PATHOLOGY

101v2.0

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

CARDIAC

PATHOLOGY

HEART FAILURE 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.

Activation of neurohormonal systems:

noradrenaline, renin-angiotensin system, ANP.

Frank-starling mechanism: Cardiac failure causes

↑EDP resulting in increased stretch of cardiac

muscle → fibres contract more forcibly, hence

↑CO.

Myocardial structural changes (hypertrophy).

This is an adaptation to chronic ↑ workload and

since myocytes can’t proliferate, concentric or

eccentric hypertrophy occurs.

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.

Pressure vs Volume Overload

Pressure overload state (eg. hypertension, valve

stenosis) causes increased SBP. Results in increased

diameter of cardiac muscle (added myofibrils).

→ CONCENTRIC HYPERTROPHY: wall thickening with

no change in chamber size.

Volume overload state (eg. valve regurge, abnormal

shunts) causes increased DBP. Results in increased

length of muscle fibres (added sarcomeres).

→ ECCENTRIC HYPERTROPHY: chamber enlargement

with some wall thickening.

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

Fine crepitant rales at lung bases (oedema in alveoli)

Mitral regurgitation (papillary muscle damage)

Atrial fibrillation (irregularly irregular heart beat)

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

ISCHAEMIC HEART DISEASE (IHD) 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.

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).

Subendocardial Infarct Transmural Infarct (old and new)

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.

HYPERTENSIVE HEART DISEASE (HHD) 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).

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.

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).

RV

Hypertrophy

LV Concentric Hypertrophy

VALVULAR HEART DISEASE (VHD) 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.

Incompetence (Insufficiency/Regurgitation) Failure of valve to close completely, allowing reverse flow. Creates backward volume overload.

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Mitral Stenosis -Cause: post inflammatory scarring (RHD).

-Clinical: LA pressure increase → pulmonary congestion and hypertension → RV hypertrophy.

-Murmur: diastolic, rumbling with opening snap. NB: stenosis of mitral and aortic valves accounting for 2/3 of all valve diseases.

Mitral Regurgitation -Causes: o Myxoid degeneration (floppy leaflet that

prolapses into LA due to abnormal ECM). o RHD, infective endocarditis. o Dilatation of valve ring (LV enlargement or

calcification of annulus). 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

Ao

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Aortic Stenosis -Causes: RHD, degenerative calcification (eg. old age, congenitally deformed valve)

-Clinical: small pulse, LV hypertrophy, angina, syncope, LV failure or sudden death.

-Murmur: systolic, ejection murmur

Aortic Regurgitation -Causes: leaflet abnormalities (eg. RHD, IE), aortic diseases (eg. degenerative aortic dilation, syphilitic aortitis, ankylosing spondylitis, rheumatoid arthritis, Marfan syndrome).

-Clinical: wide pulse pressure, collapsing pulse, LV hypertrophy, angina, LV failure

-Murmur: diastolic, opening snap, 3rd heart sound

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.

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.

Subacute endocarditis of mitral valve

IE aortic valve

CARDIOMYOPATHIES (CMP) 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).

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.

DCMP

Peripartum Cardiomyopathy

CMP during pregnancy due to

related hypertension, volume

overload, nutritional deficiency,

abnormal metabolism and altered

immune function.

Usually transient and reversible.

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.

Myocarditis 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.

OTHER HEART DISEASE Pericardial Disease 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.

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.

Shaggy Thrombosis

Fibrous Pericarditis

Tuberculous Pericarditis

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.

Transplantation 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.

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.

Shock 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.

Arrhythmias 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.

VASCULAR

PATHOLOGY

ARTERIOSCLEROSIS Arteriosclerosis 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.

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).

HYPERTENSIVE VASCULAR DISEASE 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.

Early aortic atheromatous lesion

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

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).

ANEURYSMS AND DISSECTIONS 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.

Hyaline arteriosclerosis

Hyperplastic arteriosclerosis

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:

Rupture into peritoneal cavity or extraperitoneal tissue, can be fatal. Risk of

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:

Late complication of syphilis, whereby T. pallidum affects the vasa vasorum in the

aortic adventitia, causing ‘obliterative endarteritis’ (endothelium inflammation).

Affected vessels show luminal narrowing and obliteration. Scarring of vessel wall

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.

Vasa Vasorum

Arterial network

supplying larger

blood vessels.

AAA

Ruptured Aortic Aneurysm

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.

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).

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.

VASCULITIS 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.

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.

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.

HAEMATOLOGIC

PATHOLOGY

RED CELL DISORDERS 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

(elongated and crescentic). Diagnosis on prep with reducing

agent (metabisulfate) of Hb electrophoresis.

Clinical: sickle cells are removed by splenic phagocytes

producing a chronic normocytic anaemia. Widespread

microvascular obstruction due to sickle aggregates can

cause acute pain crisis and tissue infarction.

Congestive Splenomegaly

Occurs mostly in young children due to

infarction in spleen from microvascular

obstruction. Causes scarring, shrinkage

and loss of function (autosplenectomy).

Functional asplenia leaves patients

vulnerable to infection, most die <30.

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).

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

haematological sequelae. Results from dietary deficiency,

malabsorption, competitive tapeworm uptake, bacterial

overgrowth, pregnancy, hyperthyroidism or cancer.

NB: bodies B12 stores are large, takes years to develop

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).

Perinicious Anaemia

Gastritis where auto-antibodies destroy

gastric parietal cells. Results in absence

of intrinsic factor and hence Vit B12

impaired absorption. Most common

cause of adult Vit B12 deficiency.

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.

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.

Polycythaemia 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.

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

Spherocytosis Sickle Cell Megaloblastic Iron Deficiency

BLEEDING DISORDERS 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.

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).

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.

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.

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.

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).

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).

