → T1a/b; volume, grade T2- palpable, confined to prostate. T3- extracapsular invasion → T3a/b; seminal vessel invasion T4- direct invasion of pelvic organs. N0/1- lymph node metastases → if present, N1 incurable NB: T1 and T2 have 90% 15 yr survival. T4 has 10-40% 10yr survival

Prostatic Cancer Grading
Usually determined by Gleason score. 1. A Gleason scale is used from 1-5 to grade the first and second most common tumours in the sample. 2. The Gleason score is the sum of the two grades, ranging from 2-10. NB: the score is most important, but the primary grade is also.

Prostate Specific Antigen
↑PSA is sometimes used to suggest presence of prostate cancer, however controversial. o Absent in some cancers, esp in obese (false negative). o Increased by prostate infection, irritation, benign hyperplasia, recent ejaculation (false positive).


Anatomy/Histology - Ectocervix:
squamous non-keratinizing epithelium which is glycosylated. Lactobacillus uses this glycogen to create an acidic environment within the vagina. - Endocervix: columnar mucin producing epithelium with crypts. - Transformation zone (squamo-columnar junction): squamous metaplasia can occur in this zone (benign). - Ectropion (erosions): glandular epithelium of endocervix extending out onto the ectocervix. Often seen in women who have already given birth to children.

Benign Cervical Processes
Benign Reactive Processes are common with uterine prolapse.  Hyperkeratosis: is abnormal epithelial keratin formation. Can also be parakeratosis (keratosis with maintained nuclei).  Cervicitis: may be noninfectious or infectious which are difficult to distinguish due to commensal microorganisms normally in vagina.  Tubule metaplasia/endometriosis: result in uterine like endometrial glands or stroma in the cervix. Benign Lesions these can be polypoid, papillary or cysts. - Endocervical/Endometrial Polyps: surface projections which may bleed - Nabothian Cysts: endocervical crypts get blocked leading to a buildup of mucous, form a cyst-like dilation in the endocervix. - Condyloma Accuminatum: stalk based papillary lesion caused by HPV infection. Infectious Cervicitis
May occur due to a number of organisms:  Human Papilloma Virus (HPV) is most important due to carcinogenic effects.  Other causes are Candida, Trichomonas, Neisseria, Gardnarella, Chlamydia, HSV, CMV and Tuberculosis.

Condylomatous Lesions
Caused by HPV infection.  Condyloma Accuminatum: benign papillary lesions with fingerlike projections in the cervix (also vagina, vulva). Seen on colposcopy. Generally self limiting. → HPV 6 or 11  Condyloma Planum: flat wart with oncogenic potential for cervical carcinoma (if HPV 16 or 18). → HPV 6, 11 or 16, 18 (more).

Carcinomas of the Cervix
Cervical cancer is the commonest cause of cancer death in women in 3rd world countries.  Highest rates in Africa, South America, Southeast Asia and Aborigines.  Becoming ‘rare’ in countries with long established cervical/papsmear screening.  Mean age of 52 years, 20% of cases <35 years.

Pathology: human papilloma virus (HPV) is responsible for all (>99%) cases of cervical carcinoma. The virus works by triggering alterations in cervical epithelial cells → cervical intraepithelial neoplasia (CIN) → cervical cancer.  E6 and E7 are the principle ‘transforming’ genes of HPV causing neoplastic cellular changes. o E7 interacts with the tumour suppressor Rb gene, blocks proliferation-inhibitory function of cervical cells (↑p16, ↓p21). o E6 interacts with p53 tumour suppressor gene to enhance E7’s effect.  Cervical carcinomas are associated with latent HPV of ‘high risk’ (HPV HR), most commonly HPV 16, 18 (90%), 31, 33.  Other risk factors include smoking, immunosuppression (more prone to persistent infection), number of sexual partners, high parity and low SES.

HPV-Cervical Cancer Relationship
HPV is a papillovirus of a large family with around 150 identified types. These can cause warts, or lead to the development of cancer. Cancer is only associated with HPV 16, 18, 31, 33 (HPV HR). However, despite HPV HR being the strongest risk factor for cancer, these infections are extremely common and are usually self limiting (80% disappear within a year). Higher risk is associated with persistent infection with HPV. Ie. Most women with HPV HR don’t get cancer, but most cervical cancers are caused HPV HR.

Histology: viral cytopathic effect of HPV is characteristically the formation of koilocytes (cells with nuclear atypia and cytoplastic clearing). Carcinoma Precursors: cervical interstitial neoplasia (CIN) is a carcinoma precursor lesion. Not all cases of CIN progress, some stay latent or even regress. Risk of cancer depends on type of CIN lesion.  Low Grade Squamous Intraepithelial Lesion (LSIL) characterised by productive HPV infection. They involve CIN 1 and HPV cytopathic effect. NB: CIN 1 and HPV effect is mostly self limiting. Persistent infection can cause low grade lesions to progress to high grade precursor lesions (HSIL)  High Grade Squamous Intraepithelial Lesion (HSIL) involve CIN 2 and 3 (true precursor lesions). All cervical carcinomas derive from high grade precursor lesions in the surface epithelium.

Precursor Identification and Management
 Pap Smear: an effective screening test. It identifies abnormal lesions and grades. Low Grade lesions → monitor with repeated pap smear. Detection of high grade lesions → colposcopy and biopsy.  Colposcopy: a magnified visual inspection of cervix aided by using acetic acid (vinegar) solution to highlight abnormal cells. Identifies exact site and extent of lesion.  Directed Punch Biopsy: produces an exact diagnosis. Confirmed high grade lesions → LLETZ/cone biopsy.  LLETZ (Large Loop Excision of the Transformation Zone): removal of high grade cervical dysplasia.  Cone Biospy: removal of larger abnormal areas of cervical epithelium.

Invasive Cervical Carcinoma: invariably result from HSIL.  Squamous Cell Carcinoma (60-80%) are microinvasive lesions (<5mm into stroma) with various distinctive patterns. Most common, well controlled by papsmears.  Adenocarcinomas (20%) and Adenosquamous Carcinomas (5%) have precursor/in situ stages (AIS). Most are HPV related but papsmears have not been an effective control, hence increasing in relative frequency.  Small Cell Carcinomas are high grade, aggressive neuroendocrine lesions with metastases to endometrium, rectum, bladder, GIT, ovary and breast.

Squamous CC


Morphology: early cervical cancer is only visible by colposcopy, later grossly visible.  Early: focal induration, ulceration and elevated granular area which bleeds readily on touch.  Advanced: lesions can be endophytic (ulcerated/nodular) or exophytic (polypoid/papillary). Clinical: presentation depends on stage, may be asymptomatic until cancer is in advanced stages.  Signs: abnormal papsmear, abnormal bleeding (ie. Instrumental or post sex).  Symptoms: pain (pelvic, back, leg), haematuria, weight loss (metastases).  Behaviour: can invade, form fistulas or metastasise. o Direct local invasion to LN (iliac, obturator),ureteric obstruction. o Formation of vesico-vaginal and recto-vaginal fistulas (leakage of waste into vagina). o Metastases to other organs occurs relatively late (eg. lung).  Staging: FIGO staging depends mainly on spread.  Treatment: depends on stage, includes surgery (hysterectomy, LN), radiation, chemotherapy. Prevention: cervical carcinoma can be preventing by screening or vaccination.  Pap Smear: associated with ↓ 70% in 25yrs. Can potentially prevent 90% of cancers.  HPV DNA Vaccine (Gardasil): for HPV 6,11,16,18. Effective before infection with HPV and is suitable for young girls/women. Staging and Prognosis
Staging (FIGO) is rated 0-4, with prognosis given in 5 yr survival %. 0- In situ, CIN 3 (100%) 1- Confined to cervix (90-95%) 2- Uterus, not pelvic wall (50-70%) 3- Pelvic wall, lower vagina (30%) 4- Distant metastases (20%)

Non-Carcinoma Uterine Lesions
These inflammatory and benign lesions can involve the endometrium (glands and stroma) or the myometrium (muscle). Most patients with abnormal uterine bleeding have benign conditions. Bleeds can be abnormal cyclic (heavy, painful or irregular periods), intermenstrual, post menopausal (most significant) or infertility related. Abnormalities of Cyclical Development the endometrium doesn’t always follow a uniform cyclical progression with oestrogen and progesterone stimulation.  There can be disordered proliferative changes, irregular maturation, inadequate/delayed progestogenic effect (luteal phase) or irregular/delayed shedding.  Correlation with cycle dates and hormonal assessments are required.

Endometritis acute or chronic inflammation of the endometrium characterised by the presence of plasma cells in the stroma. Variable microbiology, and is usually due to ascending infection.  Actinomyces is associated with intrauterine contraceptive devices (IUCD).  Endometritis may lead to pelvic inflammatory disease (PID). Adenomyosis a common benign lesion characterized by deep extension of endometrial tissue (glands and stroma) into the myometrium. Common in women 35-50.  Involves hypertrophy of the myometrium, causing the uterus to become bulky and heavy.  Patients can have painful (dysmenorrheal) or profuse (menorrhagia) menses.  Unknown cause. Possibly due to trauma to the uterus, and excess oestrogen over progesterone.


Endometrial Polyps these are common benign neoplasms with glandular and stromal components. Are commonly attached to the uterus by an elongated stalk (pedunculated) or flat (sessile).  Often asymptomatic, but may cause irregular bleeding, bleeding between periods and after menopause.  Cause not known, but grow in response to oestrogen and during Tamoxifen treatment. Endometrial Polyps  Neoplastic tumours may arise from these polyps.

Endometrial Carcinoma
Refers to several malignancies arising from the endometrium. It is the most common gynecological malignancy in regions with cervical cancer screening. Pathology: classified as type 1 and type 2 endometrial carcinomas. Familial risk is important with association with PTEN, MMR and p53 (type 2) gene mutations. History of Lynch syndrome or colorectal cancer also increases risk. Type 1 Endometrial Carcinomas (80-85%) are associated with unopposed oestrogen exposure and/or endometrial hyperplasia precursor lesions.  Precursor hyperplasia is classified as simple/complex and typical/atypical.  Atypical hyperplasia (endometrial intraepithelial neoplasia, EIN) has the highest cancer risk.  Endometrioid subtypes looks similar to normal endometrium.  Hyperoestrogenic states include obesity, anovulation, hormonal therapy, oestrogen secreting tumours and relative progesterone deficiency.  Often occur in younger women (pre or perimenopausal). Endometrial Carcinoma  Usually low grade/early stage, generally good prognosis. Type 2 Endometrial Carcinomas (10-15%) are not associated with raised oestrogen and involve serous or clear cell types.  Precursor lesions include EIC and serous carcinoma in-situ,  Similar molecular pathology as invasive serious carcinoma (ovarian carcinoma).  Usually occur in older patients (with post menopausal atrophic uteri)  Often high grade with extrauterine spread, generally poor prognosis.

Clinical: usually in post menopausal women (although it can occur at any age). Often confined to the uterus at diagnosis, with  Treatment: hysterectomy ± bilateral salpingo-oophorectomy (removal of ovaries and fallopian tubes). Lymph node dissection ± omental sampling in high risk cases. → postoperative radiotherapy/chemotherapy.  Prognosis: depends on staging, however overall good prognosis, 80-90% 5 yr survival.

Endometrial Cancer Staging
Stage 1: confined to uterus (subdivided according to depth of myometrial invasion). Stage 2: extension to cervix. Stage 3: Invasion of serosa, adnexae or positive peritoneal cytology. Stage 4: bladder/bowel invasion or distant metastases.

Mesenchymal Tumours
Refers to several malignancies arising from the stromal components, which are usually benign. Smooth Muscle Tumours are very common, and mostly benign.  Leiomyomas (fibroid) are benign lesions, vast majority of uterine SMT. Often multiple and typically hormone dependent, tend to grow in reproductive age group.  Leiomyosarcomas are malignant lesions, <1-2% of uterine SMT. Aggressive tumours with rapid growth, especially post-menopausal. Characterised by increased cellular atypia, mitotic activity and tumour necrosis. Not responsive to therapy (<50% 5 year survival).


Endometrial Stromal Tumours are relatively rare, with most being low grade malignancies. Often progestogen responsive.  Endometrial Stromal Sarcomas

Non-Neoplastic Ovarian Lesions
Cystic and Inflammatory Lesions are relatively common.  Cysts are common, identified on ultrasound.  Polycystic Ovarian Syndrome is a clinic-pathological syndrome of obesity, androgenism, insulin resistance, anovulation, infertility.  Inflammatory Lesions are uncommon, secondary to abdomino-pelvic sepsis, PID, autoimmune. Endometriosis is a common condition (10-15% of women) characterised by growth of tissue resembling endometrium beyond or outside the uterus. Often involves pelvic peritoneum, ovaries, rectosigmoid colon, and rarely distant sites (eg. lung).  Pathology: multifactorial involving retrograde menstruation (flow of menstrual blood into the fallopian tubes), immune and genetic factors.  Morphology: ovarian lesions are often cystic and haemorrhagic (‘chocolate cysts’)  Clinical: present with pain (may be cyclical), effects of adhesions and infertility. Managed by hormonal treatment or surgery (severe cases).  Increased risk of neoplasia (1-2%).

Ovarian Tumours
Tumours of the ovary are amazingly diverse, attributable to the diverse cell types. Ovarian tumours are classified into three groups based on these different cell types; (i) surface epithelial, (ii) germ cell and (iii) sex cord stromal tumours. 1. Surface Epithelial Tumours: (70%) derived from mesothelium covering ovaries which is constantly scarred during ovulation. Further divided into three categories each with various histological subtypes. Overall, serous subtype tumours are the most common, others include mucinous, endometrioid etc. Benign Tumours (serous/cyst adenomas) are characterised by a single layer of columnar epithelium that lines the cyst or cysts. Can have accompanying stromal component. Borderline Tumours (borderline serous tumours) mainly include serous or mucinous types.  Epithelial proliferation and atypia but no destructive tissue invasion.  Generally excellent prognosis.  Serous types: 30-40% have extraovarian ‘implants’, late recurrence/progression may occur. Malignant Tumours (serous/cyst adenocarcinoma) most ovarian malignancies are of epithelial type, hence ‘malignant surface tumours’ is used synonymously with ‘ovarian cancer’. Ovarian carcinomas are usually high grade, with a poor prognosis at later stages (most are detected late).  Pathology: the progression is debated, and precursor lesions generally aren’t identified or accessible for sampling. There is a proposed ‘dual model’ describing the pathogenesis of ovarian cancer; types 1 and 2, each associated with different mutations. o Type 1: mainly low grade carcinomas arising in precursor lesions (endometriosis, benign or borderline tumours). o Type 2: high grade carcinomas probably arising from ovarian Serous Cystadenocarcinoma surface epithelium or fallopian tubes.  Cause: not known, but risk factors include multiple ovulation, environmental and hereditary factors. Hereditary ovarian cancer (10-15% cases) mainly associated with BRCA 1 (usually high grade serous carcinoma) and less commonly BRCA 2/Lynch Syndrome.  Clinical: patients present as they would with most ovarian tumours, Ovarian Cancer Staging except in later stages when metastases occur. Stage 1: confined to ovaries. o Spread: mainly intraabdominal, paraaortic nodes, distant Stage 2: spread to pelvis. (liver, lung etc). Stage 3: spread to o Diagnosis: clinical, radiology (ultrasound, CT), serology extrapelvic peritoneum, (serum CA125) or surgical. lymph nodes or bowel wall. o Prognosis: depends mostly on stage, also grade, subtype, Stage 4: distant metastases. and response to therapy. NB: most are detected in o Screening: not yet established but could involve clinical advanced stages. examination, serum CA125 and ultrasound. 2. Germ Cell Tumours: (20%) often occur in children and young adults, usually benign with mixed differentiation.  Mature Cystic Teratoma are most common, benign dermoid cysts (recognisable dermis).  Malignant tumours are rare, with various types (see male genital notes). Often radio/chemosensitive with good prognosis. Tumour markers (AFP, Benign Cystic Teratoma HCG).

3. Sex Cord Stromal Tumours: (5-10%) relatively uncommon stromal tumours that are mostly benign.  Thecoma-fibroma consist of solid grey fibrous cells to yellow (lipid laden) thecal cells.  Granulosa-thecal cell tumours consist of granulosa and thecal cells with cystic spaces. o 3-5% of ovarian malignancies, usually post menopausal. Often with oestrogenic release (can lead to endometrial/breast cancer). o Late metastases common.  Sertoli-Leydig cell tumours (androblastomas) result in androgen production and virilism.  Many are low grade (granulosa and sertoli tumours) and may present with effects of hormone secretion. Androblastoma
Clinical Presentation of Primary Tumours Clinical presentation of all ovarian tumours is similar despite their morphological diversity, Usually asymptomatic until large enough to cause local pressure problems. -Exception: functioning neoplasms with hormonal effects (eg. granulosa-thecal tumour). Patients can present with palpable abdominal/pelvic mass, abdominal swelling (tumour, ascites), GIT symptoms (diarrhoea, constipation), vascular obstruction (DVT, oedema) or distant metastases. NB: although germ cell/stromal cell tumours make up around 30% of tumours, they are only responsible for <10% of malignant tumours as most are benign.

Metastatic Tumours: (5%) can be difficult to distinguish from a primary ovarian carcinoma histologically. Primary sites include colorectal, appendix, stomach, pancreas, endometrium, breast etc.  Krukenberg Tumour a secondary ovarian malignancy with primary site from the GIT (gastric origin most common). Metastatic carcinoma, usually bilateral with mucin producing signet ring cells. Prominent reactive stromal proliferation.

