PATHOLOGY

101 v2.0

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.
Pressure vs Volume Overload
 Activation of neurohormonal systems:
noradrenaline, renin-angiotensin system, ANP. Pressure overload state (eg. hypertension, valve
 Frank-starling mechanism: Cardiac failure causes stenosis) causes increased SBP. Results in increased
diameter of cardiac muscle (added myofibrils).
↑EDP resulting in increased stretch of cardiac
→ CONCENTRIC HYPERTROPHY: wall thickening with
muscle → fibres contract more forcibly, hence
no change in chamber size.
↑CO.
Volume overload state (eg. valve regurge, abnormal
 Myocardial structural changes (hypertrophy).
shunts) causes increased DBP. Results in increased
This is an adaptation to chronic ↑ workload and
length of muscle fibres (added sarcomeres).
since myocytes can’t proliferate, concentric or
→ ECCENTRIC HYPERTROPHY: chamber enlargement
eccentric hypertrophy occurs. with some wall thickening.

Adaptive mechanisms eventually aren’t sufficient with

sustained worsening of heart → pathologic changes (eg.
myocyte apoptosis, cytoskeletal changes, altered ECM
synthesis) cause structural and functional disturbances.

Classification: resulting failure can be classified by a variety of mechanisms:

 Forward failure: diminished cardiac output, reduced tissue perfusion.
vs Backward (congestive) failure: back pressure, venous congestion and oedema.

 Systolic failure: inability to contract normally and expel blood.

vs Diastolic failure: inability to fill ventricles.

 High output failure: heart is pumping normally, however tissue demands have greatly increased.
vs Low output failure: heart cannot keep pace with basic peripheral demands.

 Acute heart failure: quick onset, usually systolic heart failure and hypotension but no oedema.
vs Chronic heart failure: long term, often normal BP but with oedema.

 Compensated heart failure: if compensatory mechanism produce sufficient CO

vs Decompensated heart failure: compensatory mechanisms, especially hypertrophy, increase
O2 requirements, eventually leading to insufficient CO and increasing risk of ischaemic injury.

Left-Sided Heart Failure Right-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)
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.

Transmural Infarct (old and new) Subendocardial Infarct

Morphology: early changes after vascular obstruction are reversible (angina). Irreversible changes after
20-40min of severe ischaemia → myocyte death (coagulative necrosis).
 <12hrs, AMI is not grossly apparent, however Infarcts >3hrs can be seen with vital stains for
lactate dehydrogenase which leaks into blood during myocyte damage. Infarct seen as pale
zone.
 12-24hrs, infarct is grossly identified by a reddish brown discolouration (stagnant, trapped
blood). Becomes yellow and soft thereafter.
 10-14days, infarcts rimmed with highly vascularised granulation tissue.
 Weeks, fibrous scar tissue formation (from border to centre).
Extent of MI: infarction begins in subendocardial zone then spreads outwards to include transmural
thickness of chamber. Extent of infarct depends on:
 Size, site and degree of obstruction
 Rapidity of onset and extent of collateral circulation that was allowed to develop.
 Duration of occlusion, reaches full size within 3-6hrs, hence intervention can limit damage.
 Associated arterial spasm.

Clinical: severe crushing substernal chest pain, can radiate to neck, jaw, epigastrium, left arm. Can be
asymptomatic (10-15%), usually due to diabetic neuropathies or in the elderly. Dyspnoea and features of
left sided heart failure are also common.
 ECG can show pattern of injury.
o Changes in Q waves indicate transmural infarcts.
o ST segment abnormalities, T wave inversion indicate myocardial repolarisation problem.
o Arrhythmias can be detected, indicates conduction pathway damage.
 Laboratory tests are important in confirming diagnosis and are based on measuring intracellular
macromolecules which leak out of damaged cells.
o Myoglobin, troponin T and I, creatine kinase (CK), lactate dehydrogenase (LDH) etc.
o Troponins and CK-MB have high specificity and sensitivity for myocardial damage.

Treatment: goal is to salvage maximal amount of ischaemic myocardium by reperfusing tissue quickly.
 Can use thrombolysis (drugs), balloon angioplasty, coronary artery bypass graft.
 Reperfusion injury can occur, mediated by oxygen free radicals from increased leukocyte
numbers. Can cause endothelial swelling or haemorrhage.