Sum

mar

y

Hereditary Bleeding Disorders Acquired Bleeding Disorders

Haemophilia A and B: X-linked disorders of inadequate factors VIII and IX.

Liver disease or vit K deficiency: reduced factor synthesis/modification.

Von Willebrand's disease: defect in vWF resulting in impaired platelet adhesion.

ITP: causes immune platelet destruction. TTP: platelet aggregation due to vWF accumulation.

Essential thrombocythaemia: primary disorder of excess platelet production.

DIC: systemic clotting, followed by factor depletion and bleeding.

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.

WHITE CELL DISORDERS 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.

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.

Leukaemias Chronic Myeloid Leukaemia (CML) arises from mutation in a pluripotent myeloid

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.

Acute Myeloid Leukaemia (AML) neoplasm comprised of immature myeloid cells.

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).

Myelofibrosis

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.

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.

CML

AML with pallor of renal substance.

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)

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).

Lymphomas 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.

Small lymphocytic lymphoma (4%) is similar to CLL, only with no or limited

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.

Non-Hodgkins

Lymphadenopathy

(pancreas)

CLL of Coeliac LNs,

RESPIRATORY

PATHOLOGY

ATELECTASIS 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.

OBSTRUCTIVE PULMONARY DISEASE 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.

Emphysema 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 over-

inflation 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 α1-

antitrypsin deficiency.

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.

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.

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

Asthma 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.

IL-5, eosinophil recruitment (priming or sensitisation).

IL-13, increased mucous production.

TH2

Bronchiolitis Obliterans

Mucous plugs are

permanently fibrosed

which results in complete

obliteration of the

bronchiolar lumen.

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.

Bronchiectasis 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).

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.

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.)

Bronchiectasis (with emphysema)

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.

RESTRICTIVE (INTERSTITIAL) LUNG DISEASE 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 60-

100%. Fibrosis of lung is common in survivors.

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.

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.

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).

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).

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.

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.

Silicosis

The most common pneumoconiosis in the world,

usually due to crystalline silica. Ranges from:

→ Asymptomatic silicotic nodules

→ Progressive massive fibrosis (PMF).

Coal Workers Pneumoconiosis

Results from repeated exposure to coal. Can range

from:

→ Asymptomatic anthracosis

→ Simple CWP (coal macules with emphysema)

→ Progressive massive fibrosis (PMF).

Asbestosis

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.

Anthro -Silicosis

PULMONARY VASCULAR DISEASE

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.

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.

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 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.

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).

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.

Massive Pulmonary Embolism

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.

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.

PULMONARY INFECTIONS 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).

Bronchopneumonia: foci of inflammatory consolidation in patches throughout one or more lobes.

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.

NB: consolidation = exudate

combining into a firm dense mass.

Lobar Pneumonia

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.

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

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.

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.

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.

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).

S. Pneumoniae [blood sample]

S. Pneumoniae [sputum sample]

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.

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.

PULMONARY TUMOURS Carcinomas 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).

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 non-

smokers (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.

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.

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.

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.

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.

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,

fatigue, weakness, nausea.

b) Intrathoracic spread; invasion/compression of

nerves can cause related symptoms, can also

obstruct blood vessels or oesophagus.

c) Extrathoracic spread; to lymph nodes (mediastinal,

clavicular, scalene, Virchow’s nodes), liver, brain,

adrenal and bone metastases (most common).

d) Paraneoplastic syndromes; systemic syndromes

due to ectopic substance (hormone, cytokine)

production. Occurs in 3-10% of lung carcinomas.

Adenocarcinoma Squamous Cell Carcinoma Small Cell Carcinoma Large Cell Carcinoma

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

Intrathoracic Dissemination

Intrathoracic spread can cause:

o Apical neoplasms that invade the brachial

(ulnar nerve pain) or cervical (Horner’s

syndrome) sympathetic plexuses. Known as

‘Pancoast syndrome’.

o Phrenic nerve → diaphragmatic damage.

o Recurrent laryngeal nerve → hoarseness.

o Obstruction in SVC → dilation of head/neck

veins, facial swelling, cyanosis.

o Oesophageal obstruction → dysphagia.

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

metastasis (<10%).

Either obstructs lumen or penetrates bronchiolar

wall, can be central or peripheral.

Histologically, can be typical or atypical.

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

Nasopharyngeal Carcinoma

Squamous carcinoma with lymphoid infiltrate o Leading cause of death in SE Asia o Associated with EBV, other genetic and environmental links. 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

Typical Carcinoid; small rounded cells with

diffuse chromatin granules, absent/rare mitoses,

little pleomorphism. 80% 10yr survival.

Atypical Carcinoid; higher mitotic rate, increased

pleomorphism, necrosis. 50% 5 yr survival.

HEPATOBILIARY

AND PANCREATIC

PATHOLOGY

LIVER PATHOLOGY Overview 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.

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.

Usually due to excessive haemolysis (haemolytic jaundice). Can be

due to ↓hepatic uptake or impaired conjugation. Not excreted in

kidneys, stool still contains pigment (no obstruction).

Conjugated bilirubin is soluble due to conjugation with glucoronic

acid. Usually due to impaired bile flow (obstructive jaundice). Can be

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.

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

Jaundice Hereditary Syndromes

Dubin-Johnson Syndrome -

impaired transport of anions.

Gilber Syndrome- relatively

common mild conjucgation

disorder.

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 (hepato-

renal syndrome), palmar erythema, spider naevi, gynaecomastia (impaired oestrogen degradation),

prolonged prothrombin time (impaired synthesis of coagulation factors), weight loss, muscle wasting,

malabsorption, anaemia.

Hepatitis 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.

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.

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.

Amoebic Abscess

Multiple Hepatic Abscesses

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,

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.