Fallopian Tube Pathology
Salpingitis is usually due to ascending infection of the genital tract.  Can be acute or chronic with variable microbiology.  Inflammatory infiltrate and fibrosis can lead to serosal adhesions distorting the fallopian tubes → adhesions can cause hydrosalpinx, due to obstruction → infertility. Ectopic Pregnancy is very common (1/80), with the fallopian tubes being the most common site.  Signs/symptoms include pain, post vaginal bleed, and positive pregnancy test.  Increased risk with tubule abnormality (salpingitis, endometriosis)  Ultrasound diagnosis, may be surgical emergency due to acute bleeding into peritoneal cavity. Tumours of Fallopian Tube are uncommon, malignancies rarer, but incidence depends on definition.  Some ovarian and peritoneal carcinomas may arise in the fallopian tube (and perhaps previous ovarian primaries are instead secondary to fallopian carcinoma).  Increased risk with BRCA 1 patients.  Usually serous carcinomas, may spread even when in-situ. Tumours of the Peritoneum most are metastatic (GI, biliary, cervical, uterus etc), primary malignancies include mesotheliomas and carcinomas.  Most primary carcinomas are high grade serous carcinomas (similar appearance, behaviour and treatment similar to ovarian serous carcinoma).  Diagnosis of exclusion, increased risk in BRCA 1 mutation


Fibrocystic Changes
A range of changes that occur in breast tissue, due exaggeration and distortion of the normal cyclic (menstrual) hormonal changes that affect the breast.  Tend to arise during the reproductive period but may persist after menopause.  Can produce ‘lumps’ and are classified as non-proliferative or proliferative lesions. Cysts and Fibrosis are non-proliferative lesions, characterised by an increase in fibrous stroma, dilation of ducts and formation of cysts.  Most common alteration, cysts are usually multifocal and often bilateral.  Cysts are brown-blue (blue dome cysts) and filled with serious, cloudy fluid.  Cysts may calcify, become visible on mammograms (1-5cm).  These lesions don’t increase the risk of breast cancer.

Fibro-cystic Change

Epithelial Hyperplasia proliferative lesions within the ductules, terminal ducts and lobules. Can be typical or atypical (similar to ductal carcinoma in-situ).  Lumen filled with heterogenous cells of different morphologies, with irregular slit-like fenestrations, esp at periphery.  Atypical hyperplasia is associated with 5x risk of carcinoma (10x with family history). Sclerosing Adenosis lesion with proliferation of ductule and acini cells, aggregation of proliferating ductules (adenosis), and marked intralobular fibrosis (sclerosing).  Can be clinically and morphologically similar to invasive ductal carcinoma.  Hard, rubbery consistency similar to cancer, associated with 1.5-2x risk of carcinoma.

Normal Duct

Epithelial Hyperplasia

Sclerosing Adenosis

Inflammations of the breast are uncommon, causing pain and tenderness in the involved areas during the acute stages. Not all inflammations increase risk of cancer. Acute Mastitis develops when bacteria gains access to the breast tissue through ducts.  Can occur when there is; thickening of secretions, fissures in the nipples (nursing), or various forms of dermatitis involving the nipple.  Usually Staphylococcus, can induce abscess formations which heal with scarring (hardened areas within breast).  Rarely due to Streptococcus, which causes a spread out infection of entire breast, with pain, swelling and tenderness. Mammary Duct Ectasia (periductal or plasma cell mastitis) is a non-bacterial chronic inflammation of the breast. Associated with thickening of breast secretions in the main excretory ducts.  Ductal dilation with rupture leads to inflammatory changes in the surrounding breast tissue.  Characterised by lymphocytic/plasma cell infiltration and granulomas in periductal stroma.  Uncommon, generally occurring in 40s and 50s.  Lesions cause hardening on the breast and retraction of the skin and nipple, mimicking changes caused by carcinomas. Mammary Duct Ectasia Traumatic Fat Necrosis is an uncommon and innocuous lesion producing a mass, often associated with preceding trauma to the breast.  Lesions are small (<2cm), tender and sharply localised. Have central focus of necrotic fat cells surrounded by neutrophils and lipid filled macrophages.  Focus replaced by scar tissue or debris encysted in scar capsule. Calcification may then develop.

Benign Tumours
Fibroadenoma most common neoplasm of female breast, composed of fibrous and glandular tissue. Usually occurs in young females.  Lesions are discrete, firm, freely moving nodules (1-10cm).  Usually solitary, but can be multiple/bilateral.  Development of these lesions is associated with an increase in oestrogen. Phyllodes Tumor much less common, thought to arise from periductal stroma and not from pre-existing fibroadenomas.  Lesions may be small, but many grow very large, distending the breast.  Usually benign, localised and cured by excision.  Malignant lesions usually remain localised, except the most malignant (15%) do metastasise. Intraductal Papilloma a solitary neoplastic papillary growth within a lactiferous duct/sinus.  Intraductal papilloma presents clinically as (i) serous or bloody nipple discharge, (ii) presence of small subareolar tumour, or (iii) nipple retraction (rare).  Intraductal Papillomatosis involves multiple papillomas in several ducts, sometimes malignant.

Breast cancer is the second highest cause of cancer, and cancer death (15%) in women.  Lifetime risk of 1/8 for women in US/Australia, 75% occur when women over 50.  Incidence has been increasing (reason not known, possibly earlier detection via mammography). Pathogenesis: not known but genetic, hormonal and environmental influences have importance. Genetic Influences  Familial: 5-10% of breast cancers are related to specific BRCA1 and BRCA2 Genes inherited mutations. Majority are with the BRCA1 and Majority of inherited breast cancers are BRCA2 genes, less commonly involve p53, PTEN and ATM attributed to BRCA1 and BRCA2 genes genes. (highly penetrant, austosomal dominant). o Increased risk with history of breast cancer in 10  BRCA1 and BRCA2 genes are thought relative, esp if multifocal or premenopausal. to function in DNA repair, acting as o Familial cancer tend to occur at younger age and tumour suppressing genes. are more severe/bilateral.  Cancer arises when both alleles are inactive/defective, one mutant  Sporadic: 90-95% have no known cause, probably multiple BRCA allele is inherited, and the genes interacting with environmental factors contributing second allele is inactivated by to breast cancer genesis. somatic mutation. o Overexpression of HER2 proto-oncogene is found in  BRCA1 and BRCA2 mutations are rare 30% of invasive breast carcinomas. Is a member of in sporadic breast cancer. the ‘epidermal growth factor receptor’ family, and  Most patients with these mutations its overexpression is associated with poor prognosis develop breast cancer by 70yr. (stimulates cell growth, not a cause). Hormonal Influences Hormonal imbalance plays a significant role. Oestrogen stimulates growth factor production by epithelial cells. If epithelial cells are neoplastic, this production can be exaggerated, leading to an autocrine mechanism of tumour development.  Increased exposure to oestrogen peaks during the menstrual cycle. o Long duration of reproductive life (menarche to menopause), late age of pregnancy, and nulliparity (no previous pregnancy).  Prolonged exposure to exogenous postmenopausal oestrogens (ie. HRT) Environmental Influences  Age: rare under 30, however risk increases with age and plateaus after menopause.  Geography: risk much greater in Western countries, due to environmental factors such as diet, reproductive patterns, and nursing habits.  Previous Breast Lesions: in order of risk; proliferative lesions, atypical proliferative lesions, ductal/lobular carcinoma in situ.  Ionising Radiation: to the chest increases risk depending on dose and duration. Only women irradiated before 30, during breast development, seem to be affected.  Lifestyle Factors: obesity, alcohol, high fat diet; are all less well established factors.

Morphology: Breast cancers are classified into those that have not yet penetrated the limiting basement membrane (non-invasive) and those that have (invasive). Non-Invasive Carcinomas Two types of breast cancers both of which arise from the terminal duct lobular unit.  Ductal Carcinoma In-Situ (DCIS) is a neoplastic epithelial Paget’s Disease of the Nipple proliferation, precursor to invasive ductal carcinoma. Is Caused by the extension of DCIS up to typically found on mammographic examination as the lactiferous ducts and adjacent to calcifications or a mass. the skin of the nipple. Presents as a o Classified by growing pattern (solid, cremedo, unilateral crusting exudate over the cribiform, papillary, micropapillary) nipple and the areolar skin. An underlying invasive carcinoma may be o Graded as low (monotonous nuclei) or high present, and prognosis is based on the (pleomorphic) grade. underlying carcinoma. o Risk and rate of DCIS progression is thought to be proportional to grade (ie. low grade DCIS → slower progressing, low grade IDC). o Prognosis is very good (>97% survival with mastectomy ± radiation therapy, Tamoxifen). o When invasive cancer develops, it is usually in the Paget’s Disease same breast and of ductal histology.  Lobular Carcinoma In-Situ (LCIS) is an expansion of the lobules by discohesive, bland neoplastic cells. This lesion is frequently an incidental finding and doesn’t form masses or calcification. o Approximately 1/3 of women with LCIS will develop invasive carcinoma. o When invasive carcinomas develop, it occurs in either breast with the same frequency, and may be lobular or ductal carcinoma. Invasive (Infiltrating) Carcinomas Invasive Ductal Carcinoma (IDC) (80%) replaces normal breast fat, forming a hard palpable mass with abundant fibrous stroma (hence also called ‘Scirrhous carcinoma’). o Usually associated with DCIS, rarely LCIS o Invasion of lympho-vascular spaces along nerves. o 2/3 express ER and PR, 1/3 over-express HER2. Invasive Lobular Carcinoma (LCIS) (10%) consist of cells morphologically identical to cells of LCIS. o Metastasize to CSF, serosal surfaces, GIT, ovary, uterus, and bone marrow. o Mainly multicentric and bilateral. Express ER/PR receptors.  Others: there are some relatively uncommon special types of invasive carcinoma, most being rare variants of IDC . o Invasive tubular carcinoma small palpable masses (<1cm) seen on mammogram. Well formed tubules. o Medullary Carcinoma sheets of large anaplastic cells, may be mistaken for fibroadenomas. o Colloid (Mucinous) Carcinoma produce abundant quantities of extracellular mucin which invades stroma. o Metaplastic and squamous carcinomas (poor prognosis).
Ductal Carcinoma Breast Carcinoma

Inflammatory Carcinoma
A clinical presentation of an enlarged, swollen and erythematous breast, usually without a palpable mass. o Clinical appearance is due to blockage of dermal lymphocytic spaces by carcinoma. o Underlying carcinoma is generally poorly differentiated and diffusely invades the breast parenchyma. o Distant metastasis → poor prognosis.

Clinical: the most important clinical consequence is lymphatic and haematogenous spread.

Tumour Locations
Breast cancers affect the left breast slightly more. About 4% of women with breast cancer have bilateral primary tumours or sequential lesions in the same breast. Locations of the tumours within the breast are:      Upper outer quadrant (50%) Central Portion (20%) Lower outer quadrant (10%) Upper inner quadrant (10%) Lower inner quadrant (10%)

   

Outer quadrants and centrally located lesions typically spread first to the axillary nodes. Inner quadrants often involve the lymph node along internal mammary arteries. Metastases can occur in any organ, but most common in lung, bone marrow, liver, adrenals and (less commonly) the brain and spleen. Metastases may appear many years after apparent therapeutic control of the primary lesion (decades).

Prognosis: 20% mortality which is influenced by the following variables.  Staging (TNM): size of tumour, lymph node involvement Modified Blood-Richardson Grading and distant metastases. Method  Grading of Carcinoma: grading is by the modified Bloomevaluates tubule formation, nuclear grade, Richardson method, which and mitotic rate. Each feature is given a score  ER/PR: better prognosis with presence, as respond to of 1-3, and added for a final sum ranging anti-oestrogen therapy. from 3-9:  HER2 Overexpression: associated with a poorer prognosis o 3-5: Grade 1 tumour due to its growth stimulating ability. Evaluating HER2 (well differentiated, better prognosis) o 6-7: Grade 2 tumour predicts response to Herceptin (HER2 antibody). (moderately differentiated)  Proliferative Rate of Cancer o 8-9: Grade 3 tumour  Histological type of Carcinoma: special types of (poorly differentiated, poorer prognosis) carcinoma (tubular, medullary, mucinous etc) have better prognosis than invasive ductal carcinomas.

Male Breast
Gynocomastia enlarged male breast which may occur in response to oestrogen excess.  Associated with liver cirrhosis (inability of liver to metabolise oestrogen), oestrogen secreting tumours, oestrogen Therapy, and anabolic steroids  Physiologic gynocomastia often occurs in puberty and old age. Male Breast Carcinoma is uncommon, 120x less likely than females, mostly in the elderly.  Associated with BRCA2 mutations, Klinefelter syndrome, excess oestrogen, obesity, and testicular abnormalities.

(Draft, written by Natasha P.)

Macroscopic Terms
Macule Patch Papule Nodule Plaque Vesicle Bulla Blister Pustule Wheal Circumscribed lesion <5 mm diameter characterized by flatness and usually coloration. Circumscribed lesion >5 mm diameter characterized by flatness and usually coloration. Elevated dome-shaped or flat-topped lesion <5 mm across. Elevated dome-shaped lesion >5 mm across. Elevated flat-topped lesion >5 mm across Fluid-filled raised lesion <5 mm. Fluid-filled raised lesion >5 mm across. Common term used for vesicle or bulla. Discrete, pus-filled, raised lesion. Itchy, transient, elevated lesion with variable blanching and erythema formed as the result of dermal edema. Scale Dry, horny, platelike excrescence; usually the result of imperfect cornification. Lichenification Thickened and rough skin characterized by prominent skin markings; usually the result of repeated rubbing in susceptible persons. Excoriation Traumatic lesion characterized by breakage of the epidermis, causing a raw linear area (i.e., a deep scratch); often self-induced. Onycholysis Separation of nail plate from nail bed.

Microscopic Terms
Hyperkeratosis Parakeratosis Hypergranulosis Acanthosis Papillomatosis Dyskeratosis Acantholysis Spongiosis Hydropic swelling (ballooning) Exocytosis Erosion Ulceration Vacuolization Lentiginous Thickening of the stratum corneum, often associated with a qualitative abnormality of the keratin. Modes of keratinization characterized by the retention of the nuclei in the stratum corneum. On mucous membranes, parakeratosis is normal. Hyperplasia of the stratum granulosum, often due to intense rubbing. Diffuse epidermal hyperplasia. Surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae. Abnormal keratinization occurring prematurely within individual cells or groups of cells below the stratum granulosum. Loss of intercellular connections resulting in loss of cohesion between keratinocytes. Intercellular edema of the epidermis. Intracellular edema of keratinocytes, often seen in viral infections. Infiltration of the epidermis by inflammatory or circulating blood cells. Discontinuity of the skin exhibiting incomplete loss of the epidermis. Discontinuity of the skin exhibiting complete loss of the epidermis and often of portions of the dermis and even subcutaneous fat. Formation of vacuoles within or adjacent to cells; often refers to basal cellbasement membrane zone area. Referring to a linear pattern of melanocyte proliferation within the epidermal basal cell layer. Lentiginous melanocytic hyperplasia can occur as a reactive change or as part of a neoplasm of melanocytes.


        Dermatoses Lichen planus and variants Lichenoid drug reactions Lichenoid keratosis Erythema multiforme, FDE GvHD Lupis erythematosus Dermatomyositis Pityriasis lichenoides    Reaction Characterised by epidermal basal layer damage Basal vacuolar change or cell death Accompanying inflammatory infiltrate o Lymphocytes o Histiocytes o Eosinophils Histology Lichen planus  Hyperkeratosis  Epidermal hyperplasia: saw tooth pattern  Wedge shape hypergranulosis  Band like lichenoid inflammatory infiltrate  Basal vacuolar change with Civatte bodies  May have subepidermal clefting: Max Joseph space Lupis  Basal vacuolar change or dyskeratosis  Superficial and deep dermal perivascular lymphocytic infiltrate  Follicular plugging  Usually epidermal atrophy, but can be hyperplastic  Dermal mucinosis  Basement membrane thickening  May have very dense lymphocytic infiltrate: tumid lupis  IF: Positive lupis band Psoriasis  Regular epidermal hyperplasia (acanthosis – thickening)  Elongated club-shaped rete ridges  Parakeratosis (scale)  Mild spongiosis  Superficial dermal perivascular lymphocytic infiltrate  Thinning suprapapillary plates  Neutrophilic infiltration; in stratum corneum, in epidermis forming spongioform pustules, in transit in epidermis  In perivascular areas in superficial dermis

       Psoriasis Lichen simplex chronicus Pityriasis rubra pilaris Parapsoriasis Mycosis fungoides (T cell lymphoma) Secondary to infections etc    Regular epidermal hyperplasia with elongation of the rete ridges Increase mitotic activity Accompanying inflammatory infiltrate o Lymphocytes o Histiocytes o Polymorphs

                Atopic dermatitis (eczema) Allergic contact dermatitis Insect bite reaction Seborrhoeic dermatitis Stasis dermatitis Pityriasis rosea Drug reactions Pemphigus foliaceus Spongiotic vesicular disease Pemphigus vulgaris Bullous pemphigoid Epidermolysis bullosa Erythema multiforme Dermatitis herpetiformis Subcorneal pustular dermatosis Porphyria cutanea tarda (PCT)    Intraepidermal and intercellular oedema ‘eczematous reaction’ Associated inflammatory infiltrate dermatitis  Intracellular oedema within epidermis (spongiosis)  Lymphocytic exocytosis  Intra-epidermal collections of langerhans cells  Superficial perivascular lymphocytic infiltrate with some eosinophils

    Intracorneal and subcorneal Intraepidermal Suprabasilar Subepidermal o subclassified according to the inflammatory infiltrate Miscellaneous Pemphigus vulgaris  Intraepidermal vesicle- acantholysis in the supra basal layer  Superficial dermal lymphocytic and eosinophilic infiltrate with extension into the superficial epidermis  Intracellular IgG and C3 on IF  Several clinico-pathological variants Bullous pemphigoid  Sub-epidermal 100esicle containing mainly eosinophils  Superficial dermal perivascular and interstitial lymphocytic and dense eosinophilic infiltrate  Autoimmune antibodies directed against hemidesmosomes – linear IgG and C3 localised to the roof of the vesicle  Superficial dermal oedema especially in pre-bullous lesions Dermatitis herpetiformis  Sub-epidermal vesicle  Papillary dermal micro-abscesses containing neutrophils, nuclear dusts and fibrin  Histologically indistinguishable from linear IgA disease  IF: granular pattern IgA and C3 at the dermo-epidermal junction in DH, linear pattern in linear IgA disease