Complications: risk depends on infarct size, site and thickness of damaged heart wall. Sudden death
(15%), no complications (10-15%), complications (65-70%).
 Contractile dysfunction: severe pump failure (cardiogenic shock) proportional to infarct size.
 Arrhythmias: responsible for many sudden deaths due to conduction problems.
 Myocardial rupture: due to CT lysis, can occur in ventricular wall (haemopericardium and
tamponade), IV septum (shunt formation) or papillary muscle (mitral valve regurgitation).
 Pericarditis: fibrous or haemorrhagic. Typically spontaneously resolves.
 Mural thrombus ± systemic thromboembolism, pulmonary embolism
 Ventricular aneurysm
 Progressive late LV congestive heart failure.

Chronic Ischaemic Heart Disease

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

Sudden Cardiac Death

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

Pathophysiology: Hypertension results in pressure overload on LV, which adapts by depositing myofibrils
parallel to the long axes of cells. This results in concentric hypertrophy.
 Wall thickening without change in chamber size, hence cavity diameter reduced size.
 Hyperplasia cannot occur as myocytes are terminally differentiated.
Hypertrophy initially compensatory but if prolonged/excessive eventuates into myocyte contractile
failure. This is due to:
 ↑ O2 demand due to increased cell size, ↓ blood supply as capillaries don’t grow (ischaemia).
 Change in gene expression leading to less functional protein and hence ↓ contractility.

Clinical Manifestations: depend on severity, duration and underlying cause of hypertension.

 Ischaemia causes fibrous deposition which limits diastolic relaxation, leading to LA enlargement.
 Contractile failure leads to CHF, with lung congestion and subsequent wide spread oedema.
 Atrial fibrillation is common due to LA enlargement or backward CHF.
 Many patients will be asymptomatic (compensated HHD), others will suffer as mentioned above.

Pulmonary Hypertensive Heart Disease (Cor Pulmonale)

Right ventricular enlargement due to pulmonary hypertension (>30mmHg) which has been caused by
primary disorders of lung parenchyma or vasculature.

Pathology/Classification: cor pulmonale may be acute or chronic.

 Acute: commonly after massive pulmonary embolism (>50%
occlusion), causing acute right ventricular dilatation.
 Chronic: secondary to prolonged pressure overload causing lung
vasculature compression. Results in right ventricular hypertrophy.
Eventual hepatosplenomegaly, oedema and LV failure.
Note: definition excludes congenital heart disease or left ventricular RV
failure that cause right heart enlargement via pulmonary hypertension. Hypertrophy

Risk Factors: disorders predisposing to cor pulmonale include:

 Diseases of pulmonary parenchyma (eg. COPD, interstitial fibrosis, cystic fibrosis)
 Disease of pulmonary vessels (eg. PE, primary pulmonary HT, arteritis, vascular obstruction or
drug/toxin/radiation induced).
 Disorders affecting chest movement (eg. kyphoscoliosis, obesity, neuromuscular disease).
 Disorders inducing pulmonary artery constriction (eg. metabolic acidosis, hypoxaemia, chronic
altitude sickness, obstruction to major airways).
 VALVULAR 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 Incompetence
Failure of valve to open completely, obstructing
(Insufficiency/Regurgitation) Failure of valve to
forward flow. Creates a high pressure gradient
close completely, allowing reverse flow. Creates
across valve causing turbulent flow. backward volume overload.
Mitral Stenosis Mitral Regurgitation
-Cause: post inflammatory scarring (RHD). -Causes:
o Myxoid degeneration (floppy leaflet that
-Clinical: LA pressure increase → pulmonary
prolapses into LA due to abnormal ECM).
congestion and hypertension → RV
Mitral Valve Disease

o RHD, infective endocarditis.

hypertrophy.
o Dilatation of valve ring (LV enlargement or
-Murmur: diastolic, rumbling with opening calcification of annulus).
snap. o Papillary muscle fibrosis or rupture.
-Clinical: variable effects
o Little effect with prolapse, incompetence
NB: stenosis of mitral and aortic valves
usually only if chordae tendinae rupture.
accounting for 2/3 of all valve diseases.
o LV hypertrophy if onset is slow.
o Acute LV failure if papillary muscle ruptures.
-Murmur: systolic, click with prolapse
Aortic Stenosis Aortic Regurgitation
Aortic Valve Disease

-Causes: RHD, degenerative calcification (eg. -Causes: leaflet abnormalities (eg. RHD, IE), aortic
old age, congenitally deformed valve)
-Clinical: small pulse, LV hypertrophy, angina,
syncope, LV failure or sudden death.
-Murmur: systolic, ejection murmur
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 Aschoff Bodies
pericardium due to cross reacted auto-antibodies. Inflammatory lesions in heart
 Endocarditis (valves): focal fibrinoid necrosis and fibrin thrombi consisting of fibrinoid change,
along lines of closure. lymphocytes, plasma cells and
 Myocarditis: Aschoff body formation. May have LV dilatation macrophages. Diagnostic.
or failure due to mitral stenosis/incompetence. 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) IE aortic valve
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. Subacute endocarditis of mitral valve

Clinical: acute febrile illness with swinging temperature.