Haemodynamic and Vascular Abnormalities Portal Hypertension is increased resistance to portal blood flow that may

develop form pre-, intra- or post- hepatic causes. Most dominant cause is

cirrhosis (intrahepatic). May manifest as ascites (fluid/lymph in peritoneal

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.

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.

ate, anabolic steroids).

Hypersensitivity (drugs can act as haptens).

Metabolic response to drugs (paracetamol,

phenothiazines, methyldopa, halothane).

Steatosis

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.

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.

Haemochromatosis of Liver

Haemangioma 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.

BILIARY PATHOLOGY 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.

Pigment Stones small, black, multiple, radiolucent clumps of pigment. Derived

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).

Multiple

Metastatic Tumours

Mixed Cholelithiasis

(mostly pigment)

Hepato- Carcinoma

Cholecystitis 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

with oedema and fibrosis. Microscopically, has acute inflammatory infiltrate

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

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.

Gallbladder Carcinoma

Acute Calculous

Cholecystitis

PANCREATIC PATHOLOGY

Acute Pancreatitis 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

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.

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.

[Note: disorders of endocrine pancreas

discussed in Endocrine Pathology]

Psuedocysts

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.

Acute Pancreatitis

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

masses that spread widely to the liver and regional lymph nodes.

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.

Carcinoma of pancreas,

spread to humerus

GASTRO-

INTESTINAL

PATHOLOGY

(Draft)

ORAL CAVITY PATHOLOGY 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.

OESOPHAGEAL PATHOLOGY

Various problems include:

• Congenital - tracheo-oesophageal fistula, achalasia

• Infection – HSV, candida

• Varices secondary to liver cirrhosis

Oesophagitis 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)

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.

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.

.

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%.

STOMACH PATHOLOGY Various problems include:

• Menetriers disease

• Pernicious anaemia/ atrophic gastritis

• Pyloric stenosis (congenital)

Gastritis 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.

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

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.

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.

SMALL INTESTINE PATHOLOGY 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.

APPENDIX PATHOLOGY Appendicitis 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)

LARGE INTESTINE PATHOLOGY Most common problems include:

• Angiodysplasia

• Hirschprungs (congenital aganglionic megacolon)

• Colitis

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

• Severe acute abdominal pain and tenderness

• Nausea & vomiting

• Bloody diarrhoea

• Loss of bowel sounds, abdominal rigidity

• Shock, vascular collapse

Subacute

• Non-specific symptoms, episodes of bloody

diarrhoea blood loss, sepsis

Chronic

• 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:

a. Tubular adenomas (pedunculated)- 75%.

Can be sporadic of familial. Male to

female ratio of 2:1. Average age is 60.

Mostly occur in the left colon.

b. Villous adenomas (usually sessile)-

largest, least common polyp. 33% are

cancerous. Characteristic “cauliflower-

like” growth (1-10cm diameter).

c. Tubulovillous adenomas

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.

Familial Adenomatous Polyposis

A genetically inherited (autosomal dominant)

condition associated with a mutation in the APC

gene on chromosome 5. This predisposes to

multiple (hundreds) of colonic adenomas starting in

the rectosigmoid area, and eventually covering the

entire colon. This occurs during adolescence and

early adulthood. Benign polyps undergo malignant

transformation usually in the 30s and 40s.

Treatment is by total colectomy.

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.

ANAL PATHOLOGY 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.

URINARY

PATHOLOGY

GLOMERULAR DISEASES Glomerulonephritis 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).

DISEASES OF TUBULES & INTERSTITIUM 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:

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.

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.

Acute Pyogenic

Pyelonephritis

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.

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.

Chronic

Pyelonephritis

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.

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.

DISEASES OF THE BLOOD VESSELS 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.

Multifocal Renal Infarction

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).

CYSTIC DISEASES OF THE KIDNEY Simple Cysts Generally innocuous lesions occur, as single or multiple cystic spaces.

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.

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.

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.

HUS

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.

Dialysis Associated Cysts

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.

Adult ADPKD

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).

URINARY OUTFLOW OBSTRUCTION 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

by hypercalciuria but can be due to other metabolic abnormality,

or even idiopathic. Favoured by ↑pH.

Struvite (Magnesium Ammonium Phosphate) (15%) occur in

persons with persistently alkaline urine due to UTIs. Urea splitting

bacteria (eg. P. Vulgaris, Staph) predisposes persons to stones.

Uric Acid Stones (6%) gout and diseases involving rapid cell

turnover (eg. leukemia) lead to high uric acid levels in the urine

and the possibility of the uric acid stones. Favoured by ↓pH.

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.

Medullary Cystic Disease

Child ARPKD

Causes of Calcium Stones

Hypercalcuria (60%); ↑ gut absorption,

↓ renal reabsorption, hypercalcaemia

(↑PTH, vit D etc).

Hyperuricosuria (20%); ↑ uric acid in

urine, promoting Ca deposition.

Hyperoxaluria (5%); hereditary ↑ in

oxalate in urine.

No known metabolic problem (15%)

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.

Hydronephrosis 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.

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.

TUMOURS 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.

Hydronephrosis

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.

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.

Renal Cell Carcinoma

BLADDER PATHOLOGY Cystitis 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.

MALE GENITAL

PATHOLOGY

PENILE PATHOLOGY 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 (balanitis)

Inflammation of inner surface of prepuce (posthitis) usually accompanied by 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 Xerotica Obliterans (BXO)

Involves thickened white plaques and fissures on glans and prepuce. o Non retractile prepuce or discharge. o Treated with circumcision. 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 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.

Condyloma Acuminatum

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

TESTICULAR PATHOLOGY 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 Seminomas

Characteristic classic triad of large tumour cells (with 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 Seminomas

Occur only in testes (2% of germ cell tumours). 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 Carcinoma

Ill-defined invasive masses with foci of haemorrhage and 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%.

PROSTATE PATHOLOGY Prostatitis 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.