      Granulomas annulare Necrobiosis lipoidica Sarcoidosis TB, leprosy, syphilis Fungal infections Foreign bodies etc  Chronic dermal inflammation with histiocytes or epithelioid histiocytes o Sarcoidal, TB granulomas o Necrobiotic granulomas o Suppurative granulomas o Foreign body granulomas Granuloma annulare  Dermal necrobiotic granulomatous reaction  Well circumscribed foci of necrobiosis surrounded by palisade of epithelioid histiocytes and multinucleated histiocytes and patchy lymphocytic infiltrate Sarcoidosis  Tight and naked granulomatous inflammatory infiltrate  Usually no necrosis  Various inclusion bodies (non specific); Asteroid bodies, Schaumann bodies, Calcium oxalate crystals, Hamazake-Wesenberg bodies. Leukoclastic vasculitis  AKA hypersensitivity vasculitis  Affects small vessels in the superficial dermis  Fibrinoid necrosis  Swollen endothelium  Perivascular lymphocytic infiltrate, nuclear dust and RBC extravasation Hereditary angioedema  Decreased of dysfunctional esterase inhibitor leads to increased kinin formation

       Senile purpura Disseminated intravascular coagulation Uticaria Vasculitidies (leukoclastic, lymphocytic) Sweet’s syndrome Hypersensitivity Henoch Scholein purpura       Non-inflammatory purpuras Vascular occlusive diseases Uticarias Vasculitidies Neutrophilic dermatoses others

Benign Tumours
Epidermal origin         Seborrhoeic keratosis Wart Squamous papilloma Lentigines Naevi; junctional, compound, dermal Syringoma Trichoepithelioma Sebaceoma

Melanocytic Skin adnexal

Soft tissue

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Dermatofibroma Hemangioma Neural tumours Lipomas

Neurofibromatosis:  NF1 (classic) 1:4000 Chr 17  NF 2 (central acoustic) 1:50 000 Chr 22  Systemic involvement: hypertensive headaches (pheochromocytomas) pathological #, (bone cysts), mental retardation, astrocytomas, short stature, precocious puberty (early menses, clitoral hypertrophy), iris hamartoma (NF1)  Skin: Café-au-lait macules, neurofibromas, plexiform neurofibromas                        Sun exposure (UV-B) Radiation, X-ray exposure Thermal burns Pre-existing organoid naevi, epidermal naevi BCC naevus syndrome Xeroderma pigmentosum Arsenic poisoning Stasis dermatitis of the legs PUVA therapy for psoriasis Transplant, AIDS and immunosuppressed Sun exposure (UV-B) Chronic ulceration Trauma, Burns, Frostbite Fistula tracts, pilonidal sinus Hidradenitis suppurativa Marjolin’s ulcer Dystrophic epidermolysis bullosa Lichen sclerosus etc Increased sun sensitivity (pale skin, blond/red hair, freckles, poor tan History of painful or blistering sunburns during childhood or adolescence (2 or more before 20) Intermittent intense sun exposure Dysplastic naevi Others- genetics, PVC, xeroderma pigmentosum        Multifocal superficial Nodular Infiltrating Morphoeic Mixed Other (Tumour cells can resemble epidermal basal layer)

Malignant Tumours
Basal cell carcinoma         Squamous cell carcinoma    Most common skin tumour 70% all skin malignancies BCC:SCC = 5:1 Sun exposed skin of fair individuals 80% head and neck Male, older patient Most slow growing (some aggressive) Metastasis rare Second most common skin malignancy Sun exposed areas of fair skinned individuals Most arise in the head and neck, dorsum of hands, vermillion border Malignant melanoma of melanocytes Qld highest rate in world 55.8/100000 Lifetime risk 1/87 4.6% male mortality

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Similar to SCC from other sites Malignant squamous cells with dermal invasion Dyskeratosis, acantholysis Spindle cell, verrucous, adenosquamous variants

Malignant melanoma

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Lentigo maligna melanoma (5-15%) Superficial spreading melanoma (50-70%) Nodular melanoma (15-35%) Acral lentigonous melanoma (5-10%) Desmoplastic, neutropaenic melanoma Unclassified histo types

Histological classification of melanoma has no effect on the prognosis of the tumour Melanoma prognosis depends on the clinical staging, melanoma thickness, level of invasion and a few other histological classifications Staging  Metastasis in any form (local, satellite nodule, metastasis in a scar, regional lymph node metastasis, distal visceral metastasis) confers a poor prognosis, as it indicates that melanoma cells have entered the systemic circulation and can survive the body’s defence mechanism  Metastasis is only lethal if it affects a vital organ Microscopic description: minimum essential elements CORRECT diagnosis of MM  Spitz naevus (benign)  Nevoid melanoma  Melanoma arising in naevus  Dysplastic naevus  Atypical melanocytic lesions  Melanocytic tumour of unknown biologic potential, minimal deviation melanoma, malignant blue naevus, mucosal melanoma etc Maximum tumour  SIZE mm  5 year survival %  Measures tumour volume thickness according to the  Vertical measure from the granular layer of the epidermis to the  < 0.76  98 method of Breslow, deepest part of melanoma  0.76-1.49  96 measured to the nearest  One dimensional estimate of the tumour bulk or tumour volume  1.5-2.99  86 0.1mm  Most accurate yet imprecise guide to the behaviour of some  3.0-3.99  79 melanomas (thin melanomas that metastasise  4<  58 Clark level of invasion LEVEL Level of invasion  anatomical compartment I Intraepidermal in situ  Provides useful prognostic information in melanoma arising in very thick or very thin skin and in thin melanomas II Invasion of papillary dermis III Invasion/expansion of papillary dermis IV Invasion of reticular dermis V Invasion of subcutaneous layer Completeness of excision  Entire tumour must be thoroughly sampled  Margins examined for the presence of invasive melanoma, in situ melanoma and other atypical melanocytic lesions Microscopic measurement of margins of excision

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Pituitary abnormalities result in mechanical and functional problems.  Mechanical: raised ICP, bony erosion (sella turcica) and local pressure on anatomical relations (3rd ventricle, hypothalamus, optic chiasm or CN III-VI).  Functional: hypo or hyperpituitary secretion with associated clinical syndromes. Hormone Hypersecretion Hyposecretion GH Gigantism, Acromegaly Dwarfism PRL Amenorrhoea, impotence ACTH Cushing’s disease Hypoadrenalism FSH/LH Usually silent, rare testes enlargement Hypogonadism or menstrual irregularities TSH Very rare – causes hyperthyroidism Hypothyroidism Plurihormonal GH + PRL with other combos – probably Panhypopituitarism (Simmond’s disease common eg. Sheehans syndrome) ADH Inappropriate ADH secretion Diabetes insipidus Pathological Hyperplasia (primary or secondary to Surgery, tumour destruction of >75% of Lesion ectopic promoters of secretion), gland, ischaemia (eg. Sheehans Neoplasia syndrome), inflammation, hypothalamic lesions etc.

Anterior Hyperpituitarism
Pituitary Adenomas Most common cause of hyperpituitarism is an isolated adenoma in the anterior lobe (3% are associated with MEN-1). Found in 20% of population post-mortem, represent about 15% of all intracranial neoplasms, most non-functioning and benign. Mutation of the GNAS1 gene, which results in continual activation of Gsprotein is a common cause.

Pituitary Adenoma

They are classified on basis of cell type, function and size:  Cell type: based on immunohistochemical stains of hormone(s) produced by neoplastic cells.  Function: can be clinically functional (clinical symptoms due to hormone excess), silent (hormone production demonstrated without clinical manifestations) or hormone negative (no hormone specific differentiation demonstrated, rare).  Size: microadenoma (<1cm) or macroadenoma (>1cm). Note that silent/hormone negative adenomas tend to be larger when diagnosed as they usually come to clinical attention at a later stage (eg. after mechanical symptoms). Most functional pituitary adenomas consist of one cell type and produce one hormone, although there are exceptions. Clinical symptoms vary according to type of cells involved: Type of Adenoma Clinical Manifestations Prolactinoma -Most common hyperfunctioning pituitary adenoma resulting in amenorrhea, galactorrhea, loss of libido and infertility. -Often composed of chromophobe cells (lack of granules/staining). -Stalk effect; condition can be caused by compression of stalk which prevents dopamine from inhibiting prolactin release GH-producing -Somatotroph adenomas are second most common, often plurihormonal Adenoma with prolactin. -Gigantism occurs when excess secretion occurs before epiphyses close resulting in hepatic secretion of ILGF-I and hence increased body size with disproportionate long arms and legs.

Corticotroph Adenoma Thyrotroph Adenoma Gonadotroph Adenoma Non-functioning and Hormone negative

-Acromegaly occurs when such secretions occur after epiphyses close resulting in acromegalic facies, goitre, hyperstosis (thoracic vertebrae), cardiomegaly (with hypertension), barrel chest, insulin resistance, male sexual dysfunction, large hands and feet, arthritis, peripheral neuropathy and thickened skin (increased glands). -Excess ACTH results in Cushing’s disease (hypercortisolism) which can occur from other sources (see below). -Rare cause of hyperthyroidism (see below) -Difficult to recognise due to lack of clinical syndrome. -Usually detected later when mass (eg. impaired vision, headaches) or hypopituitary effects (pressure invasion) occur. -Usually detected later when mass (eg. impaired vision, headaches) or hypopituitary effects (pressure invasion) occur.

Other Causes Hyperpituitarism can occur from non-neoplastic causes, although less common:  Pituitary hyperplasia can be primary, or secondary to changes in peripheral target organs.  Carcinomas are exceedingly rare. Often extend beyond sella turcica with distant metastases.  Hypothalamic disorders can result in increased stimulation and hyperplasia of pituitary cells.  Ectopic secretion of hormones by extra-pituitary tumours is rare.

Anterior Hypopituitarism
Hypofunction of adenohypophysis is usually caused by acquired conditions (rarely congenital):  Non-functioning pituitary adenomas are usually detected at Sheehan Syndrome a later stage after they enlarge causing mass effects. Postpartum panhypopituitarism Enlargement can cause pressure atrophy of adjacent cells. (Simmond’s disease) results from  Ischaemic necrosis of anterior pituitary is important cause, haemorrhage caused by increased however >75% loss of parenchyma must be lost before pituitary size without increased blood flow during pregnancy. clinical consequences develop. This can occur in Sheehan Sheehan’s results in decreased syndrome or less commonly in DIC, elevated ICP, sickle cell MSH, TSH, prolactin, ACTH and anaemia or traumatic injury. FSH/LH.  Removal of the pituitary by surgery or radiation.  Disorders that interfere with delivery of stimulating hormones from hypothalamus eg. hypothalamic tumours. Less frequent, usually accompanied by posterior pituitary dysfunction.  Other pathological lesions eg. traumatic, inflammatory (TB, syphilis, fungi etc.), vascular, infiltrative (amyloid etc.).

Posterior Pituitary Syndromes
Abnormal oxytocin synthesis and release has not been associated with any significant clinical abnormalities. Important syndromes of the posterior pituitary involve ADH production.  Syndrome of inappropriate ADH (SIADH) secretion is ADH Diabetes Insipidus excess caused by local injury to hypothalamus or extracranial diseases Diabetes insipidus is an ADH (usually ectopic production in the lung). Results in hyponatraemia and related disorder that causes cerebral oedema (neurologic dysfunction). No peripheral oedema. diabetes like symptoms  ADH deficiency (diabetes insipidus) can occur from damage to (polyuria, polydipsia). pituitary by trauma, infection/inflammation, surgery or tumours. 30% Central form is a result of ADH deficiency due to various causes. of cases are familial. Loss of ADH causes failure of water resorption by Nephrogenic form is caused by the renal tubules resulting in abundant dilute urine (polyuria), renal tubular unresponsiveness excessive thirst (polydipsia) and increase serum sodium/osmolality.
to ADH.

Hyperthyroidism is the most common cause of thyrotoxicosis (increased T3/T4) although the terms are used interchangeably. Causes: varying, all of which have an increase in T3/T4 associated with a decrease in TSH (except pituitary neoplasm).  Grave’s disease is most common endogenous cause (see side note)  More commonly: nodular colloid goitre, functioning thyroid adenoma  Less commonly: carcinoma, ectopic production, drugs, secondary to pituitary adenoma (increased TSH) Grave’s Disease (Primary Hyperplasia/Goitre)
The most common cause of hyperthyroidism (85%), especially in young females with HLA-B8 and –DR3 gene haplotypes (define which antigens detected by Tcells). Pathology: It is an autoimmune disorder caused by IgG antibodies (TSI, TGI, TBII are also immunoglobulins) that bind the TSH receptor and mimic TSH action resulting in diffuse hyperplasia/hypertrophy of follicles and lymphoid infiltrates. Clinically: triad of thyrotoxicosis (follicle hyperplasia), opthalmopathy (exophthalmos, lid lag) and dermopathy (pretibial myxoedema).

Clinical Manifestations: changes (often subtle) are due to the hypermetabolic state and overactive sympathetic nervous system, induced by excessive thyroid hormone:  Constitutional: warm sweaty skin, flushed, heat intolerance, weight loss  Cardiac: palpitations, tachycardia, high output cardiac failure  Neuromuscular: nervousness, agitation/irritability, tremor, muscle weakness/wasting  Ocular: wide staring glaze, lid lag, exophthalmos (proptosis) in Grave’s disease  Goitre: associated with hyperfunctioning goitre

Causes: reduction in thyroid function can arise from a primary or secondary cause.  Primary: intrinsic abnormality of the thyroid, congenital (eg. aplasia/hypoplasia, metabolism defects) or acquired (eg. surgery, radiation, iodine deficiency, goitrogens, thyroiditis).  Secondary: hypothalamic or pituitary disease (uncommon)

Thyroid Atrophy

Clinical Manifestations: can manifest itself as cretinism or myxoedema depending on when it develops in the patient.  Although all cases of hypothyroidism have low T4, TSH is increased in primary cases while decreased in those due to secondary disease.  Pathological features also depend on cause; the gland may be atrophic or enlarged (goitre). Cretinism
Hypothyroidism that manifests in infancy or early childhood resulting from lack of T3/T4 during development. Cretinism results in; impaired mental/physical development, dry rough skin and face abnormalities (puffy eyes, large tongue, broad nose).

Hypothyroidism that develops in older children and adults (more common in females). Low T3/T4 causes subtle changes; slowing of physical/mental activity, lethargy, weakness, cold intolerance, slow speech, constipation and hypercholesterolaemia. Mucopolysaccharide rich oedema also causes subcutaneous thickening, broadened/course facial features and a hoarse voice.

Persistent enlargement of the thyroid that can occur in eu-, hypo- and hyperthyroid states. Goitre is the most common manifestation of thyroid disease.  Simple colloid goitre; diffuse hyperplasia of follicular cells (to 150gm) → irregular colloid accumulation → simple goitre.  Nodular colloid goitre; simple colloid goitre → recurrent episodes of hyperplasia and involution → more irregular enlargement of thyroid → cut surface with nodules of irregular size separated by fibrous tissue. Benign Note: haemorrhage, cysts, scarring and calcification in nodular goitre. Multinodular Goitre Causes: often endemic iodine deficiency, goitrogens (cabbage, turnips, CaCl2, cyanates, iodides etc.), metabolic defect or Grave’s disease (see above). Clinical Manifestations: dominant symptoms caused by mass effects (eg. airway obstruction, dysphagia, vessel compression, cosmetic problems).  If goitre is insufficiently compensating for iodine deficiency hypothyroidism will result.  Other goitres are hyperfunctioning (toxic) resulting in hyperthyroidism.

Thyroiditis encompasses a diverse group of disorders characterised by some form of thyroid inflammation. Hashimoto’s Disease
Chronic lymphocytic (Hashimoto) thyroiditis is most common cause in populations with sufficient iodine. It occurs at any age, being more common in females. Pathology: HLA-DR5 and HLA-DR3 associations (define Tcell antigen recognition). Deficient suppressor Tcells permit development of variety of auto-antibodies. Overall effect is depletion of thyroid epithelial cells and mononuclear cell replacement (Hurthle cells). Rare atrophy and fibrosis. Clinically: usually hypothyroidism, however may be hyper (transient) or euthyroidism. Associated painless enlargement. Slight increase risk of lymphoma, carcinoma.

Non Specific Forms  Infective thyroiditis: invasion results in acute illness with severe thyroid pain.  Palpation thyroiditis: caused by vigorous clinical palpation of gland resulting in follicular disruption associated with chronic inflammation (however no abnormalities). Specific Forms  Hashimoto disease: autoimmune disease, most common cause in populations with sufficient iodine.  De Quervain’s disease: self limiting disease, probably secondary Hashimotos Disease to viral infection.  Reidel’s struma: rare idiopathic (likely autoimmune) disease with extensive fibroses involving the thyroid and neck structures. Thyroid becomes hard and fixed.

de Quervain’s Disease
Subacute granulomatous (de Quervain) thyroiditis is a self limited disease, commonly affecting middle aged women. Probably secondary to a viral infection, also has HLAB35 associations. Granulomatous inflammation causes painful enlargement, fever, malaise ± transient hyperthyroidism.

Thyroid Neoplasms
Thyroid gland gives rise to a variety of neoplasms that present mostly as solitary thyroid nodules.  Only 1% of all thyroid nodules are neoplastic, most of which are epithelial.  Different types of neoplasms have very different natural histories.  Diagnosis involves imaging, cytology, excision and histological assessment. Thyroid Adenomas are the most common benign neoplasm. They are derived from the follicular epithelium with differing patterns.  Most are non-functional, functional adenomas usually result from mutations activating the TSH receptor (causes follicular growth and hyperthyroidism).  Adenoma cells are histologically demarcated from parenchymal cells by a well-defined, intact capsule. Distinguished from follicular carcinoma by lack of capsular/vascular invasion. Papillary Carcinoma (80%) most common thyroid carcinoma often occurring in young females. Increasing incidence associated with radiation and alterations in RET proto oncogene.  Often multifocal (may be hidden) and metastasise to regional lymphatics, however prognosis is very good (0.2% mortality).  Diagnosis based on nuclear features (ground glass nuclei, pseudo inclusions), even in absence of papillae. Psammoma calcified bodies are also characteristic.
Thyroid Carcinoma

Follicular Carcinoma (15%) second most common form, usually affecting older females.  Fairly uniform follicular epithelial pattern with two types: o Microinvasive where there is minimal capsular ± vascular invasion (better prognosis) o Widely invasive where extensive and obvious invasion of parenchyma occurs  Diagnosis by evidence of capsular/vascular invasion (micro or widely invasive) and elimination of papillary carcinoma nuclear features.  Can metastasise via blood vessels rather than lymphatics to bones, liver, lungs etc. Medullary Carcinoma (5%) cancer of neuroendocrine (nonepithelial) origin, derived from parafollicular cells (C cells). May be preceded by C cell hyperplasia.  Most secrete calcitonin and have amyloid stroma.  Cytologically variable, may also be solitary or multifocal.  Behaviour also variable, metastasise via blood or lymphatics (65% 10yr survival).  25% are familial cases associated with MEN syndromes 2A/B or other inherited disorders (screening of families essential). Other 75% are sporadic cases. Anaplastic Carcinoma rare, highly aggressive neoplasm that is associated with previous thyroid disease.  Thought to arise from dedifferentiation of already differentiated/damaged cells.  Usually bulky, locally invasive and widely metastatic (very poor prognosis).  Spindle, giant and small cell histological variants.