Morphology: most common in the central and transitional zones (ie. inner part) of the prostate.

Macroscopic: firm rubbery enlargement up to 200g (normal 2g).

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.

CZ/TZ- Hyperplasia,

PZ- Carcinomas

Benign Prostatic Hypertension

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.

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 Adenocarcinoma

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).

FEMALE GENITAL

AND BREAST

PATHOLOGY

CERVICAL PATHOLOGY

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.

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.

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.

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.

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).

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.

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.

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.

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.

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%)

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.

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.

UTERINE PATHOLOGY 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.

Squamous CC Adenocarcinoma

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.

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).

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.

Adenomyosis

Endometrial Polyps

Endometrial Carcinoma

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.

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.

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

OVARIAN PATHOLOGY 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%).

Leiomyoma

Ovarian Cancer Staging

Stage 1: confined to ovaries.

Stage 2: spread to pelvis.

Stage 3: spread to

extrapelvic peritoneum,

lymph nodes or bowel wall.

Stage 4: distant metastases.

NB: most are detected in

advanced stages.

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

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,

except in later stages when metastases occur.

o Spread: mainly intraabdominal, paraaortic nodes, distant

(liver, lung etc).

o Diagnosis: clinical, radiology (ultrasound, CT), serology

(serum CA125) or surgical.

o Prognosis: depends mostly on stage, also grade, subtype,

and response to therapy.

o Screening: not yet established but could involve clinical

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,

HCG).

Serous Cystadenocarcinoma

Benign Cystic Teratoma

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.

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.

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

Androblastoma

BREAST PATHOLOGY

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.

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.

Fibro-cystic Change

Normal Duct Epithelial Hyperplasia Sclerosing Adenosis

Inflammations 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.

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.

Mammary Duct Ectasia

Carcinomas 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

inherited mutations. Majority are with the BRCA1 and

BRCA2 genes, less commonly involve p53, PTEN and ATM

genes.

o Increased risk with history of breast cancer in 10

relative, esp if multifocal or premenopausal.

o Familial cancer tend to occur at younger age and

are more severe/bilateral.

Sporadic: 90-95% have no known cause, probably multiple

genes interacting with environmental factors contributing

to breast cancer genesis.

o Overexpression of HER2 proto-oncogene is found in

30% of invasive breast carcinomas. Is a member of

the ‘epidermal growth factor receptor’ family, and

its overexpression is associated with poor prognosis

(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.

BRCA1 and BRCA2 Genes

Majority of inherited breast cancers are

attributed to BRCA1 and BRCA2 genes

(highly penetrant, austosomal dominant).

BRCA1 and BRCA2 genes are thought

to function in DNA repair, acting as

tumour suppressing genes.

Cancer arises when both alleles are

inactive/defective, one mutant

BRCA allele is inherited, and the

second allele is inactivated by

somatic mutation.

BRCA1 and BRCA2 mutations are rare

in sporadic breast cancer.

Most patients with these mutations

develop breast cancer by 70yr.

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

proliferation, precursor to invasive ductal carcinoma. Is

typically found on mammographic examination as

calcifications or a mass.

o Classified by growing pattern (solid, cremedo,

cribiform, papillary, micropapillary)

o Graded as low (monotonous nuclei) or high

(pleomorphic) grade.

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

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).

Paget’s Disease of the Nipple

Caused by the extension of DCIS up to

the lactiferous ducts and adjacent to

the skin of the nipple. Presents as a

unilateral crusting exudate over the

nipple and the areolar skin. An

underlying invasive carcinoma may be

present, and prognosis is based on the

underlying carcinoma.

Paget’s Disease

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.

Ductal Carcinoma Breast Carcinoma

Clinical: the most important clinical consequence is lymphatic and

haematogenous spread.

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

and distant metastases.

Grading of Carcinoma: grading is by the modified Bloom-

Richardson method, which

ER/PR: better prognosis with presence, as respond to

anti-oestrogen therapy.

HER2 Overexpression: associated with a poorer prognosis

due to its growth stimulating ability. Evaluating HER2

predicts response to Herceptin (HER2 antibody).

Proliferative Rate of Cancer

Histological type of Carcinoma: special types of

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.

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%)

Modified Blood-Richardson Grading

Method

evaluates tubule formation, nuclear grade,

and mitotic rate. Each feature is given a score

of 1-3, and added for a final sum ranging

from 3-9:

o 3-5: Grade 1 tumour

(well differentiated, better prognosis)

o 6-7: Grade 2 tumour

(moderately differentiated)

o 8-9: Grade 3 tumour

(poorly differentiated, poorer prognosis)

SKIN

PATHOLOGY

(Draft, written by Natasha P.)

Macroscopic Terms

Macule Circumscribed lesion <5 mm diameter characterized by flatness and usually coloration.

Patch Circumscribed lesion >5 mm diameter characterized by flatness and usually coloration.

Papule Elevated dome-shaped or flat-topped lesion <5 mm across.

Nodule Elevated dome-shaped lesion >5 mm across.

Plaque Elevated flat-topped lesion >5 mm across

Vesicle Fluid-filled raised lesion <5 mm.

Bulla Fluid-filled raised lesion >5 mm across.

Blister Common term used for vesicle or bulla.

Pustule Discrete, pus-filled, raised lesion.

Wheal 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 Thickening of the stratum corneum, often associated with a qualitative abnormality of the keratin.

Parakeratosis Modes of keratinization characterized by the retention of the nuclei in the stratum corneum. On mucous membranes, parakeratosis is normal.

Hypergranulosis Hyperplasia of the stratum granulosum, often due to intense rubbing.

Acanthosis Diffuse epidermal hyperplasia.

Papillomatosis Surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae.

Dyskeratosis Abnormal keratinization occurring prematurely within individual cells or groups of cells below the stratum granulosum.