Causes: excess PTH secretion can be primary, secondary or tertiary and is classified accordingly.  Primary – parathyroid adenoma (commonest, up to 90%), primary hyperplasia, parathyroid carcinoma rare. Parathyroid Adenomas
Typically solitary (if multinodular, hyperplasia suspected). Most in inferior glands (may be ectopic and hard to locate). Pathology: usually chief cell type with monoclonal origin. Most are sporadic, 25% of these have similar Ch11 mutation to familial forms. Rarely associated MEN 1.

Parathyroid Hyperplasia
Primary hyperplasia typically involves all glands. Pathology: mainly chief cells with nodular pattern (polyclonal origin). Hyperplastic chief cells completely replace fatty tissue normally preset in adult parathyroid. May be familial (associated with familial Ch11 gene loss and MEN 1).

Parathyroid Carcinomas
Very rare with variable sizes. Diagnosis is difficult as it requires evidence of invasion ± metastasis. Normally slowly progressive.

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Secondary – hyperplasia usually due to renal disease; less commonly vit D deficiency, intestinal malabsorption, calcitonin producing tumour or pseudo-hypoparathyroidism. Tertiary – ectopic secretion of PTH like substance by non-parathyroid tumour eg. lung SCC, renal, ovarian cancers.

Clinical Manifestations: most clinical problems relate to hypercalcaemia caused by increased PTH. Can be summarised as “painful bones, renal stones, abdominal groans and psychic moans”.  Metastatic calcification; kidneys, blood vessels, lungs, GIT, skin, conjunctiva (worse if phosphate retention).  Bone lesions; osteoporosis, fractures, osteitis fibrosa cyctica (triad of osteoclast Ca resorption, peritrabecular fibrosis and cystic brown tumours)  Renal lesions; calculi, nephrocalcinosis, renal failure  GIT lesions; nausea, vomiting, peptic ulcers, pancreatitis, cholelithiasis  Others; hypertension, muscle atrophy, weakness, headaches, depression, seizures

Causes: hypoparathyroidism is much less common with varying causes.  Surgical removal, often advertently during thyroidectomy  Autoimmune disorder, commonly polyglandular  Congenital absence (polyglandular) and familial syndromes are less common. Clinical Manifestations: characterised by hypocalcaemia and hyperphosphataemia.  Hypocalcaemia; increased neuromuscular excitability, tetany, seizures, paraesthesiae  Cardiac arrhythmias; ECG changes due to decrease serum Ca  Morphological changes; calcification of lens (cataracts), dental abnormalities  Psychiatric disturbances

Pancreatic Endocrine Neoplasms
Islet cell neoplasms are rare, only accounting for 2% of all pancreatic tumours. Characteristics vary and tumours may be functional/non-functional, solitary/multiple and benign/malignant.  Insulinomas; β-cell tumours are the most common of this group and may result in hyperinsulinism. Attacks of hypoglycaemia cause altered consciousness and may be precipitated by exercise or fasting. Approximately 10% are malignant.  Gastrinomas (Zollinger-Ellison syndrome); marked hypersecretion of gastrin due to tumour in pancreas or duodenum. This causes severe peptic ulceration ± diarrhoea. >50% are malignant.  MEN 1; pancreas as well as pituitary, parathyroid ± thyroid, adrenal cortex  Others; glucagonoma, somatostatinoma, VIPoma, multihormonal (all rare).

Diabetes Mellitus
Diabetes mellitus is a group of metabolic disorders sharing the common underlying feature of hyperglycaemia. They result from defects in insulin secretion and/or action, causing abnormalities in carbohydrate, fat and protein metabolism:  Normal glucose metabolism dysregulated (homeostasis disruption)  Inability to transport glucose into cells  Diminished protein synthesis  Breakdown of fat to produce energy can result in ketone body formation and acidosis. Classification Although all forms share hyperglycaemia, the underlying causes vary widely. The vast majority of cases fall into two primary broad classes: Type 1 (insulin dependent) Type 2 (non-insulin dependent) Description -Autoimmune disease characterised by -Combination of peripheral resistance to the progressive destruction of islet β-cells insulin and inadequate pancreatic in pancreas response (β-cell dysfunction) -Leads to “absolute insulin deficiency” -Leads to “relative insulin deficiency” Clinical -Accounts for 10% of cases -Accounts for 80-90% of cases -Early onset (<20yr) -Late onset (>30yr) -Normal weight -Obese (part of metabolic syndrome) Biochemical -Insulin levels low -Insulin can be normal (high early) -Antibodies to islet cells -No islet auto-antibodies -Ketoacidosis common -Ketoacidosis rare -Association with HLA-DR3/4 -Polygenic inheritance Pathology -Non specific T-cell/cytokine insulates -Variety of genetic defects and obesity often with auto-antibodies against β- contribute to insulin resistance. cells. -β-cell dysfunction means inability to -Later atrophy, fibrosis and β-cell adapt to peripheral resistance. depletion/degranulation. -Islet amyloidosis and degeneration at later stages. A variety of monogenic and secondary causes make up the remaining causes of diabetes:  Diseases of the pancreas; haemochromatosis, pancreatitis, neoplasms  Endocrine diseases; Cushing’s, Acromegaly, hyperthyroidism, phaeochromocytoma  Others; genetic defects, infections, carcinoid syndrome, drug-induced, gestational

Clinical Manifestations The clinical manifestations of diabetes include;  Polyuria; glycosuria induces osmotic dieresis  Polydipsia; renal water loss combined with hyperosmolarity  Polyphagia; increased protein and fat metabolism  Weight loss (without appetite loss),  Fatiguability  Clinical signs of diabetes related complications (see below).

Diagnosis If a patient is suspected of diabetes from such clinical signs then a diagnosis is confirmed based on blood glucose tests:  Random blood glucose conc. >11mmol/L, with classical signs/symptoms  Fasting glucose conc. >7mmol/L, on more than one occasion  OGTT with glucose conc. >11mmol/L, 2hrs after carbohydrate load on more than one occasion

Complications The long term complications of diabetes are similar regardless of aetiology. Complications arise due to (1) formation of advanced glycosylation end products (AGEs), (2) activation of protein kinase C (PKC) and (3) accumulation of intracellular sorbitol (polyol that causes osmotic injury):  Biochemical disturbances; severe complications Diabetes Associated Diseases resulting in ketoacidosis and death, seen less with The disease processes mentioned on the left adequate control. lead to various common diabetic complications  Accelerated atherosclerosis; hyaline atherosclerosis in various organs: narrows vascular lumen. Leads to coronary,  Heart; ischaemic heart disease is leading cerebral, renal and peripheral vascular disease. cause of death due to diabetes  Eyes; haemorrhages, microaneurysms,  Diabetic microangiopathy; increased permeability diabetic retinopathy, cataracts, glaucoma. of small vessels and protein deposition in basement  Diabetic nephropathy; renal failure due to membrane. Especially leads to retinal, peripheral glomerular and vascular lesions. nerve and glomerular disease.  Peripheral neuropathy; sensory, motor and  Predisposition to infection; especially bacterial and ANS dysfunction, mostly in extremities. fungal infections of skin, mucosa and urinary tract.  Gangrene; peripheral due to vascular Related to impaired leukocyte function and insufficiency. diminished blood supply.

The most important cortical lesions are growth disorders which may result in abnormal function.  Adrenocortical hyperplasia; can be diffuse or nodular, often with minimal enlargement. Can be congenital (enzyme deficiency triggers hyperplastic compensation), idiopathic or secondary to ACTH excess.  Adrenocortical adenoma; usually small solitary, yellow nodule. Lipid laden pleomorphic cells make diagnosis difficult. Many are non-functional.  Adrenocortical carcinoma; usually large, unencapsulated, highly anaplastic and malignant. Smaller ones difficult to distinguish from adenoma. Lymphatic or blood metastasis to lungs etc.  Less common; aplasia, hypoplasia, diff number of glands, atrophy.

Adrenocrotical Adenoma (arrow is remaining tissue)

Adrenocrotical Carcinoma

Metastatic Adrenal Carcinoma

Adrenal Necrosis (bilateral)

Adrenocortical Hyperfunction (Hyperadrenalism)
Hypercortisolism (Cushing Syndrome) Conditions that cause excess glucocorticoid levels:  Exogenous/ iatrogenic administration is most common cause  Cushing disease (secondary to pituitary disease) is most common endogenous cause  Primary adrenal hyperplasia, adenoma, carcinoma (ACTH independent hypercortisolism)  Ectopic ACTH or cortisol release (eg. small cell lung cancer)

Cushing Disease
Specific form of Cushing syndrome (hypercortisolism) which is secondary to primary hypothalamic-pituitary disease. In majority of cases the pituitary gland contains ACTH producing adenoma. In remaining patients corticotroph hyperplasia is the cause.

Symptoms; weakness, fatigue, central obesity, moon facies, skin striae, hypervolaemia, cardiac hypertrophy and hypertension, osteoporosis, diabetes mellitus, psychic disorders/emotional disturbance, menstrual problems (amenorrhoea), purpura and skin ulcers (poor healing). Hyperaldosteronism Conditions that cause excess mineralocorticoid levels. These cause Na retention and K excretion with resultant hypokalaemia and hypertension.  Primary aldosterone-secreting adenoma (Conn Syndrome)  Secondary to excess renin release (eg. decreased renal perfusion, hypovolaemia, pregnancy)  Other causes; bilateral hyperplasia, carcinoma, rare familial entities Symptoms are usually ill defined; headache, polydipsia, polyuria, nocturia, muscle weakness, discomfort, tetany, paralysis, paraesthesiae, visual disturbance.

Adrenogenital Syndromes Conditions that cause excess release of androgens from adrenal cortex. This can occur as a pure syndrome or as a component of Cushing disease. The adrenal causes of androgen excess include:  Adrenocortical neoplasms, usually carcinomas  Congenital adrenal hyperplasia (CAH), a group of congenital disorders that result in enzyme defects which affect steroid biosynthesis (mainly cortisol). Note: With reduced cortisol, compensatory increase in ACTH release results in secondary hyperplasia of adrenal cortex (bilateral). Symptoms; are most commonly associated with virilism (excess androgen causing signs of masculinity in females).

Adrenocortical Insufficiency (Hypoadrenalism)
Causes: adrenocortical insufficiency is the reduction of adrenal hormones, can be caused by primary or secondary diseases.  Acute adrenocortical insufficiency most commonly occurs in massive adrenal haemorrhage (eg. Waterhouse-Friderichsen syndrome, anticoagulative drugs, postoperative DIC, pregnancy) or rapid steroid loss (eg. patients quickly removed off corticosteroid therapy).  Chronic adrenocortical insufficiency (Addison’s Disease) is most commonly caused by autoimmune adrenalitis.  Secondary adrenocortical insufficiency occurs due to hypothalamic or pituitary disease. Can occur as part of panhypopituitarism. Waterhouse-Friderichsen Syndrome
Massive haemorrhage due to overwhelming septicaemia, especially seen in infants. Associated with meningococcal sepsis and DIC.

Addison’s Disease
Primary chronic adrenocortical insufficiency usually caused by autoimmune adrenalitis. Other main causes include tuberculosis, AIDS and non functioning malignancies.

Clinical Manifestations: can vary between primary and secondary cases.  Patients typically present with fatigue, weakness and gastrointestinal symptoms.  Primary disease can also cause hyperkalaemia, hyponatraemia with resulting hypotension and cardiac arrhythmias due to reduced aldosterone.  Primary disease also causes hyperpigmentation due to MSH release.

Uncommon neoplasm arising from adrenal neuroendocrine chromaffin cells (phaechromocytes). Vary in size and can be secretory (functional) or non-secretory.  10% are associated with familial syndromes (eg. MEN-2, von Hippel-Lindau disease, SturgeWeber syndrome), half of these cases are bilateral.  10% are extra adrenal (eg. other paraganglionic tissue related to ANS), these are known as paragangliomas.  10% are bilateral, many due to familial syndromes above.  10% are malignant, histologically determined only by metastasis.

Clinical Manifestations: Secretory lesions produce symptoms as a result of increased catecholamines in the blood.  Paroxysmal or sustained hypertension, as well as associated cardiac symptoms.  Headache, sweating, tremor, fatigue, GI symptoms

Other Neoplasms of Adrenal Tissue
Neuroblastomas are the most common extra cranial solid tumour of childhood (90% <5yr) arising along the sympathetic chain. Around 30% develop in the adrenal medulla. These vary in size and prognosis, are highly metastatic. Other neoplasms include ganglioneuroblastomas and ganglioneuromas.

Multiple endocrine neoplasia (MEN) syndromes are a rare group of inherited diseases resulting in proliferative lesions in multiple endocrine glands.  Multiple tumours occur at a younger age, either synchronously or metachronously.  Autosomal dominant, family follow up important. Effected Organs Genetic Abnormality MEN-1 -Parathyroid (95%), primary hyperplasia -Loss of tumour suppressor -Pancreas (40%), endocrine neoplasms (usually gene at Ch11q13. metastatic) or less commonly gastrinomas -Unknown mechanism of -Pituitary (30%), mostly prolactin or GH secreting action. MEN-2a -Thyroid, medullary carcinoma in virtually all cases -Inheritance of RET proto-Adrenal medulla (50%), phaeochromocytomas oncogene on Ch10q11. -Parathyroid (30%), primary hyperplasia -Multiple tyrosine kinase mutations. MEN-2b -Thyroid and adrenal medulla disease similar as 2a -No parathyroid involvement -Extraendocrine manifestations.


Fracture Healing and Repair The ideal situation for fracture healing relies upon; minimal necrosis and abscess (sequestrum), wound immobilisation (precise anatomical reduction), good vascular supply, lack of infection, and minimal physical stress. The sequence of events which follows bone fracture includes the following: STAGE I Haematoma and fibrin clot formation encases ends of bone. STAGE II STAGE III STAGE IV STAGE V Traumatic inflammation, usually forms soft callus. Mediator release eg. PDGF, TGF-b, ILs. Demolition phase - macrophages remove debris. Granulation tissue formation (derived from periosteum/endosteum). pH low (acid tide). Woven bone ± cartilage formation, at this stage pH high (alkaline tide). Union occurs when repaired bone spans the fracture site, which may be achieved by any of the processes below. a) Where immobilisation is adequate mesenchymal cells are able to differentiate to form woven bone. Calcification follows. The mass of tissue uniting the bone ends is known as a hard "callus". b) With increasing motions at the fracture site cartilage forms instead. If movement limited normal callus will form. However, if persistent and excessive motion occurs, a cleft will form causing non-union of the fracture. Termed a pseudoarthrosis. c) If there is an excessive gap between the fracture fragments the fracture site is spanned by dense fibrous connective tissue. Healing can occur from here. If a callus forms it is invaded by capillaries and bone cells. Non-viable woven bone or cartilage is removed by osteoclasts. Osteoblasts begin to lay down osteoid, which calcifies to form lamellar bone, arranged in flat plates or Haversian systems. Remodelling: continued osteoblastic and osteoclastic activity results in an eventual return to normal.



Acute Pyogenic Osteomyelitis is infection of bone that may be classified upon the basis of; pathogen, time course (acute, subacute or chronic), or route of infection (haemotagenous or direct). Pathogens/Route: S. aureus is most common in adults and children >3yrs, but other pathogens do occur. 1. Haematogenous osteomyelitis acute infection occurs more commonly in children, typically in metaphyseal regions with high vascular flow eg. in the femur, tibia, humerus and radius.  Neonatal osteomyelitis often also involves adjacent joint, usually following haematogenous infection by S. aureus, group B strep or E. coli.  In adults haematogenous spread probably occurs through periosteal vessels, hence most often seen in the cortex of long bones or in flat bones, eg vertebra.  IV drug users develop pseudomonas osteomyelitis, often involving the spine or pelvis. 2. Direct osteomyelitis results from direct introduction of pathogens into skeleton from outside body. Most commonly affects bones which are prone to injury and have the least soft tissue covering eg. phalanges, tibia and forearm bones.  Infections are often polymicrobial, and most often due to compact/comminuted fractures, puncture wounds etc.  Iatrogenic infection may occur as a result of surgical procedures (joint replacement etc.).  Diabetics at increased risk due to neuropathic foot ulcerations and altered immune function. Pathology: trauma is a predisposing factor as it is associated with stasis and/or thrombosis, thus providing a nidus for infection.

1. In acute pyogenic osteomyelitis organisms lodge in Haversian canals or marrow spaces and elicit an acute inflammatory response. 2. Oedema from inflammatory reaction raises intracompartmental pressure → compromises blood supply to osteocytes resulting in eventual necrosis of bone. 3. Infection walled off by granulation tissue then dense fibrous tissue → trapped, necrotic bone (sequestrum). 4. In local infection Brodie’s abscesses form, otherwise exudate passes through the periosteum. Can lift the cortex in children, or rupture, forming a draining sinus. 5. New reactive bone (involucrum) forms around abscess in attempt to isolate the infection.