Acantholysis Loss of intercellular connections resulting in loss of cohesion between keratinocytes.

Spongiosis Intercellular edema of the epidermis.

Hydropic swelling (ballooning)

Intracellular edema of keratinocytes, often seen in viral infections.

Exocytosis Infiltration of the epidermis by inflammatory or circulating blood cells.

Erosion Discontinuity of the skin exhibiting incomplete loss of the epidermis.

Ulceration Discontinuity of the skin exhibiting complete loss of the epidermis and often of portions of the dermis and even subcutaneous fat.

Vacuolization Formation of vacuoles within or adjacent to cells; often refers to basal cell-basement membrane zone area.

Lentiginous 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.

REMOVE ONES NOT USED.

INFLAMMATORY DERMATOSES Lichenoid

Dermatoses Reaction Histology

Lichen planus and variants

Lichenoid drug reactions

Lichenoid keratosis

Erythema multiforme, FDE

GvHD

Lupis erythematosus

Dermatomyositis

Pityriasis lichenoides

Characterised by epidermal basal layer damage

Basal vacuolar change or cell death

Accompanying inflammatory infiltrate o Lymphocytes o Histiocytes o Eosinophils

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

Psoriasiform 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

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

Spongiotic Atopic dermatitis (eczema)

Allergic contact dermatitis

Insect bite reaction

Seborrhoeic dermatitis

Stasis dermatitis

Pityriasis rosea

Drug reactions

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

Vesiculobullous Pemphigus foliaceus

Spongiotic vesicular disease

Pemphigus vulgaris

Bullous pemphigoid

Epidermolysis bullosa

Erythema multiforme

Dermatitis herpetiformis

Subcorneal pustular dermatosis

Porphyria cutanea tarda (PCT)

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

Granulomatous 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.

Vasculopathic 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

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

SKIN TUMOURS Benign Tumours Epidermal origin Seborrhoeic keratosis

Wart

Squamous papilloma

Melanocytic Lentigines

Naevi; junctional, compound, dermal

Skin adnexal Syringoma

Trichoepithelioma

Sebaceoma

Soft tissue 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

Malignant Tumours Basal 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

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

Multifocal superficial

Nodular

Infiltrating

Morphoeic

Mixed

Other

(Tumour cells can resemble epidermal basal layer)

Squamous cell carcinoma

Second most common skin malignancy

Sun exposed areas of fair skinned individuals

Most arise in the head and neck, dorsum of hands, vermillion border

Sun exposure (UV-B)

Chronic ulceration

Trauma, Burns, Frostbite

Fistula tracts, pilonidal sinus

Hidradenitis suppurativa

Marjolin’s ulcer

Dystrophic epidermolysis bullosa

Lichen sclerosus etc

Similar to SCC from other sites

Malignant squamous cells with dermal invasion

Dyskeratosis, acantholysis

Spindle cell, verrucous, adenosquamous variants

Malignant melanoma

Malignant melanoma of melanocytes

Qld highest rate in world 55.8/100000

Lifetime risk 1/87

4.6% male mortality

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

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 thickness according to the method of Breslow, measured to the nearest 0.1mm

Measures tumour volume

Vertical measure from the granular layer of the epidermis to the deepest part of melanoma

One dimensional estimate of the tumour bulk or tumour volume

Most accurate yet imprecise guide to the behaviour of some melanomas (thin melanomas that metastasise

SIZE mm 5 year survival %

< 0.76 98

0.76-1.49 96

1.5-2.99 86

3.0-3.99 79

4< 58

Clark level of invasion

anatomical compartment

Provides useful prognostic information in melanoma arising in very thick or very thin skin and in thin melanomas

LEVEL Level of invasion

I Intraepidermal in situ

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

ENDOCRINE

PATHOLOGY

PITUITARY GLAND PATHOLOGY Overview 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 or menstrual irregularities

Hypogonadism

TSH Very rare – causes hyperthyroidism Hypothyroidism

Plurihormonal GH + PRL with other combos – probably common

Panhypopituitarism (Simmond’s disease eg. Sheehans syndrome)

ADH Inappropriate ADH secretion Diabetes insipidus

Pathological Lesion

Hyperplasia (primary or secondary to ectopic promoters of secretion), Neoplasia

Surgery, tumour destruction of >75% of gland, ischaemia (eg. Sheehans 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 Gs-

protein is a common cause.

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 Adenoma

-Somatotroph adenomas are second most common, often plurihormonal 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.

Pituitary Adenoma

-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).

Corticotroph Adenoma

-Excess ACTH results in Cushing’s disease (hypercortisolism) which can occur from other sources (see below).

Thyrotroph Adenoma -Rare cause of hyperthyroidism (see below)

Gonadotroph Adenoma

-Difficult to recognise due to lack of clinical syndrome. -Usually detected later when mass (eg. impaired vision, headaches) or hypopituitary effects (pressure invasion) occur.

Non-functioning and Hormone negative

-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

a later stage after they enlarge causing mass effects.

Enlargement can cause pressure atrophy of adjacent cells.

Ischaemic necrosis of anterior pituitary is important cause,

however >75% loss of parenchyma must be lost before

clinical consequences develop. This can occur in Sheehan

syndrome or less commonly in DIC, elevated ICP, sickle cell

anaemia or traumatic injury.

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

excess caused by local injury to hypothalamus or extracranial diseases

(usually ectopic production in the lung). Results in hyponatraemia and

cerebral oedema (neurologic dysfunction). No peripheral oedema.

ADH deficiency (diabetes insipidus) can occur from damage to

pituitary by trauma, infection/inflammation, surgery or tumours. 30%

of cases are familial. Loss of ADH causes failure of water resorption by

the renal tubules resulting in abundant dilute urine (polyuria),

excessive thirst (polydipsia) and increase serum sodium/osmolality.