Osteomyelitis of Femur

Morphology: suppurative exudate in bone marrow, neutrophil polymorphs, RBC’s, fibrin and debris. Osteoclast activity at necrotic margins. Can have granulation tissue or abscess depending on stage. Outcome: determined by the anatomic location, the host response (resistance), the number and relative virulence of the pathogens, and the effectiveness of therapy.  Ideal outcome; with resolution and repair, the sequestrum is resolved, the organisms are dealt with by the immune response and the defect fills with granulation tissue.  Ultimately undergoes intramembranous ossification and healing. Clinical: local pain and fever, especially in children. May be difficult to distinguish from a neoplasm.  X-rays often normal for first 14days, inflammation and reactive bone seen with time.  Intense uptake isotope scans can be used, but MRI imaging will often reveal infection/abnormality the earliest.  Conclusive diagnosis either by blood cultures (may be -ve) or from the lesion itself. Chronic Osteomyeltis
Chronic osteomyelitis develops following an inadequate host response (eg. inadequate antibiotic therapy, inadequate surgical removal of necrotic sequestrum or in immuno-compromised individuals).  Necrotic bone within the sequestrum provides a haven for bacteria which persists within non-healing cavity.  The infection may gradually spread, extending beyond the confines of the involucrum and bone into the adjoining soft tissues.  Having done so, the infection will dissect its way to the skin surface forming draining sinus tracts.  May undergo malignant change (eg. SCC) or amyloidosis.

Tuberculous Osteomyelitis
Tuberculous infection of bone results from spread from TB located elsewhere in the body, usually the lungs.  The spine is the most commonly affected site (Potts disease), the hip and knee are also often involved. Multifocal and joint disease are not uncommon.  Causes chronic granulomatous reaction, lacking the oedema, haemorrhage and raised intra-compartmental pressure associated with pyogenic infections of bone.  As such, extensive necrosis of surrounding bone is less common, hence also less reactive bone formation.  Much slower course, with damage due to extension of the inflammatory process through bone, periosteum, soft tissue and into adjoining joint spaces.

Pott’s Disease
Kyphotic deformity of thoracic spine during tuberculous osteomyelitis.  Destruction of anterior vertebral end plates → spreads to IV discs → involves adjoining vertebral bodies.  Large, cold abscesses filled with necrotic gaseous material may form in the soft tissues eg. the paravertebral/psoas musculature.  Can also cause spinal cord compression, meningitis and/or ankylosis (fixation).

Pott’s Disease

Joint Infection
Acute septic arthritis is the invasion of the joints by pathogenic microorganisms which trigger an immune response and degradation of the cartilage. Infection of joint may occur by:  Haematogenous dissemination to synovium.  Extension from adjacent focus of osteomyelitis or soft tissue infection.  Direct implantation of organisms via trauma or operative intervention. Pathogens: S. aureus is most common.  In neonates/infants can also be due to Strep, H. Influenzae and gram –ve rods. Most often affecting single hip, knee or ankle joint.  Adults prone to developing septic arthritis are individuals with chronic inflammatory arthridities. Non-gonococcal causes are a medical emergency, gonococcus is often easily treated with antibiotics alone. Fungal causes usually only in immunocompromised. Pathology: presence of pathogens incites an acute inflammatory reaction within the joint capsule and synovium, with swelling and effusion.  Inflammatory response causes degradation of the cartilage, esp articular cartilage.  Cellulitis and suppurative exudates may extend beyond the joint capsule → complete joint disruption into soft tissues with sinus formation. Morphology: hallmarks evident within the synovial tissues where there is dense, mixed inflammatory cell infiltrate. Patchy fibrinous exudate at synovial surface which may be eroded in some areas. Synovial blood vessels are congested and prominent. Clinical: clinical course determined by the pathogens involved, host response and therapy. Early recognition, diagnosis and treatment is critical due to rapid cartilage damage.  Often present with a swollen, red, warm and painful joint. Associated fever and ↑WCC.  Purulent material may be recovered on joint aspiration.  Diagnosis by aspiration and synovial fluid examined for the crystals and microorganisms.  Treatment by surgical incision, drainage, immobilisation and antibiotic therapy Tuberculous arthritis most often involves large joints, as a result of haematogenous colonisation within the synovium. Cases chronic granulomatous inflammation throughout the joint cavity.  Destroys the articular cartilage and also infiltrates and destroys subchondral bone.  Joint destruction is often followed by the formation of fibrous scars, ie. fibrous ankylosis.  Early manifestations of chronic swelling and effusion, with few acute signs of inflammation.  With progression there is loss of range of motion of the joint, which may be accompanied by the formation of draining sinuses.

Clinical arthritis is the consequence of loss of the joint’s normal function, which depends on many joint structures (ligaments, tendons, muscles) as well as articular cartilage and surrounding bone. Joints must be able to move freely, stay stable during use and distribute force during stress.  Pathology: acute or chronic injuries that result in – articular surface alterations, loss of supporting structure integrity, or alteration in the mechanical properties of tissues – can cause arthritis. Relatively common changes include: o Cartilage clefting, repair and metaplasia, ± necrosis. o Synovial hyperplasia/hypertrophy, haemosiderin ± loose bodies. o Bone necrosis, reactive sclerosis, microfractures and osteophytes. o Synovial fluid changes in colour and content (cell count, proteins, pathogens etc).  Clinical: common signs and symptoms include: o Symptoms; pain, stiffness, deformity, loss of function, systemic illness. o Signs; heat, redness, swelling, loss of movement, deformity, tenderness, crepitus Can be classified as; non-inflammatory ‘osteoarthritic’, inflammatory ‘rheumatic’, infectious (see above) or metabolic ‘crystal’ arthritis.

Non-Inflammatory Arthirits
Osteoarthritis is a non-inflammatory functional joint disorder, characterised by altered joint anatomy and loss of articular cartilage. Pathology: many cases are idiopathic, other causes include trauma, metabolic conditions, infection, avascular necrosis, other forms of arthritis, congenital alterations etc.  Result in damaged cartilage and alteration in shape of the articular surfaces.  Articular cartilage exhibits fibrillation and clefting. Variable loss and thinning can expose underlying bone (eburnation).  Subchondral bone reveals sclerosis, cystic change, fractures, exostoses and osteophytes. Osteoarthritis Process
1. ↑ chondrocyte activity due to various stimuli (eg. trauma) 2. Abnormal quantity and quality of proteoglycan and collagen production. 3. Joint may maintain normal function for years but eventually, the arrangement and size of collagen fibres are altered. 4. Proteoglycans begin to break down faster than they can be synthesized resulting in degenerative cartilage (pieces can fragment into joint).

Clinical: typical presentation of pain (esp with use/activity), stiffness and reduced mobility in joint. No inflammatory or systemic signs.  Affects all societies and races, is more common in women, and increases with age.  Individual risk factors for arthritis include genetic influences, hormonal factors, obesity, trauma and occupation.  Patterns of clinical presentation include disease limited to a large single joint (sometimes bilateral), a generalised process (involving joints of fingers/hands, knees and hips), and Charcot joints.

Charcot joint is an extreme form of osteoarthritis seen in patients with neurological dysfunction. There is rapidly destructive osteoarthritis, production of loose bodies, severe subluxation and even dislocation of the joint.

Osteonecrosis (Avascular Necrosis) is necrosis of bone and bone marrow in absence of infective cause.  Pathology: a relatively common disorder with vast majority of cases are secondary to trauma. Collapse and fracture of the necrotic subchonral bone disturbs joint anatomy and function. Non-traumatic AVN occurs primarily in younger adults, and is often bilateral. Has been linked to corticosteroid use, alcoholism, infections and embolism, however, a large number of cases have no Avascular Necrosis obvious aetiologic factor.  Morphology: necrotic bone is recognised by the absence of osteocytes from lacunar spaces. The marrow space is also necrotic. May be evidence of osteoblastic and osteoclastic activity.  Clinical: significant cause of joint pain and disability. Clinical signs and symptoms similar to OA, though usually sudden onset and younger patient. Spondylosis is osteoarthritis of the spine, including degenerative disc disease (osteochondrosis). Associated with vertebral osteophytes, ligamentous disease, facet joint changes and neurological complications.  Spinal changes: most often in cervical and lumbar spine. Degenerative spondylolisthesis is a displacement of the Osteophytes from facet joint degeneration can impinge on vertebral body on the one intervertebral foramina. Can cause vascular congestion, vertebral directly below it. It is artery insufficiency and nerve root irritation. associated with degeneration  Vertebral disc changes: can displace in any direction. If posteriolly of the facet joints and can can potentially impinge on nerve roots and if anteriorly on the result in spinal stenosis. contents of the spinal canal.

Rheumatoid Arthritis
Rheumatoid arthritis is a chronic systemic disorder of unknown aetiology, which effects females more often than males. The peak age of onset is in the fourth to sixth decade. Pathology: although the cause is unclear, 70% to 80% of affected individuals test positive for histocompatibility antigen DW4 and there are some familial cases.  It is clear that there is a immunological reaction and increased formation of degradative enzymes within the joint.  Rheumatoid factors (RF) are immunoglobulins that complex with IgG. Approximately 70% of patients are RF +ve. Morphology: joint destruction with little reparative activity. The synovium demonstrates chronic inflammation, hypertrophy and hyperplasia, frequently with fibrinous exudates at the surface. Clinical: has great clinical heterogeneity but does have characteristic symptoms.  General malaise, with pain and stiffness in the joints (most marked in the morning).  Usually effects several joints in a symmetric pattern, especially those of the hands and lower limb. These joints are hot, swollen and tender.  Complications of joint instability, including subluxation, dislocation and ankylosis.
Synovium from joint with RA

Rheumatoid nodule from elbow

Extra-Articular RA Manifestations
There are numerous extra-articular manifestations of Rheumatoid Arthritis (Rheumatoid Disease).  Subcutaneous rheumatoid nodules occur in approximately one third of cases, usually on support structures of the joint.  Weakness/skeletal muscle atrophy is common.  Limited forms of vasculitis can occur and manifest as cutaneous vasculitis, peripheral neuropathies, ischaemic leg ulcers etc. Rarely serious.  Pleuritis, pleural effusion most common in lung.  Ocular disease includes episcleritis and scleritis  Cardiac and neurological disease are uncommon may occur as a result of vascular compromise.

Spondylarphropathies (RA Variants)
Group of conditions in which RF is usually –ve but involve inflammation in the spine and peripheral joints.  Anklyosing Spondylitis; low back pain and stiffness due to synovial inflammatory changes. Eventual fusion.  Psoriatic Arthritis; psoriasis usually precedes the onset of arthritis but may follow or accompany it.  Enteropathic Arthritis/Spondylitis; patients with chronic colitis, can develop peripheral arthritis/spondylitis.  Reactive Arthritis; infection of GIT, followed weeks later by a sterile synovitis. Reiter’s syndrome is an example. All these diseases exhibit: enthesopathy, synovitis, dactylitis, sacroileitis, spondylitis, extra-articular inflammation (eg. GIT), family history, antigen HLA - B27.

Metabolic/Crystal Arthropathies
Gout is characterised by episodic acute attacks of inflammatory arthritis, and chronic deposition of urate crystals around affected joints. May occur sporadically or as a hereditary condition. Pathology: can be due to inherited (primary) or acquired (secondary) metabolic defects that cause hyperuricamia.  Uric acid in the end product of the catabolism of purines and is excreted by kidneys.  During ↑synthesis and/or ↓secretion it supersaturates plasma and extracellular fluids → begins to precipitate due to insolubility.  Prolonged hyperuricaemia leads to chronic deposition to urate crystals in joints and tissues (eg. kidney) → provoke episodic acute (usually monoarticular) inflammatory reactions when they precipitate.

Gout of Big Toe

Gout of 2nd Digit

Morphology: crystals can be seen in microscopic examination of synovial fluid under polarised light.  It reveals an inflammatory exudate and the presence of negatively birefringent needle shaped crystals in gout.  Crystal deposits form lobulated collections. These collections are ringed by characteristic deposits of histiocytes and multinucleate giant cells. Clinical: gout is divided into various clinical stages.  Acute gouty arthritis: the acute arthritis is characterised by a swollen painful joint (often the big toe), rapid clinical onset, low grade fever and leucocytosis.  Chronic tophaceous gout: the chronic stage in which diffuse deposits are seen  Complications include chronic urate nephropathy and uric acid calculi (urolithiasis).

Psuedogout Calcium pyrophosphate deposition disease (chondrocalcinosis). Signs are similar to osteoarthritis, with varying degrees of synovitis. Joints of involvement include hips, knees, ankles, shoulder, elbows, wrist. Chalky white deposits with rhomboidal crystals.

Normal Bone Histology
Cortical (compact) bone is composed of dense compact cylindrical units, referred to as osteons or haversian systems. It forms the external shell of bone and more prominent in the diaphysis (shaft). Cancellous (trabecular) bone a network of avascular plates called trabeculae. It forms the internal medullary cavity (holds bone marrow) and is more prominent in the epiphyses (ends). Bone is composed of 90% ECM (collagen type 1, calcium hydroxyapatite crystal). Rest cellular elements:  Osteoblasts produce matrix (osteiod) and control its mineralisation, are found at the surfaces of bone.  Osteocytes are osteoblasts that have become incorporated into bone matrix. They occupy lacunar spaces and maintain cellular contact via interconnecting canaliculi.  Osteoclasts are cells responsible for the resorption of bone matrix. Reside in Howship’s lacunae. Periosteum is layer of dense CT on outside of bone. Endosteum is layer of cell rich CT that lines marrow cavity. Lamellar bone has an organised and layered structure and represents mature bone. Woven bone is the immature and disorganised precursor of lamellar bone.

Normal Calcium Regulation
Bone contains 99% of calcium in the body, stored as hydroxyapatite crystals. Interactions between minerals, hormones and a number of mechanical/environmental stimuli regulate calcium and hence bone metabolism. Phosphate is also controlled by similar mechanisms. PTH: increases blood Ca by increasing osteoclastic bone reabsorption, renal Ca resorption and renal vit D release. Vit D (calcitriol) increases gut absorption of calcium. Calcitonin: decreases blood Ca by inhibiting osteoclastic effects. Not as important, most effects due to low PTH.

Osteoporosis is any degree of skeletal fragility associated with an increased risk of fracture. The bone has normal composition and structure but is of reduced skeletal mass. There is an inadequate amount of mineralisation (proportional loss of matrix and mineral). Pathology: generally an age related disorder where there is an imbalance between resorption and new bone formation (continual process). This imbalance may become manifest at different ages and in different sites of the skeleton. Various factors influence this incline towards resorption.  Peak bone mass achieved in skeleton and the rate of bone loss thereafter.  Calcium metabolism and hormone status, especially oestrogens, with the disease occurring earlier and more rapid in menopausal women.  Physical activity which has been shown to increase bone mass. Classification: is based on the cause osteoporosis, which can be primary (involutional) or secondary.  Type 1 Primary Osteoporosis is post-menopausal. It is related to the loss of the protective effects of oestrogen on the skeleton and increased bone turnover. Bone loss is predominantly from cancellous bone, typically resulting in spinal and forearm fractures.  Type 2 Primary Osteoporosis is age-related (usually >70). Proportionate loss from both cortical and cancellous bone occurs, with typical hip fractures.  Secondary Osteoporosis is due to several other disorders; endocrine diseases (Cushing’s, thyrotoxicosis, hypogonadism, hyperparathyroidism etc.), drugs, malabsorption and haematological diseases.
Osteoporosis with crush fracture and kyphosis

Morphology: the bone is essentially structurally normal but is decreased in quantity. Trabeculae are thin and widely spread, haversian canals are enlarged. Clinical: asymptomatic in itself, but presents with complications, namely pain, microfractures and deformity (eg. height loss). Fractures are a high risk, esp in hip, vertebrae and radius.  Diagnosis: serum is normal, X-ray can indicate density loss but is inaccurate. Densinometry to show decreased bone density, histological bone thinning and fracture history are more accurate.  Prevention: maximise peak bone growth and avoid/modify risk factors, esp in menopausal.

Osteomalacia and Rickets are characterized by defective mineralisation of the organic matrix. The lack of mineralisation affects both the quality and quantity of bone formed. Deformities of weight-bearing bones and pathological fractures may result. Pathology: normal skeletal mineralisation depends upon the presence of sufficient calcium and phosphate at the mineralisation sites, normal cellular function, and absence of inhibitory/deleterious metabolic factors. Any factor which interferes with these requirements may be associated with the development of these diseases.  Often vitamin D related; vit D deficiency, disturbance in metabolism (sunlight), increased resistance (phosphate wasting, enzymatic deficiency, end organ insensitivity, renal acidosis).  Other dietary deficiencies; calcium, phosphate.  GIT disorders; gastric or hepatobiliary disease, malabsorption syndromes etc.  Drug associated; phenytoin, aluminium, heavy metals etc.  Tumour associated; oncogenic ostemalacia.  Chronic renal failure, hepatic disease. ↑ Osteoid (non-mineralised bone), due to Ca deficiency. Osteomalacia occurs in adults, resulting in osteopenia (reduced overall skeletal mass). May clinically be asymptomatic or have various features underlying the disorder.  Soft bone (deformity), fragile (fractures), bone pain/tenderness (back, hips, generalised), proximal muscle weakness (hypocalcaemia).  Multiple bilateral and symmetric lucencies may be seen on X-rays, altered calcium, phosphorus and vit D in serum tests. Rickets is when the growing skeleton is involved, including both bone and the cartilage matrix of the growth plates. Results in inadequate endochondral ossification, and a variety of distinctive skeletal abnormalities may develop.  Reduced bone length, prone to deformities/fractures, deranged bone growth and development, weakness and hypotonia.  Microscopically, excessive osteoid, islands of cartilage, fibrosis and widened diameter.

Hyperparathyroidism is a surplus of PTH released from chief cells of the parathyroid gland. Pathology: excess PTH has various effects on bone, also resulting in hypercalcaemia.  Increased bone resorption (↑ osteoclastic activity) resulting in mobilisation of Ca2+/PO42-.  Cysts (macro or micro) or rarer brown tumours (large localised areas of resorption).  Marrow fibrosis, resulting in ‘osteitis fibrosa cystica’. Classification: occurs in two major forms, primary and secondary.