Sheehan Syndrome

Postpartum panhypopituitarism

(Simmond’s disease) results from

haemorrhage caused by increased

pituitary size without increased

blood flow during pregnancy.

Sheehan’s results in decreased

MSH, TSH, prolactin, ACTH and

FSH/LH.

Diabetes Insipidus

Diabetes insipidus is an ADH

related disorder that causes

diabetes like symptoms

(polyuria, polydipsia).

Central form is a result of ADH

deficiency due to various causes.

Nephrogenic form is caused by

renal tubular unresponsiveness

to ADH.

THYROID GLAND PATHOLOGY

Hyperthyroidism 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)

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

Hypothyroidism

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)

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).

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).

Myxoedema

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.

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).

Thyroid Atrophy

Goitre 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.

Note: haemorrhage, cysts, scarring and calcification in nodular 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 Thyroiditis encompasses a diverse group of disorders characterised by some form of thyroid

inflammation.

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

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.

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.

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 HLA-

B35 associations. Granulomatous inflammation causes

painful enlargement, fever, malaise ± transient

hyperthyroidism.

Benign Multinodular Goitre

Hashimotos Disease

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.

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.

Thyroid Carcinoma

PARATHYROID GLAND PATHOLOGY Hyperparathyroidism 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.

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

Hypoparathyroidism 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

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.

ENDOCRINE PANCREAS PATHOLOGY 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 the progressive destruction of islet β-cells in pancreas -Leads to “absolute insulin deficiency”

-Combination of peripheral resistance to insulin and inadequate pancreatic response (β-cell dysfunction) -Leads to “relative insulin deficiency”

Clinical -Accounts for 10% of cases -Early onset (<20yr) -Normal weight

-Accounts for 80-90% of cases -Late onset (>30yr) -Obese (part of metabolic syndrome)

Biochemical -Insulin levels low -Antibodies to islet cells -Ketoacidosis common -Association with HLA-DR3/4

-Insulin can be normal (high early) -No islet auto-antibodies -Ketoacidosis rare -Polygenic inheritance

Pathology -Non specific T-cell/cytokine insulates often with auto-antibodies against β-cells. -Later atrophy, fibrosis and β-cell depletion/degranulation.

-Variety of genetic defects and obesity contribute to insulin resistance. -β-cell dysfunction means inability to adapt to peripheral resistance. -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

resulting in ketoacidosis and death, seen less with

adequate control.

Accelerated atherosclerosis; hyaline atherosclerosis

narrows vascular lumen. Leads to coronary,

cerebral, renal and peripheral vascular disease.

Diabetic microangiopathy; increased permeability

of small vessels and protein deposition in basement

membrane. Especially leads to retinal, peripheral

nerve and glomerular disease.

Predisposition to infection; especially bacterial and

fungal infections of skin, mucosa and urinary tract.

Related to impaired leukocyte function and

diminished blood supply.

Diabetes Associated Diseases

The disease processes mentioned on the left

lead to various common diabetic complications

in various organs:

Heart; ischaemic heart disease is leading

cause of death due to diabetes

Eyes; haemorrhages, microaneurysms,

diabetic retinopathy, cataracts, glaucoma.

Diabetic nephropathy; renal failure due to

glomerular and vascular lesions.

Peripheral neuropathy; sensory, motor and

ANS dysfunction, mostly in extremities.

Gangrene; peripheral due to vascular

insufficiency.

ADRENAL CORTEX PATHOLOGY

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.

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)

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.

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.

Metastatic Adrenal Carcinoma

Adrenocrotical Adenoma (arrow is remaining tissue) Adrenocrotical Carcinoma

Adrenal Necrosis (bilateral)

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.

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.

ADRENAL MEDULLA PATHOLOGY Phaeochromocytoma 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, Sturge-

Weber 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.

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.

Phaeochromocytoma

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.

MEN SYNDROMES 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 -Pancreas (40%), endocrine neoplasms (usually metastatic) or less commonly gastrinomas -Pituitary (30%), mostly prolactin or GH secreting

-Loss of tumour suppressor gene at Ch11q13. -Unknown mechanism of action.

MEN-2a

-Thyroid, medullary carcinoma in virtually all cases -Adrenal medulla (50%), phaeochromocytomas -Parathyroid (30%), primary hyperplasia

-Inheritance of RET proto-oncogene on Ch10q11. -Multiple tyrosine kinase mutations. MEN-2b

-Thyroid and adrenal medulla disease similar as 2a -No parathyroid involvement -Extraendocrine manifestations.

MUSCULO-

SKELETAL

PATHOLOGY

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 Traumatic inflammation, usually forms soft callus. Mediator release eg. PDGF, TGF-b, ILs.

STAGE III Demolition phase - macrophages remove debris.

STAGE IV Granulation tissue formation (derived from periosteum/endosteum). pH low (acid tide).

STAGE V

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.

STAGE VI

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.

STAGE VII Remodelling: continued osteoblastic and osteoclastic activity results in an eventual return to normal.

BONE AND JOINT INFECTIONS Osteomyelitis 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.

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.

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).

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

Osteomyelitis

of Femur

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.

DEGENERATIVE JOINT DISEASE 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.

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.

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).

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.

Osteoarthritis

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

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.

Osteophytes from facet joint degeneration can impinge on

intervertebral foramina. Can cause vascular congestion, vertebral

artery insufficiency and nerve root irritation.

Vertebral disc changes: can displace in any direction. If posteriolly

can potentially impinge on nerve roots and if anteriorly on the

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.

Avascular Necrosis

Degenerative spondylolisthesis

is a displacement of the

vertebral body on the one

directly below it. It is

associated with degeneration

of the facet joints and can

result in spinal stenosis.

Synovium from

joint with RA

Rheumatoid

nodule from elbow

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.

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).

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.

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.

Gout of Big Toe

Gout of 2nd Digit

METABOLIC BONE DISEASE

Osteoporosis 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.

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 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/Rickets 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.

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 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.

↑ Osteoid (non-mineralised bone), due to Ca deficiency.

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

detected incidentally)

Present with signs and symptoms related to hypercalcaemia

(abdominal cramps, constipation, muscle fatigue, peptic

ulceration, renal calculi, cardiac valve calcification etc.).

Have bone related disease (only 10%).

Secondary hyperparathyroidism results from chronic parathyroid

stimulation by low serum calcium (occasionally associated with other

disease processes). The clinical features are usually dominated by those

of chronic renal failure, vit D deficiency and malabsorption. In general,

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.

Tertiary Hyperparathyroidism

Represents autonomous and

continuing PTH secretion in the

absence of low serum calcium.

NB: many other causes of

hypercalcaemia eg. vit D

intoxication, familial condition,

sarcoidosis. Doesn’t have to be

hyperparathyroidism.

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.

MUSCULOSKELETAL NEOPLASMS 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

Less common, aggressive benign lesion, classically located in epiphysis with 80% skeletally mature. Majority are at articular end of a long bone.

Osteogenic Sarcoma

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 10-20yrs (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 Disease

Metastasis to bone is the most common bone malignancy, and location for 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 Myeloma

Malignant plasma cell proliferation with osteolytic lesions. Is most common primary 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, leukaemias.

Discussed with the haematological system.

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 Intermediate: haemangioendothelioma Malignant: angiosarcoma

Adipose Tissue Neoplasms

Benign: lipoma Malignant: liposarcoma

Smooth Muscle Tumours

Benign: leiomyoma Malignant: leiomyosarcoma

Skeletal Muscle Tumours

Benign: rhabdomyoma Malignant: rhabdomyosarcoma

Mesenchyme (CT) Tumours

Benign: fibroma 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.

Fibromatosis is fibroblastic

proliferation forming collagen.

Aggressive clinical behaviour,

infiltrative. Repeated local

recurrence, but no metastases.

-Deep: muscle, abdominal.

-Superficial: palmar, plantar,

penile, infancy.

Rhabdomyosarcoma

of forearm

Fibrosarcoma

of thigh

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.

SKELETAL MUSCLE DISEASE Classification of Myopathies

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.

Eg. Guillain Barre (motor unit), Myasthenia Gravis (NM junction) Eg. congenital myopathies, muscular dystrophies

Distal Predominant Myopathies

Symmetrical distal weakness of hand/foot, no sensory involvement.

Eg. Charcot-Marie Tooth

Channelopathies (Episodic Weakness)

Episodic weakness, due to defective Cl, Na, Ca etc channels (↓ AP, contractility).

Eg. potassium imbalances (Na, Ca), congenital myotonias (Cl)

Exercise-Induced Myopathies

Rare painful weakness with cramping and myoglobinuria.

Eg. metabolic myopathies of glycogen, lipid etc.

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

two disorders as there is an absence of dystrophin

completely. Has early onset, manifesting when child

starts walking and relentlessly progresses till death

(usually around 20yr).

Becker’s Muscular Dystrophy is a milder form since

dystrophin is made, but it is in altered quality and/or

quantity. Has later onset, often in late childhood/early

adolescence, and slower, progression. more clinical

variability and overlap makes it harder to prognosticate.

Clinical Signs of Duchenne’s

Kids have a very characteristic way of

getting from lying to standing

(Gower’s maneuver with lordosis).

Waddling decompensation of gait as

muscle function deteriorates.

Large calves due to fatty

replacement (pseudohypertrophy).

Abnormal posture due to progressive

weakness → wheelchair bound.

Myxoid Liposarcoma 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.

[Original notes by Ben H.]

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 →

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.

Myositis 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.

Duchenne’s

NERVOUS SYSTEM

PATHOLOGY

MASS LESIONS OF THE CNS 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.

Hydrocephalus 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.

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).

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). NCH

CH

CEREBROVASCULAR DISEASE 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.

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.

Subarachnoid haemorrhage is most frequently due to rupture 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)

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).

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.

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.

Common symptoms; headache, vomiting, hemiparesis, hemisensory loss, coma.

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.

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.

Berry Aneurysm, ruptured

Hypertensive Haemorrhage

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 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.

CNS TRAUMA 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 acceleration-

deceleration 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.

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).

Epidural Haematoma

TUMOURS OF THE CNS Overview 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.

Gliomas 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.

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.

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.

Glioblastomas

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.

Astrocytoma

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.

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

(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.

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.

Medulloblastoma

Meningioma

Schawnnoma- bilateral CNVIII

Astrocytoma (glioblastoma) Ependymoma Oligodendroglioma

Metastatic Melanoma

INFECTIONS OF THE NERVOUS SYSTEM Overview 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

nerve palsies and meningoencephalitis may also occur.

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.).

Acute Meningitis

(with abscesses)

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.

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 encepha-

lopathy with signs of diffuse inflammation of entire

brain (panencephalopathy).

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.

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, immuno-

compromised 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.

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.

NEURODEGENERATION AND DEMENTIA 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.

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.

Clinical: classic symptoms of cogwheel rigidity, bradykinesia, resting tremor and

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 α-

synuclein 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.

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.

Parkinsonism – substantia nigra pallor.

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.

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.

Alzheimer’s – cortical atrophy

Synuclein-

opathies

eg. Parkinsonism

Pure Motor

Tauopathies

eg. Pick’s

Disease

Alzheimer’s Disease

Pure Dementia

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).

DEMYELINATING DISORDERS

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:

Demyelination and formation of plaques.

Ephatic neurotransmition (ephaptic neurotransmission causes

episodes of pain and spasm).

Protean symptoms (so variable can suggest other diagnoses).