Primary hyperparathyroidism uncontrolled production of parathyroid hormone from neoplastic or hyperplastic parathyroid tissue. In most cases (>95%) is caused by sporadic parathyroid adenoma or hyperplasia, rarely carcinoma or familial MEN syndromes.  Patients may be asymptomatic (biochemical abnormality NB: many other causes of detected incidentally) hypercalcaemia eg. vit D  Present with signs and symptoms related to hypercalcaemia intoxication, familial condition, (abdominal cramps, constipation, muscle fatigue, peptic sarcoidosis. Doesn’t have to be ulceration, renal calculi, cardiac valve calcification etc.). hyperparathyroidism.  Have bone related disease (only 10%). Secondary hyperparathyroidism results from chronic parathyroid Tertiary Hyperparathyroidism stimulation by low serum calcium (occasionally associated with other Represents autonomous and disease processes). The clinical features are usually dominated by those continuing PTH secretion in the of chronic renal failure, vit D deficiency and malabsorption. In general, absence of low serum calcium. the osseous pathology is less severe than that seen in primary hyperparathyroidism. Clinical/Morphology: primary and secondary bone changes are essentially identical.  Macroscopic: X-ray may reveal diffuse osteopaenia and/or circumscribed areas of lucency (esp in the phalanges). These reflect resorption of cortical bone.  Microscopic: increased osteoclast activity, with increased bone resorption and a characteristic tunnelling or dissecting pattern. Mesenchymal cells and fibrous tissue replaces lost bone.

Paget’s Disease of Bone
Pagets disease of bone is an idiopathic disorder that represents derangement of bone remodelling and turnover. May involve one bone (monostotic) or multiple bones (polyostotic). Mostly commonly involves the pelvis and skull but virtually any bone may potentially be affected. Pathology: extensive bone remodelling that evolves in three phases: 1. Osteolytic phase; acceleration of resorption. 2. Mixed lytic/blastic phase; efforts at bone replacement by appositional formation, whilst bone resorption continues. 3. Osteoblastic/sclerotic phase; continuing bone formation with diminished resorption. Results in thick, soft, porous bone that is prone to compression and deformity. Normal bone architecture is lost. Morphology: remodelling is disordered and purposeless resulting in thickened bone with mosaic patterns of cement lines. Clinical: relatively common in late adult life with greatly variable presentation depending upon site, extent of disease and presence of complications.  Signs: often asymptomatic or patients present with pain, increasing bone size, deformity or fracture.  Diagnosis: raised alkaline phosphatase as a result of osteoblastic activity or radiological changes (bone deformity, thickening, coarseness).  Complications: stress, fracture, high output heart failure, sarcoma.

Paget’s disease in clavaria

Renal Osteodystrophy
Refers to a range of skeletal abnormalities seen in association with chronic renal disease and haemodialysis. Associated with phosphate retention, hypocalcaemia, decreased vit D and sometimes a metabolic acidosis. The clinical and pathological manifestations of renal osteodystrophy are variable.  Hypocalcaemia may trigger secondary hyperparathyroidism  Acidosis promotes osteoporosis/osteopenia.  Various manifestations eg. osteomalacia, osteosclerosis and OFC can occur in combination.

Bone Neoplasms
Neoplasms and tumour-like conditions of the musculoskeletal system are a remarkably diverse group of entities, which can be divided into the following groups. 1. Primary neoplasms, which can involve any cell normally present in the bone or soft tissue. 2. Secondary or metastatic bone neoplasms. 3. Primary neoplasms of haemopoietic marrow (myeloma, lymphoma, etc.). 4. Psuedoneoplastic lesions (pseudotumours) are processes which may mimic neoplasia. Primary Bone Neoplasms Particular histological types of primary bone tumours tend to occur in particular age groups and at particular sites. Little is known of the factors responsible for the development or progression of the majority of primary bone tumours. Most are sporadic and of unknown aetiology.  Benign tumours can be inactive (asymptomatic, remain intracompartmental), active (grow steadily) or aggressive (symptomatic, grow rapidly with infiltration).  Sarcomas can be low grade (indolent course, gradual expansion, slow metastases) or high grade (rapid growth, extracompartmental spread, high rate of metastases, often involve neuromuscular bundles). Osteochondroma Most common benign tumour of bone, typically sporadic/multiple (diaphyseal aclasis). Often in metaphyses of long bones eg. femur, tibia, humerus, pelvis.  Morphology: sessile or peduculated mass, around 4cm, project away from cortical surface. Consists of cartilage cap; periostial covering with lamellar bone and bone marrow.  Clinical: usually asymptomatic, may present as incidental finding or with mass/ pressure effects. Giant Cell Tumour Osteogenic Sarcoma Less common, aggressive benign lesion, classically located in epiphysis with 80% skeletally mature. Majority are at articular end of a long bone. Most common primary malignant tumour of bone (not marrow) yet still rare, 0.2% of human malignancy. This malignant stroma produces bone/osteoid. Also in metaphyses of long bones eg. femur, tibia.  Morphology: diagnostic feature is the presence of a sarcomatous stroma forming both osteoid and mineralised bone matrix. Otherwise very variable, intramedullary (in medullary cavity) is most common type.  Clinical: pain, swelling, fracture common. Most often in 1020yrs (growth spurt) and males. Haematogenous dissemination to lungs or other bones. Chondrosarcoma Malignant tumour of cartilage, 20% of bone tumours. Tumour osteoid is not directly from sarcomatous stroma. Develop in any bone preformed in cartilage eg. pelvis, femur, ribs, sternum, craniofacial. Most common in 30-60yrs.

Secondary Bone Neoplasms Metastatic Metastasis to bone is the most common bone malignancy, and location for Disease metastases with virtually every malignancy being able to invade bone.  Spread: metastatic deposits reach bone via vascular systems, lymphatics are less likely. The most common sites of involvement are bones of the axial skeleton though virtually any bone can be affected. Most common sources include breast, prostate, lungs, kidney, thyroid.  Morphology: metastasis may produce combinations of osteoblastic and osteoclastic activity, and as such may be lytic, blastic or mixed in appearance. Most are osteoclastic, however prostatic and breast carcinomas become typically blastic. Typically have destructive changes with moth eaten appearances. Extension into soft tissue and periosteal reaction can be present.  Clinical: presentation is with pain, swelling or tenderness. Acute presentation may result from fracture, mass effect or hypercalcaemia. Identification of the primary site of origin is important, as it may influence therapeutic decisions. Primary Marrow Neoplasms Multiple Malignant plasma cell proliferation with osteolytic lesions. Is most common primary Myeloma malignant neoplasm of bone. Most often located in vertebral bodies, ribs, pelvis and skull. The neoplastic cells are characterized by production of a single homogenous immunoglobulin product .  Morphology: spectrum of differentiation may be seen.  Clinical: can cause hypercalcaemia, anaemia, renal failure, amyloidosis. Radiology reveals lytic, punched out, little areas of periosteal reaction and destruction. Bone scans are typically negative. Lymphomas, Discussed with the haematological system. leukaemias. Clinical Aspects of Bone and Soft Tissue Neoplasms
Presentation: musculoskeletal tumours may present in a number of generally non-specific ways. Depends on anatomical location, rate of growth, size attained and secondary changes (eg. necrosis, haemorrhage). Local effects (pain, swelling) reflect mass effect and impingement on surroundings. Systemic effects are less common.  Benign inactive lesions may asymptomatic and discovered incidentally. Aggressive benign lesions are usually symptomatic, grow rapidly and permeate surrounding structures.  Low grade sarcomas tend to have a relatively indolent course. High grade sarcomas tend to have a relatively rapid growth extra-compartmental and metastatic spread. Diagnosis: management decisions in rest upon tissue diagnosis from biopsy. Must obtain sufficient sample (for accurate diagnosis and classification), but consider possible procedure complications. Without careful planning, biopsies may lead to adverse effects (20%) on treatment and outcome as a result of misdiagnosis or procedural complications. The radiological assessment of neoplasms of bone also plays an invaluable role. Plain X-rays reflect growth patterns outlined above, while more sophisticated imaging (CT, MRI, PET) enhances the diagnostic work-up. Staging: musculoskeletal and soft tissue neoplasms use the Enneking system (not haematopoietic or metastatic neoplasms).  Grade of biological aggressiveness: G0 (benign), G1 (low grade malignant), G2 (high grade malignant).  Site: T0 (confined by capsule), T1 (extracapsular, intracompartmental), T2 (extracompartmental)  Metastases: M0 (local), M1 (metastasised).

Soft Tissue Neoplasms
Soft tissues are those which are non- epithelial, reticuloendothelial, CNS and skeletal. They are of mesodermal and neuroectodermal origin, including fibrous CT, smooth muscle, skeletal muscle, fat, peripheral nerves and blood/lymphatic vessels.  Soft tissue tumours are complex and highly heterogenous. They may be classified as benign, borderline, malignant or pseudoneoplastic (appear as tumours, but are not).  The vast majority of tumours have unknown patho-aetiology. Associated with radiation, carcinogens, trauma and inherited/familial disorders.  Growth pattern is affected by its proliferative, matrix forming and destructive characteristics, also influenced by response in surrounding tissues.  Generally non-specific symptoms. Depends on anatomical location, rate of growth, size attained and secondary changes (eg. necrosis, haemorrhage). Local effects (pain, swelling) reflect mass effect and impingement on surroundings.  Incidence of 3 per 1000, with most being benign (100:1). Could be many more as many benign neoplasms are not biopsied. Classified by pattern of soft tissue differentiation and cell origin type. This histogenesis is disputed/uncertain in some tumours. Can present in any cell population of soft tissue. Vascular Neoplasms Benign: haemangioma Rhabdomyosarcoma Intermediate: haemangioendothelioma of forearm Malignant: angiosarcoma Adipose Tissue Benign: lipoma Neoplasms Malignant: liposarcoma Smooth Muscle Benign: leiomyoma Tumours Malignant: leiomyosarcoma Fibrosarcoma Skeletal Muscle Benign: rhabdomyoma of thigh Tumours Malignant: rhabdomyosarcoma Mesenchyme (CT) Benign: fibroma Tumours Malignant: fibrosarcoma Benign Soft Tissue Tumours Are often, but not invariably, <5cm, superficial to deep fascia, soft, moveable and non-tender. May have static or intermittent growth. Can be active, inactive or aggressive.  Inactive tumours are asymptomatic (discovered incidentally), remain intracompartmental (completely encapsulated) and seldom deform/distort surrounding tissue eg. ganglion cyst.  Active tumours are benign lesions that grow steadily and expand by defoeming/distorting surrounding tissue boundaries. Remains encapsulated eg. tenosynovial giant cell tumour.  Aggressive benign tumours are usually symptomatic, grow rapidly, permeate and infiltrate surrounding structures eg. deep fibromatosis. Ganglion Cysts develop by myxoid
softening and cystic degeneration of joint capsule or tendon sheath. Common in distal upper/lower limb and spine. Not lined by true synovium. Do not communicate with joint cavity. Cf Baker’s cyst= synovial herniation.

Tenosynovial Giant Cell Tumours are a localised type of
giant cell tumour in tendon sheaths. Diffuse- pigmented villonodular synovitis (PVNS). Locally aggressive, non metastasising neoplastic process.


is fibroblastic proliferation forming collagen. Aggressive clinical behaviour, infiltrative. Repeated local recurrence, but no metastases. -Deep: muscle, abdominal. -Superficial: palmar, plantar, penile, infancy.

Malignant Sarcomas Are often, but not invariably, >5cm, deep to deep fascia, firm, fixed and tender. Progressively increases in size and symptomatic. Grow locally, compressing adjacent tissue, form a pseudocapsule (ie. unencapsulated). Common haematogenous metastases.  Low grade sarcomas have relatively indolent course and gradual local expansion. Ultimately may have extracompartmental spread, low rate of metastatic spread eg. myxoid liposarcoma.  High grade sarcomas have relatively rapid growth, extracompartmental spread and metastatic spread. Often involve neurovascular bundles eg. synovial sarcoma. Myxoid
commonest liposarcoma subtype, is low grade. Liposarcomas are often in thigh and retroperitoneum. Usually deep seated large lesions with variable appearances (eg. fatty, myxoid). Non specific presentation.


Synovial Sarcoma 5-10% of all soft tissue sarcomas,
usually in young males. Grow close to joints, tendons, bursae but rarely involve synovial membrane. Most around knee and ankle, presenting with enlarging mass and pain. Seldom systemic. Often long duration of symptoms (years) before developing metastases.

Classification of Myopathies

[Original notes by Ben H.]

You can classify myopathies by looking at different types of deficient proteins in skeletal muscle and contractile apparatus. This is complicated as there are so many different, obscure and rare causes. A more logical approach is to use clinical patterns: Proximal (Generalised) Myopathies Acute: symmetric difficulty using large muscles of the hip and shoulder. Chronic: lifelong slowly progressing disorders. Symmetrical distal weakness of hand/foot, no sensory involvement. Episodic weakness, due to defective Cl, Na, Ca etc channels (↓ AP, contractility). Rare painful weakness with cramping and myoglobinuria. Eg. Guillain Barre (motor unit), Myasthenia Gravis (NM junction) Eg. congenital myopathies, muscular dystrophies Eg. Charcot-Marie Tooth Eg. potassium imbalances (Na, Ca), congenital myotonias (Cl) Eg. metabolic myopathies of glycogen, lipid etc.

Distal Predominant Myopathies Channelopathies (Episodic Weakness) Exercise-Induced Myopathies

Muscular Dystrophy
A group of inherited muscle disorders resulting in weakness and dysfunction of the muscles. Two main diseases are Duchenne’s and Becker’s, both lacking the major contractile protein dystrophin.  Duchenne Muscular Dystrophy is the more severe of the Clinical Signs of Duchenne’s two disorders as there is an absence of dystrophin  Kids have a very characteristic way of completely. Has early onset, manifesting when child getting from lying to standing starts walking and relentlessly progresses till death (Gower’s maneuver with lordosis). (usually around 20yr).  Waddling decompensation of gait as muscle function deteriorates.  Becker’s Muscular Dystrophy is a milder form since  Large calves due to fatty dystrophin is made, but it is in altered quality and/or replacement (pseudohypertrophy). quantity. Has later onset, often in late childhood/early  Abnormal posture due to progressive adolescence, and slower, progression. more clinical weakness → wheelchair bound. variability and overlap makes it harder to prognosticate.

Genetics: X-linked mutations (mostly deletions in Ch Xp21) hence manifests mostly in males.  Females are usually just carriers, however they can express phenotype depending on how much of the X-chromosome is inactivated.  Very large gene so there’s lots of room for abnormalities (hence the variation in Becker’s).  2/3 are familial, other 1/3 are sporadic new mutations. Pathology: dystrophin is at periphery muscle cells and is responsible for transducing the contractile force of intracellular sarcomere to extracellular CT matrix → shortens muscle causing contraction.  In dystrophin deficiency there is sarcolemma instability and the work of the sarcomere is not manifest in muscle movement.  Membrane is then ‘ripped apart’ when contraction occurs and there is a degeneration of muscle fibres (inflammatory response) → chronic necrotizing myopathy.  Results in CK release (↑ serum CK), fibrous regeneration/repair and hypertrophy of the remaining fibres.  Eventually there is a failure of regeneration and existing fibres atrophy → Duchenne’s replaced by connective tissue and fat. NB: dystrophin isoforms may play a role in the CNS causing abnormalities and mild mental retardation. Can also affect myocardium and this with respiratory failure is usually the cause of death.

Inflammatory conditions of skeletal muscle. Below are three non-infectious causes. Dermatomyositis is an acute inflammatory proximal myopathy that affects children and adults. Characteristic muscle pain doing simple things; rising from chair, walking up stairs, brushing hair.  Pathology: B-cell mediated autoimmune disease resulting in complement mediated injury. Strong association with cancer especially Ovarian.  Clinical: classic skin alterations; rash around eyes (helitrope discoloration) and knuckle pads. Dystrophic calcification can be seen on x-ray. CHO-lowering drugs can cause a similar disease.  Treatment: RNA synthetase anti-Jo-1 is a common target. Polymyositis is a sub-acute proximal myopathy that affects adults. Steadily progressing with difficulty performing proximal muscular activities.  Pathology: T-cell mediated (CD8+) autoimmune disease. Chronic necrotizing myositosis (elevated CK normal BVs). Inflamed endomysium → myofibril necrosis → phagocytosis.  Clinical: pure myopathy, no skin manifestations.  Treatment: RNA synthetase anti-Jo-1 is a common target. Inclusion Body Myositis is a non-responsive, relentlessly progressive disease that affects older aldults.  Pathology: more sporadic than familial. Idiopathic histiocyte destruction of myofibrils. See characteristic rimmed vacuoles in sarcolemma.  Clinical: begins with distal muscular involvement and asymmetric weakness, eventually fatal.  Treatment: RNA synthetase anti-Jo-1 is a common target.


Cerebral Oedema
Accumulation of excess fluid within the brain parenchyma (intra/extracellular but not ventricular).  Vasogenic oedema occurs when integrity of the blood-brain barrier is disrupted. Increased vascular permeability allows fluid to shift into cellular spaces of the brain. May be localised (adjacent to inflammation or tumour) or generalised.  Cytotoxic oedema is secondary to neuronal, glial or endothelial membrane injury. This can be due to ischaemic or toxic insult.  Interstitial oedema occurs during obstructive hydrocephalus where increased pressure causes rupture of CSF-brain barrier. This permits CSF to penetrate brain and spread into extracellular spaces of white matter.

Causes: accumulation of excessive CSF within the ventricular system. Result of some form of imbalance between CSF formation (choroid plexus) and resorption (arachnoid granulations).  Most cases occur due to impaired flow or resorption of CSF.  Rare cases are due to increased production. Communicating Hydrocephalus
Results from impaired resorption of CSF or during obstruction of CSF pathways in subarachnoid space (not ventricular system). This is a general condition where all the ventricular system is enlarged. Can be caused by inflammation (meningitis), subarachnoid haemorrhage or tumour (meningeal carcinomatosis).

Non-Communicating Hydrocephalus
Results from obstruction of CSF pathways within ventricular system. Ventricular system behind point of obstruction becomes dilated. Can be caused by congenital malformations, tumours, inflammation or haemorrhage. Commonly in intraventricular foramen (Monro) and cerebral aqueduct (Sylvius).



Clinical Manifestations: dilation of ventricular system, interstitial oedema and reduction in white matter volume is common to all forms.  Adults experience raised ICP with associated headache, vomiting, papilloedema and raised SBP.  Infants experience enlargement of head as cranial sutures are not yet fused.

Cerebral Herniation
Cerebral herniation occurs when ICP causes displacement of soft tissue of the brain through available openings. An increase in volume in intracranial contents (eg. pathological mass, oedema) results in increased ICP due to the limited capacity of blood, cerebral tissue and CSF to compress.  Subfalcine herniation displacement of cingulate gyrus under the edge of the falx. This can compress on branches of anterior cerebral artery.  Transtentorial herniation occurs when uncal notch on medial temporal lobe displaces under the tentorium. This can compress the posterior cerebral artery, CN III (fixed dilated pupil), midbrain and aqueduct (Sylvius).  Tonsillar herniation is displacement of cerebellar tonsils through foramen magnum. Life threatening due to compression of vital centres in the medulla.  Transcalvarial herniation is external as it is due to a skull defect (surgical or traumatic).

Cerebrovascular disease is the third leading cause of death (after CVD and cancer). The term denotes any abnormality of the brain caused by pathological process of the blood vessels. The three basic processes are thrombosis, embolism and haemorrhage.

Hypoxic-Ischaemic Encephalopathy
Brain requires constant supply of oxygen and glucose (15% of CO, 20% of O2 consumption). It is hence susceptible to hypoxic damage when blood/oxygen supply is disrupted. Causes: CNS changes that result from alterations in normal perfusion (cerebral perfusion pressure = systemic BP – ICP).  Global cerebral ischaemia occurs when there is generalised reduction of cerebral perfusion resulting in widespread ischaemic/hypoxic injury. o Hypoxaemic hypoxia; reduction in Po2 of blood eg. severe anaemia, CO poisoning, near drowning, respiratory arrest, status epilepticus. o Stagnant hypoxia; global reduction in blood flow eg. cardiac arrest, profound hypotension, raised ICP, respirator brain (brain dead person kept on ventilation). o Histotoxic hypoxia; cyanide/sulphide exposure, inhibiting mitochondrial enzymes.  Local cerebral ischaemia occurs when arterial occlusion leads to localised damage in the distribution of the compromised vessel. Arterial thrombus or emboli most common. Morphology: can vary greatly and depends on underlying cause.  Macroscopically; range from widespread petechiae (esp at white/grey junction) to total necrosis of white matter with brown discolouration. o Global ischaemia causes brain swelling with wide gyri and narrow sulci. o Respirator brain can cause browning of cortical regions.  Microscopically; areas of haemorrhage, eosinophilia, necrosis and thrombosis may be present.

Infarction and Vascular Disturbance
Cerebral infarction occurs when hypoxia/ischaemia leads to irreversible injury, usually as a result of occlusive vascular disease. All components are involved in infarction, not just neurons.  Non-haemorrhagic infarcts occur during permanent occlusion due to ischaemic (pale) necrosis. This can develop into a haemorrhagic infarct.  Haemorrhagic infarcts occur in transient occlusion where ischaemic tissue experiences reperfusion and resulting blood seepage. Causes: commonly involves major cerebral arteries, with their central distribution and watershed areas most affected.  Emboli are most common, usually as thromboemboli arising from cardiac or arterial source.  Thrombotic occlusions are usually a result of atherosclerosis.  Vasopsasms are a rare cause  Hypotension may precipitate infarct, especially in watershed areas.

Non-Haemorrhagic Infarct

Haemorrhagic Infarct Haemorrhagic Infarct

Morphology: depends on interval between occlusion and examination.  12-36hrs first well developed changes including slight softening, discolouration and blurred grey/white interface.  7days tissue becomes soft and friable.  10days liquefactive necrosis is evident.  Later repair results in cystic change and reactive gliosis.

Lacunar Infarcts
Small <1cm infarcts (single or multiple) due to microvascular disease or emboli. Most commonly seen in hypertensive patients and associated with severe deficits (eg. hemiplegia).

Intracranial Haemorrhage

Parenchymal haemorrhage is mostly caused by rupture of small intraparenchymal vessels. Often extends into ventricles and less commonly to leptomeninges (pia/arachnoid mater).  Usually caused by hypertension, also associated with trauma, neoplasms, infection, berry aneurysm, cerebral amyloid angiopathy and other vascular disease.  Area affected varies greatly, brain swelling and herniation quite common.  10% of all strokes, 15% of all hypertension deaths. Hypertensive Haemorrhage
Pathogenesis: is due to hypertensive weakening of parenchymal arterioles. Overall effect is hyaline arteriolar sclerosis.   Replacement of smooth muscle with collagen, fragmentation of elastica. Associated with the development of minute aneurysms that may rupture (Charcot-Bouchard microaneurysms).

Classification: based on type of lesion caused by haemorrhage.  
Hypertensive Haemorrhage

Massive and small types have a predilection for certain locations (eg. 50% in posterior putamen, 10% in thalamus). Slit haemorrhages occur in small penetrating vessels, leaving a slitlike cavity. Not common but may cause epilepsy. Petechial haemorrhage occurs in acute hypertensive encephalopathy with severe neuro symptoms.

Presentation: depends on site and volume, often progressing over hours or days.

Subarachnoid haemorrhage is most frequently due to rupture vomiting, hemiparesis, hemisensory loss, coma. Common symptoms; headache, of a berry aneurysm. Blood seeps into the subarachnoid space between the pia and arachnoid mater. 15-20% go unnoticed. Other causes include:  Rupture of other aneurysms (eg. fusiform, giant, infective).  Vascular malformation (eg. arteriovenous malformation, cerebral amyloid angiopathy), however these are more likely to cause parenchymal haemorrhage.  Systemic factors (eg. bleeding diathesis) Berry Aneurysm
Saccular aneurysm that develops at points of weakness of tunica media of cerebral arteries. Causes 4.4% of stroke mortality, incidental in 2-3% of autopsies. Risk Factors: mainly hypertension. Also AVM, fibromuscular dysplasia, collagen defects, polycystic kidney disease, coarctation of aorta. Location: most at points of arterial branching. May be multiple.  
Berry Aneurysm, ruptured

85% in anterior part of Circle of Willis, 10-15% in vertebra-basilar system.

Presentation: rupture causes sudden severe headache. May localised symptoms or cause coma/death within minutes.   Third die within 72hrs, another third have serious complications Half have warning symptoms related to sentinel leak.

Epidural and subdural haemorrhages are often associated with trauma and are considered below with haematomas caused by CNS trauma.  Epidural haematoma is blood collected between the clavaria and dura mater. Arterial origin.  Subdural haematoma is blood collected between dura mater and arachnoid. Venous origin.

Stroke is a term for a disease with acute onset of a neurological deficit as the result of vascular lesion (either loss of blood supply or haemorrhage). It is the clinical designation that applies to all the above conditions. Clinical: major cause of hospital admission and death (10% of all mortality). Of those that survive 50% are severely disabled, 10% return to normal activity. Suddenness of onset indicates vascular cause:  Embolic: very sudden, maximal deficit immediate.  Thrombotic: similar but stepwise progression.  Haemorrhagic: usually progresses steadily over minutes or hours. Cause: various disease processes may lead to stroke.  Large vessel arterial disease is most commonly caused by atherosclerosis. Plaque rupture leads to thrombosis. More common in Circle of Willis, vertebrals or carotid bifurcation. May be precipitated by viscosity syndromes or caused by other rare diseases (eg. arterial dissection).  Small vessel arterial disease is a rare cause of stroke. Conditions include primary angitis of the CNS (PACNS), inflammatory disorders and connective tissue disorders.  Emboli are a common cause and may be cardiogenic, atherosclerotic, air, infectious or neoplastic emboli. Often middle cerebral artery involved.  Thrombi are relatively uncommon and may follow infection, surgery, trauma or any hypercoagulable condition.

Traumatic Parenchymal Injuries
Contusions are caused by a blunt impact to the head causing rapid tissue displacement and disruption of vascular channels.  Brain collides with skull at site of initial impact (coup injury) and on opposite side (countercoup).  Injury caused by subsequent haemorrhage, tissue injury and oedema (ie. bruising).  Concussion is reversible altered consciousness following head trauma without contusion. Lacerations occur when there is penetration of the brain causing tearing and vascular disruption.  Caused by either a projectile or fragment of fractured skull.  Subsequent injury and haemorrhage along linear path.

Contusion with Haematoma

Laceration Trauma (gunshot)

Diffuse axonal injury is widespread shearing injury to axons in the brain due to sudden accelerationdeceleration impact (produce rotational forces). Believed to cause 50% of traumatic comas.  Injury greatest in areas where density difference is greatest (two thirds of DAI lesions occur at grey/white matter junction).  Axons are not typically torn at the time of injury; rather they usually become separated hours or days after the injury.  Mechanisms include biochemical cascades (triggered by primary injury) that cause axoplasmic membrane alteration, transport impairment and retraction ball formation (shearing). Secondary injury can be cranial or systemic.  Cranial: raised ICP (oedema, haematoma), hydrocephalus, infection, seizure.  Systemic: hypoxia and hypotension are most common, pyrexia, electrolyte disturbance.

Traumatic Vascular Injuries
Vascular injury is a frequent component of head trauma and results from direct trauma and disruption or the vessel wall, leading to haemorrhage. Depending on which vessels rupture, haemorrhage may occur in any of several compartments. Epidural haematoma (extradural) is blood collecting between the ‘periostial layer of dura mater’ and the ‘calvaria of the skull’.  Presentation: usually due to torn middle meningeal artery, often with cranial fracture. Only 1% of all hospital admissions, mostly male.  Clinical: brief concussion followed by drowsiness and possible coma.  Treatment: if excessive compression of brain occurs, craniotomy may be required.  Outcome: 20-55% die usually due to herniation. Reduced to 10% with optimal treatment.

Epidural Haematoma

Subdural haematoma (dural border) is extravasated blood that splits open and collects between the ‘meningeal layer of dura mater’ and ‘arachnoid mater’ (in potential space).  Presentation: usually due to rupture of bridging veins, often after a fall or assault. Causes 21% of severe brain injuries. Elderly patients may have chronic form usually due to drugs (not trauma).  Clinical: generalised headache or confusion, as most haematomas develop within 48hrs.  Treatment: observation and craniotomy if required. Brain swelling may be uncontrollable.  Outcome: 50-90% die, depends on age, GCS, surgery time (within 4hrs).

Classification: is based on type of differentiated cell within the tumour (eg. astrocytic, meninges).  Primary neoplasms: can originate from any cell present in the CNS. Other primary neoplasms are undifferentiated or are embryonic in character.  Secondary neoplasms: are metastatic neoplasms from other site of body.  Pseudoneoplastic lesions: are psuedotumours and other processes (eg. cysts, haematomas, malformations) that may clinically and raiologically mimic neoplasia. Causes: majority of cases have sporadic unknown cause. Contributing factors include age, sex, radiation, immunodeficiency and genetic syndromes (eg. von Hippel Lindau). Clinical Effects: depend on location, rate of growth, size and secondary changes.  Localised: loss of function, neuro deficits, inappropriate excitation, seizures.  Generalised: raised ICP and associated problems. Growth Patterns: considered as compression vs infiltration.  Can have meningeal involvement or CNS seeding (spread throughout CNS).  Rarely penetrate dura or metastasise outside CNS.

Tumours of the brain parenchyma that resemble different types of glial cells. These neuron support cells include astrocytes, oligodendrocytes and ependymal cells. Astrocytomas (80-90%) is a group of tumours, each with different behaviour, histology and distribution.  Fibrillary (diffuse) astrocytomas are the most frequent adult brain tumour, esp 40-60yrs. o Have broad clinical behaviour and inherent tendency to anaplastic change. o Classified into three groups based on degree of differentiation; low grade diffuse astrocytoma, anaplastic astrocytoma and glioblastoma. Low Grade Diffuse Astrocytomas
Well differentiated tumour with initial slowly progressing symptoms. Eventually anaplastic degeneration occurs leading to clinical deterioration. Macroscopic: ill defined infiltrative tumour. It is solid, firm and tough (± cystic). Microscopic: variable cell morphology, usually fibrillary and increased nuclei.

The least differentiated form which may evolve from astrocytoma (via anaplastic degeneration) or be present from start. Rapidly fatal. Macroscopic: white matter of hemispheres is variegated (colourful), haemorrhage, necrosis, thrombosed vessels. Circumscribed expansion of cerebral tissue. Microscopic: anaplastic astrocytes, endothelial proliferation, mitotic activity.

 

Pilocytic astrocytomas are relatively benign tumours, often cystic. Typically occur in younger population and located in cerebellum. Other special astrocytomas include sub-ependymal and pleomorphic forms.

Oligodendrogliomas (10-15%) are most common in cerebral hemispheres, esp 40-60yrs. Patients may have several years of neurological complaints (often including seizures), however has better prognosis than astrocytomas.

Ependymomas (2-6%) are most common in the ependyma-lined ventricular system, esp <20yrs. Most are infratentorial, children in the fourth ventricle, adults in the spinal cord.

Astrocytoma (glioblastoma)



Other Tumours
Neuronal tumours include cells resembling the neuron parenchyma.  Central neurocytoma are low grade neoplasms found within the ventricular system.  Gangliogliomas have a mixture of glial elements and mature appearing neurons.  Neuroepithelial tumours are a low grade and usually in childhood. Medulloblastomas occur predominantly in children and exclusively in the cerebellum (midline/vermis and lateral/hemispheres).  Tumour is largely undifferentiated and highly malignant, with poor prognosis.  Can extend into fourth ventricle, peduncles and meninges (CSF spreading).  Can be found elsewhere in CNS, called primitive neuroectodermal tumour (PNET). Meningiomas are predominantly benign tumours of adults (esp female 60yrs). Usually attached to the dura and project into sudural space (arise from arachnoid cells).  Compresses parenchyma but usually not invasive (may invade bone, sinuses or dura).  Slow growing, symptoms usually due to compression of underlying brain.


Shwannomas are benign tumours arising from Schwann cells with symptoms referable to compression of involved nerve or adjacent structures (often acoustic loss, CN VIII).  Encapsulated and attached to, but does not replace, nerve. Firm, solid and sometimes cystic.  Two patterns of growth; Antoni type A (spindle bipolar cells) and type B Schawnnoma- bilateral CNVIII (microcystic). CNS Lymphomas are most common in the immunocompromised, esp AIDS and EBV.  Primary lesions are uncommon except in Hodgkins. Majority are B-cell high grade lymphomas.  Secondary involvement is a late complication of meningeal, nerve root or epidural lymphoma.
Metastatic Melanoma

Pituitary neoplasms account for 10-15% of intracranial neoplasms (see endocrine notes).  Symptoms from mass effects or secretory abnormalities. Metastatic tumours are secondary tumours that comprise of 20-25% of adult CNS tumours.  Metastases form sharply demarcated, multifocal masses usually at white/grey border.  Most common primary sites are; lung, breast, skin, kidneys, GIT.

Acute infections of the CNS require early recognition and prompt appropriate therapy. Can be classified by site, pathogen, route of infection or clinical course.  Site: can affect brain all its coverings including leptomeninges (meningitis), parenchyma (encephalitis, cerebritis/abscess), spinal cord (myelitis) and nerve roots (radiculitis).  Pathogens: bacteria (mostly suppuratives, sometimes granulomatous), viruses, fungi or parasites/protozoa. Considered as pathogenic or opportunistic.  Route: haematogenous (commonest), direct implantation (traumatic/iatrogenic), local extension of infection (sinuses, mastoid) or peripheral nerve conduit (eg. rabies).  Clinical: may all present with non-specific fever and headache until altered consciousness, focal neurological signs and/or seizures develop.

Infections of Leptomeninges
Acute Pyogenic Meningitis is inflammation of the leptomeninges and CSF mostly due to bacteria. Bacteria have poor access to CSF, but once gained proliferate rapidly in this excellent culture medium.  Common Pathogens: E. coli and S. agalactiae in neonates. H. influenza, S. pneumonia, N. meningitidis in children and young adults.  Clinical Signs: febrile illness with evidence of headache, photophobia, irritability, neck stiffness or altered consciousness.  Diagnosis: lumbar puncture reveals cloudy/purulent CSF, increased pressure, raised protein, decreased glucose and raised neutrophils. Culture positive for bacteria.  Complications: organisation of exudate by fibrosis can cause hydrocephalus, spinal arachnoiditis or spinal cord infarction. Cranial Acute Meningitis nerve palsies and meningoencephalitis may also occur.
(with abscesses)

Aseptic Meningitis is clinical term for meningitis without recognisable organism. In most cases viral pathogen is eventually found.  Common Pathogens: echovirus and coxsackie A/B (enteroviruses), HSV2  Clinical Signs: similar but less fulminant than pyogenic meningitis, usually self limiting.  Diagnosis: CSF reveals lymphocytosis, moderate protein elevation and normal glucose. Chronic Meningitis is caused by mycobacteria and spirochetes, often with parenchymal components.  Tuberculous meningitis causes increased cellularity and protein in the CSF. May result in well circumscribed parenchymal mass (tuberculoma) or spinal TB (Potts Disease).  Neurosyphilis is a tertiary stage of syphilis with major meningeal manifestation. Paretic (progressive mental/physical function loss) and tabes dorsalis (dorsal root damage) forms.  Neuroborreliosis is nervous system involvement by B. burgdorferi.

Infections of Parenchymal
Brain Abscesses are focal suppuratives infections nearly always caused by bacteria. Known as cerebritis if no abscess forms. Fungi and parasites are rarer causes.  Causes: direct implantation of organisms, local extension from adjacent foci (mastoiditis or sinusitis), or haematogenous spread (primary site from heart, lungs, bones etc.).
Pyogenic Abscesses

 

Morphology: discrete, non invasive, destructive parenchymal lesions. o Macroscopic: central liquefactive necrosis surrounded by fibrous capsule. o Microscopic: vascularisation, granulation tissue. Reactive gliosis outside fibrous capsule. Clinical Signs: fever ± signs related to focal deficits and raised ICP. Complications: rupture can cause ventriculitis, meningitis, venous sinus thrombosis. HSV Encephalitis
Commonest cause of sporadic encephalitis. Fulminant infection that is rapidly fatal if untreated. Only some patients have prior herpetic lesions. Cause: usually due to HSV 1, immunocompromised and neonates mostly HSV 2. Morphology: large bilateral, irregular areas of necrosis and haemorrhage. Clinical: alterations in mood, memory and behaviour reflect frontal/temporal involvement. Diagnosis: PCR of virus from CSF, isolation from brain biopsy. Treat with acyclovir.