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).

[Original notes by Ben H.]

NB: Ephaptic transmission

is when two nerves

communicate with each

other via an artificial

synapse.

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.

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

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.

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.

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)

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.

Demyelination due to MS

APPENDIX

LABRATORY/CHEMICAL PATHOLOGY Lab

LABRATORY TEST INTERPRETATION Lab

GLOSSARY OF NAMED DISODERS List of names that David would like to dedicate Nobel prizes/MSN lists to, or something like that.

Addison Destruction of the adrenal cortex, most commonly caused by autoimmune disorders (80% of cases). Other causes include infection, AIDS or cancer.

Amsler Criteria for diagnosing vaginosis.

Aschoff Foci of fibrinoid necrosis during rheumatic heart disease in the myocardium. Consists of macrophages, lymphocytes, and plasma cells that turn into a scar.

Barrett Replacement of oesophageal squamous epithelium with metaplastic columnar epithelium.

Bartholin Inflammatory occlusion of Bartholin vulvovaginal glands.

Bence Jones Cast nephropathy due to light chains binding to glycoproteins in the tubular lumen.

Berger IgA nephropathy causing glomerulonephritis, and glomerula hematuria.

Bowen A neoplastic skin disease, usually a form of squamous cell carcinoma.

Brudzinski Sign of meningitis when flexion of neck causes flexion of the hips and knees.

Chagas Disease caused by Trypanosoma cruzi. Symptoms include myocarditis in 50% of population.

Charcot-Leyden Microscopic crystals found in people who have allergic diseases such as asthma or parasitic infections.

Churg Strauss Granulomatous and eosinophil rich inflammation involving the respiratory tract, with necrotizing vasculitis affecting small to medium sized vessels associated with asthma and blood eosinophilia.

Conn Primary hyperaldosteronism, usually due to an adenoma. May be secondary to Cushings.

Curschmann Refers to desquamated epithelium found in biopsies of asthmatic patients.

Cushing Hypercortisolism due to pituitary hyper secretion, or an adenoma.

DIC Thrombohemorrhagic disorder secondary to other disease. Disseminated Intravascular Coagulation.

Duke Criteria for diagnosing endocarditis.

Fallot Consists of ventricular septal defect, dextroposed aorta overriding the septal defect, pulmonary stenosis with RV outflow obstruction, and RV hypertrophy.

Gleason Staging system for prostate cancers consisting of 5 stages.

Graves Autoimmune disorder, with hyperplasia of the thyroid, with associated othalmopathy and dermopathy.

Guillan-Barre Acute inflammatory demyelinating polyradiuloneuropathy.

Hashimoto Autoimmune disorder, causing hyper or hypothyroidism depending on its course.

[Written by David H.]

Henoch Schonlein 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.

Janeway Erythemous nodular lesions on palms and soles. Found in infective endocarditis.

Jones Criteria for diagnosing rheumatic fever.

Kaposi Patches, nodules, raised plaques, due to HHV-8

Kawasaki Arteritis of large medium and small size arteries. Usually occurs in children, and is self limiting.

Kernig Sign of meningitis when flexing hip at 90 degrees and extending the knee causes pain.

Koplik Small irregular red spots found on the inside of cheek and tongue. Found in early stage measles.

Lambert-Eaton Paraneoplastic disorder of the neuromuscular junction, commonly occurring with small cell carcinoma of the lung. Causes neuronal stimuli to release less synaptic vesicles.

Menetrier Hyperplasia of surface mucous cells in the stomach with fundic gland atrophy.

Monckeberg Medial calcification in small to medium sized muscular arteries.

Ormond Retroperitoneal fibrosis of unknown cause. May encroach on ureters.

Paget 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.

Plummer Vinson Mucosal protrusions into the oesophageal lumen forming webs.

Raynaud Vasospasm of arterioles, with cyanosis of digits.

Riedel Fibrosis of the thyroid of unknown etiology, extending into contiguous neck structures.

Roth Retinal haemorrhages. Observed in mainly in infective endocarditis but also in leukaemia, diabetes, pernicious anaemia, and ischemic events.

Sheehan Ischemic necrosis of the anterior pituitary

Sipple Medullary thyroid carcinoma, with pheochromocytoma, and parathyroid hyperplasia. Aka. MEN-2A

Stevens-Johnson Hypersensitivity reaction that causes the skin to necrose, with the epidermis separating from the dermis.

Syndenham Neurological disorder with rapid involuntary purposeless movements. A diagnostic criterion for rheumatic fever.

Takayasu Granulomatous inflammation of aorta and major branches.

Turner Chromosomal disorder causing in females causing features such as short stature, lymphoedema, broad chest, low hairline, low-set ears, and a webbed neck.

von Hippel-Lindau Hemangioblastomas in cerebellar hemispheres, retina, brain stem, and spinal cord, with cysts involving the pancreas liver and kidney, and paragangliomas.

vonWillebrand Required for Factor 8 stabilisation, used in the coagulation cascade, for platelet adhesion and aggregation. Causes bleeding when levels are low.

Waterhouse-Friderichsen Acute adrenal cortex insufficiency due to destruction from infection, or DIC, or other causes.

Wegners Granulomatous inflammation of upper and lower respiratory tract, with necrotizing vasculitis of small vessels namely in the lung and glomeruli.

Wermer 3P's. Parathyroid hyperplasia, pancreatic lesions, Pituitary adenoma. Aka. MEN-1

Whipple Systemic infection due to Tropheryma whippelii occurring in the small intestine causing GIT symptoms.

Wickham Striae or white dots that appear in Lichen Planus in the skin.

Wilms Triphasic nephroblastoma primarily occurring in children.

Zollinger-Ellison Condition consisting of multiple peptic ulcers, gastric hyper secretion, and is often caused by an endocrine cell tumour increasing gastrin production.