Viral Encephalitis is a parenchymal infection that is invariably associated with meningitis.  Causes: Some viruses infect specific cell types (tropism), others involve preferential areas due to their route of entry. o VZV - dorsal root ganglion cells. o Poliomyelitis - anterior horn, motor neurons. o Papovavirus of PML - oligodendrocytes. o Rabies - only neurons. o HSV - inferior frontal and temporal lobes.  Clinical Signs: symptoms include fever, headache, photophobia, weakness and seizures.

Subacute Encephalitis is also mostly viral, however does not clinically resemble an acute infection. Have a long latent period.  Causes: subacute sclerosing panencephalitis (SSPE) from measles virus, progressive multifocal leukoencephalopathy (PML) from papova virus, progressive rubella panencephalopathy, HIV.  Clinical Signs: general symptoms of encephalopathy with signs of diffuse inflammation of entire brain (panencephalopathy).

Progressive Multifocal Leukoencephalopathy (PML)
PML is a viral infection of white matter that preferentially affects oligodendrocytes. Cause: JC virus (a papovirus), invariably in the immunocompromised. Pathology: route of entry unknown (not systemic). 65% exposed to virus by age 14, evidence of reactivation. Produces demyelination with no effective treatment.

Other CNS Infections
Epidural and Subdural Infections can involve bacteria or fungi.  Epidural abscesses are usually a complication of osteomyelitis. Symptoms from mass effects or spinal cord compression.  Subdural empyema is accumulation of pus in this potential space as a complication of infection in sinuses or skull. Symptoms generally from mass effect. Parasitic Infections mostly due to toxoplasmosis or cysticercus.  Cysticercus remain dormant for years, eventually degenerate inducing granuloma formation, focal scarring and calcification. May involve parenchyma, meninges or ventricular system.  Seizures most common symptom, can cause raised ICP if ventricular.

Neurodegeneration (ND) is progressive and irreversible loss of specific vulnerable neuronal populations. Results in increasing disability and eventual death. ND involves a very complex interplay of genetic and environmental factors. Classification: old methods had overlap between the diverse range of ND diseases. Modern methods are according to familial vs sporadic aetiology:  Familial ND result from genetic mutations and tend to have an early onset.  Sporadic ND is largely due to environmental factors and tends to have a late onset.  Many ND have both a common sporadic form and uncommon familial form. NB: can also have pathological classification (subcortical or cortical), as is done below. Pathology: it is thought that neuroinflammation and altered protein dynamics play a large role in the disease processes. This may include abnormal protein breakdown, folding or aggregation. These abnormalities can render proteins soluble (neurotoxic) or insoluble (filaments/deposits). This leads to cellular dysfunction and neuronal death. Clinical: dementia is the development of memory impairment and other cognitive deficits during normal consciousness. It is a clinical sign that is present in many ND diseases and is not a normal part of aging.
Dementia vs Neurodegeneration (ND) ND is a disease process, dementia is a clinical sign.  Not all ND results in dementia eg. motor ND may only result in somatic deficit.  Not all dementias are due to ND eg. some dementias are caused by vascular disease.

Subcortical Degenerations
Motor Neuron Disease involves neurodegeneration of upper motor neurons (Betz cells) in the motor cortex and/or lower motor neurons in the spinal cord, both resulting in weakness. Clinical: depends on location, sensory systems and cognitive functions are usually unaffected, but types with dementia do occur. Death within 5 years due to respiratory failure or aspiration.  UMN loss also results in hyperreflexia, hypertonicity, paresis and +ve Babinski sign.  LMN loss also results in hyporeflexia, hypotonicity, muscle wasting and fasciculations. Pathology: most cases are sporadic. Specific forms of degeneration have familial cause eg. 10% of amyotrophic lateral sclerosis (ALS) are due to a SOD-1 gene mutation. Morphology: loss of associated motor neurons with shrunken ventral nerve roots. Inclusion bodies in surviving motor neurons (bunina bodies). Neuronal swelling. Parkinsonism results from degeneration of dopaminergic neurons of the substantia nigra. Is distinct from other such conditions by the presence of Lewy bodies. Parkinsonism – substantia Clinical: classic symptoms of cogwheel rigidity, bradykinesia, resting tremor and nigra pallor. postural instability. Dementia occurs 40% of the time. Most common ND movement disorder. Pathology: most cases are idiopathic and sporadic. Some autosomal forms exist. Morphology: diagnostic feature is presence of Lewy bodies, an inclusion of αsynuclein in surviving neurons. Grossly, there is pallor of the substantia nigra. Progressive Supranuclear Palsy (PSP) is characterised clinically by axial rigidity (akinesia), supranuclear gaze palsy and mild dementia. Clinical: death within 6-7yrs due to aspiration pneumonia.

Pathology: unknown, there is accumulation of tau (protein that stabilises microtubule) within neurons and glial cells. Morpholgy: atrophy of midbrain and pallor of substantia nigra. Microscopically there is; inclusions of tau aggregate, neuronal loss and gliosis. Huntington’s Chorea is an inherited autosomal dominant disease characterised by progressive movement disorders and dementia. Clinical: rapid involuntary movements (chorea), rigidity and cognitive decline (dementia). Pathology: mutation gene IT-5 gene on Ch 4. Involves >40 repeats of CAG sequence (normally <34).  Codes for huntingtin (large polyglutamine protein) which aggregates in abnormal tissue.  The repeats expand in children of affected males (occurs during spermatogenesis). Morphology: loss of neurons in the form of caudate, putamen and cortical atrophy. Microscopically, astrocytic gliosis and huntingtin inclusions (in surviving neurons) can be seen.

Cortical Degenerations
Alzheimer’s Disease is the commonest cause of dementia (50-75%) characterised by memory and higher intellectual impairment. Clinical: progressive dementia with eventual end stage cachexia, death by bronchopneumonia. 4% in >75yrs, 40% for >90. Pathology: neurodegeneration of cortical/subcortical neurons due to the build up of various proteins.  Amyloid precursor protein (APP) is a transmembrane glycoprotein which when abnormally cleaved forms Aβ amyloid. This aggregates extracellularly and forms plaques.  Small Aβ aggregates can alter neurotransmission and can be toxic. Large aggregates lead to neuronal death and elicit an inflammatory response. Alzheimer’s – cortical atrophy  Surviving neurons develop filaments of hyperphosphorylated tau inclusions. These neurofibrillary tangles (NFT’s) can cause neuritic plaques. Morphology: macroscopically shows variable cortical atrophy and widening of cerebral sulci. Diagnosed by the microscopic presence of extracellular amyloid plaques and intracellular NFT’s. Lewy Bodies Dementias are the second most common type of dementias (10-25%). Hallmark of cortical lewy bodies in deep grey matter. Clinical: fluctuating cognitive decline can cause recurrent visual hallucinations and spontaneous motor features of Parkinsonism. These often coexist with Alzheimer’s features. Pathology: most cases idiopathic and sporadic. Morphology: mild-moderate fronto-temporal atrophy, pallor of substantia nigra and locus coeruleus.

Pick’s Disease is a fronto-temporal dementia with rapid deterioration in personality. Morphology: fronto-temporal atrophy is very severe with ‘knife edge gyri’. Residual swollen neurons with spherical inclusions (pick bodies). Filamentous inclusions of tau protein.

Pure Dementia

Alzheimer’s Disease

Pure Motor



eg. Pick’s Disease eg. Parkinsonism

Other dementias are either rare or not caused by neurodegeneration. These include ALS- (motor neuron), corticobasal degeneration-, diffuse frontal- and Ch 17- related dementias. Vascular dementia is a non-neurodegenerative cause resulting in acquired intellectual impairment. Prion Disease is the accumulation of abnormal cellular protein called prion protein (PrP). Clinical: no means of treating and body has no immune response. Must be prevented by avoiding exposure (right) and sterilising contaminants. Pathology: PrPc are normal proteins found in cell membranes. PrPSc is an infectious folded isoform that is able to convert PrPc in body to PrPSc.  PrPSc causes neurodegenerative disease by forming amyloid aggregate within the CNS resulting in holes/vacuoles in neurons, reactive astrogliosis and white matter degeneration. Morphology: atrophy in most cases with ventricular enlargement. Spongioform change with neuronal loss and astrocytosis. Accumulation of prion protein both intracellularly and extracellularly (as amyloid plaques).
Cruetzfeldt-Jacob Disease (CJD)

Prion infection that is due to sporadic change in 85%. It can occur via:  Spontaneous change in protein structure (1:106).  New variant consumption (BSE contaminated meat).  Canabolism (kuru).  Iatrogenic inoculation (avoided by recombinant tissue). Familial cases make up 15% and are due to a polymorphism at codon 129. This confers susceptibility to spontaneous change in PrPc to PrPSc.


[Original notes by Ben H.]

Demyelination is the destruction of normal myelin with a relative preservation of axons. This can affect the CNS and PNS. Various features common to all demyelinating disorders: NB: Ephaptic transmission  Demyelination and formation of plaques. is when two nerves  Ephatic neurotransmition (ephaptic neurotransmission causes communicate with each episodes of pain and spasm). other via an artificial  Protean symptoms (so variable can suggest other diagnoses). synapse. Pathogenesis/Morphology: due to an abnormal T-cell mediated autoimmune response to several myelin proteins, which forms plaques. This is preceded by perivascular inflammation. 1. Active Plaques: activation of inflammatory cells → myelin fragmentation/phagocytosis by microglia. Some oligodendrocytes (support myelin) are also destroyed. 2. Inactive plaques: inflammation slowly resolves (about 6 wks) and glial cells respond by proliferating to form a hardened, sclerotic plaque (astrocytosis). 3. Shadow plaques: remaining oligodendrocytes attempt to remyelinate, however form abnormal grouping of axons → allows short circuits → permanent ephaptic transmission. NB: if the inflammatory process is arrested early, plaques are partially remyelinated. In advanced lesions, astrocytosis creates a barrier between oligodendrocytes and their axonal targets. Morphology: characteristic central vessel surrounded by a zone of demyelination at the periphery. This zone is filled with lymphocytes and macrophages (microglia).  Plaques vary in size and shape and can occur anywhere in the white matter, often at angles of ventricles, white-grey junction and surface of brain stem/spinal cord (forms grey depressions).  Active early plaques are pink (inflamed), inactive old plaques are grey (sclerosed).

Clinical: signs are highly protean (variable) and depend on site and extent of plaques.  Cerebellar/brainstem: wide based gait, autonomic dysfunction (eg. BP).  Spinal cord: weakness, sensory loss, bowel and bladder dysfunction.  Optic nerve: sudden unilateral blindness which is self limiting lasting 2-3 wks. NB: ephaptic neurotransmission causes neuralgia and muscle spasms. Diagnosis: can be asymptomatic so need to use investigations. Best test is MRI as it reveals ‘silent’ plaques. CSF sample (electrophoresis) and evoked response tests (visual/auditory/somatosensory) can be used to support diagnosis.

Multiple Sclerosis
CNS disease with intermittent and seemingly random neurological symptoms, can occur at any age.  Manifests as well demarcated area of demyelination which causes multifocal white matter plaques. There is axonal preservation, except late in disease.  White matter is more affected than grey matter as it has a predominance of myelinated axons.  In cases of severe demyelination lasting years, cavities form Demyelination due to MS when axons break down which can mimc infarcts.  Abnormal Tcell response to several myelin proteins, thought to be precipitated by viral infection. Other associations with bacteria, defective gliosis, diet, genetic, toxins.
Charcot (Classic) Type has three clinical patterns;  Relapsing-remitting with attacks once every 2 years (commonest).  Primary progressive with later onset and spinal cord involvement.  Secondary progressive. Acute Fulminant Type is a rare clinical presentation and tends to happen as a one off severe episode.  Acute (Marburg Type) occurs in younger people, has a rapid course, large plaques Involves destruction of myelin and some neuronal loss.

 Neuromyelitis Optica (Devic’s Disease) occurs
especially in Asian populations.

 Concentric Sclerosis (Balo’s Disease)

Acute Disseminated Encephalomyelitis (ADEM)
Rare but severe global monophasic episode of demyelination from an immune response.  T-cell mediated hypersensitivity immune response that follows infection/vaccination (can be latent from 3days to 3 weeks). Usually resolves with steroids and plasmapheresis.  Microscopically see tiny little plaques of demyelination which resolve with time and steroid therapy (ie. because they are so small they are able to resolve).  There is also a more fulminant and fatal haemorrhagic variant. Produces gross petechial haemorrhages throughout white matter.

Trigeminal Neuralgia
Involves intense lanciating pain localized to small areas of the face, lasting secs (Tic doloreaux).  Due to localized demyelination of sensory fibres in the proximal CNS that arepart of trigeminal root. Most commonly caused by compression of overlying artery or vein.  Results in attempts at remyelination and abnormal groupings → ephaptic neurotransmission with unexpected pain from normal touch sensation.




Addison Amsler Aschoff Barrett Bartholin Bence Jones Berger Bowen Brudzinski Chagas Charcot-Leyden Churg Strauss

[Written by David H.]

List of names that David would like to dedicate Nobel prizes/MSN lists to, or something like that.
Destruction of the adrenal cortex, most commonly caused by autoimmune disorders (80% of cases). Other causes include infection, AIDS or cancer. Criteria for diagnosing vaginosis. Foci of fibrinoid necrosis during rheumatic heart disease in the myocardium. Consists of macrophages, lymphocytes, and plasma cells that turn into a scar. Replacement of oesophageal squamous epithelium with metaplastic columnar epithelium. Inflammatory occlusion of Bartholin vulvovaginal glands. Cast nephropathy due to light chains binding to glycoproteins in the tubular lumen. IgA nephropathy causing glomerulonephritis, and glomerula hematuria. A neoplastic skin disease, usually a form of squamous cell carcinoma. Sign of meningitis when flexion of neck causes flexion of the hips and knees. Disease caused by Trypanosoma cruzi. Symptoms include myocarditis in 50% of population. Microscopic crystals found in people who have allergic diseases such as asthma or parasitic infections. Granulomatous and eosinophil rich inflammation involving the respiratory tract, with necrotizing vasculitis affecting small to medium sized vessels associated with asthma and blood eosinophilia. Primary hyperaldosteronism, usually due to an adenoma. May be secondary to Cushings. Refers to desquamated epithelium found in biopsies of asthmatic patients. Hypercortisolism due to pituitary hyper secretion, or an adenoma. Thrombohemorrhagic disorder secondary to other disease. Disseminated Intravascular Coagulation. Criteria for diagnosing endocarditis. Consists of ventricular septal defect, dextroposed aorta overriding the septal defect, pulmonary stenosis with RV outflow obstruction, and RV hypertrophy. Staging system for prostate cancers consisting of 5 stages. Autoimmune disorder, with hyperplasia of the thyroid, with associated othalmopathy and dermopathy. Acute inflammatory demyelinating polyradiuloneuropathy. Autoimmune disorder, causing hyper or hypothyroidism depending on its course.

Conn Curschmann Cushing DIC Duke Fallot Gleason Graves Guillan-Barre Hashimoto

Henoch Schonlein

Janeway Jones Kaposi Kawasaki Kernig Koplik Lambert-Eaton

Menetrier Monckeberg Ormond Paget

Plummer Vinson Raynaud Riedel Roth Sheehan Sipple Stevens-Johnson Syndenham Takayasu Turner von Hippel-Lindau vonWillebrand Waterhouse-Friderichsen Wegners Wermer Whipple Wickham Wilms Zollinger-Ellison

Systemic hypersensitivity reaction of unknown caused with purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis. Causes increased vascular fragility. Has IgA deposits around the body. Erythemous nodular lesions on palms and soles. Found in infective endocarditis. Criteria for diagnosing rheumatic fever. Patches, nodules, raised plaques, due to HHV-8 Arteritis of large medium and small size arteries. Usually occurs in children, and is self limiting. Sign of meningitis when flexing hip at 90 degrees and extending the knee causes pain. Small irregular red spots found on the inside of cheek and tongue. Found in early stage measles. Paraneoplastic disorder of the neuromuscular junction, commonly occurring with small cell carcinoma of the lung. Causes neuronal stimuli to release less synaptic vesicles. Hyperplasia of surface mucous cells in the stomach with fundic gland atrophy. Medial calcification in small to medium sized muscular arteries. Retroperitoneal fibrosis of unknown cause. May encroach on ureters. Usually refers to the bones or nipple. In bones it is a chronic disease resulting in enlarged and deformed bones, suspected to have a viral cause. When referred to the breast, it is a cancer that appears like eczema. Mucosal protrusions into the oesophageal lumen forming webs. Vasospasm of arterioles, with cyanosis of digits. Fibrosis of the thyroid of unknown etiology, extending into contiguous neck structures. Retinal haemorrhages. Observed in mainly in infective endocarditis but also in leukaemia, diabetes, pernicious anaemia, and ischemic events. Ischemic necrosis of the anterior pituitary Medullary thyroid carcinoma, with pheochromocytoma, and parathyroid hyperplasia. Aka. MEN-2A Hypersensitivity reaction that causes the skin to necrose, with the epidermis separating from the dermis. Neurological disorder with rapid involuntary purposeless movements. A diagnostic criterion for rheumatic fever. Granulomatous inflammation of aorta and major branches. Chromosomal disorder causing in females causing features such as short stature, lymphoedema, broad chest, low hairline, low-set ears, and a webbed neck. Hemangioblastomas in cerebellar hemispheres, retina, brain stem, and spinal cord, with cysts involving the pancreas liver and kidney, and paragangliomas. Required for Factor 8 stabilisation, used in the coagulation cascade, for platelet adhesion and aggregation. Causes bleeding when levels are low. Acute adrenal cortex insufficiency due to destruction from infection, or DIC, or other causes. Granulomatous inflammation of upper and lower respiratory tract, with necrotizing vasculitis of small vessels namely in the lung and glomeruli. 3P's. Parathyroid hyperplasia, pancreatic lesions, Pituitary adenoma. Aka. MEN-1 Systemic infection due to Tropheryma whippelii occurring in the small intestine causing GIT symptoms. Striae or white dots that appear in Lichen Planus in the skin. Triphasic nephroblastoma primarily occurring in children. Condition consisting of multiple peptic ulcers, gastric hyper secretion, and is often caused by an endocrine cell tumour increasing gastrin production.

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