 Changing heart murmur, heart failure, splinter haemorrhages, retinal haemorrhages (Roth’s
spots), petechiae, finger clubbing, splenomegaly.
 Requires blood culture for diagnosis.

Complications: heart valve perforation, incompetence, myocardial abscess formation.

 Embolism can occlude artery causing infarct, or may be septic and cause metastatic abscesses.
 Glomerulonephritis from microemboli or circulating immune complexes.
CARDIOMYOPATHIES (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. Peripartum Cardiomyopathy
 Acquired: alcohol, pregnancy (multifactorial), mineral deficiency CMP during pregnancy due to
related hypertension, volume
(eg. selenium, Ca, PO4), thyroid disease, toxic (eg. cocaine,
overload, nutritional deficiency,
cobalt), chronic tachycardia. Certain forms may be reversible.
abnormal metabolism and altered
 Familial: 20% of DCMP, genetically heterogenous. Autosomal immune function.
dominant, recessive and x-linked forms. Result in abnormalities Usually transient and reversible.
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.
DCMP

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.
  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 Endomyocardial Fibrosis:
an excessively rigid LV wall and impaired diastolic filling. dense fibrosis of endocardium and
subendocardium from apex to AV
valves. Seen in young people in Africa.
Pathology: can be idiopathic or associated with; hypertrophic CMP,
systemic diseases that affect the myocardium (eg. radiation fibrosis, Loeffler Endomyocarditis:
amyloidosis, sarcoidosis) and constrictive pericarditis. endomyocardial fibrosis associated with
 Similar pathology to endomyocardial fibrosis, Loeffler eosinophilia from any cause.

endomyocarditis and endocardial fibroelastosis of infancy. Endocardial Fibroelastosis of Infancy:

 Mural thrombi are a complication in all these conditions. fibrous thickening of LV.

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 Shaggy Fibrous Tuberculous

Pericardial Disease Thrombosis Pericarditis Pericarditis

Pericardial conditions include inflammatory diseases and effusions. Isolated disease is unusual,
pericardial lesions are usually associated with heart, surrounding structure or systemic disease.

Pathology: may be infectious, non-infectious or immune related. Inflammatory exudates may serous,
fibrous, haemorrhagic, suppurative or caseous.
 Infectious Pericarditis: virus is most common infectious cause (eg. coxsackie, echovirus,
mumps). Bacteria and fungi may be involved. Myocarditis may also be present, especially with
viral disease.
 Non-Infectious Pericarditis: more commonly secondary to AMI, uraemia, irradiation, neoplasia,
myxoedema or trauma.
 Hypersensitivity/Autoimmune Pericarditis: rheumatic fever, collagen vascular disease (eg. SLE),
drug induced or post cardiac injury.
Clinical: may be acute (<6wks), subacute (<6mnths) or chronic
Pericardial Effusions
(>6mnths).
Effusions <500mL do not interferes
 Roughened pericardial surface can be heard as greatly with heart function.
‘pleural rub’.
Rapid accumulation of fluid, often due
 Effusion present as globular appearance on x-ray.
to catastrophic haemorrhage (eg. AMI,
 Healed/chronic cases may result in adhesive ruptured aneurysm, trauma) can cause
pericarditis, adhesive mediastinopericarditis or cardiac tamponade and restrictive HF.
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.
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 1. Fatty Streaks

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.
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

Macrophage hypothesis: macrophages transport LDL

4. Atrophic Lesions
into intima and secrete chemo-attractants and lipases, Plaques that impinge on underlying media causing
leads to oxidation of lipid. atrophy.
 Weakening of media and destruction of internal
NB: Gelatinous lesions are expansions of intima by elastic lamina.
proteoglycan rich ECM, macrophages, SMCs. Unknown  May lead to lymphocytic reaction in adventitia or
relationship to fatty streaks and fibrous plaques. cause aneurysm.
Clinical Aspects of Atherosclerosis Early aortic
Signs and Symptoms: plaques develop slowly over decades but may cause acute atheromatous lesion
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.
Vascular Pathology in Hypertension
Vascular changes during hypertension include: atherosclerosis acceleration, degenerative changes in
walls of larger arteries, and arteriosclerosis in small vessels (hyaline or hyperplastic).

Benign Hypertension (95%) persists slowly over years and is of moderate degree. Is usually idiopathic,
although can be due to renal disease.
 Small arteries/arterioles undergo hyaline arteriosclerosis.
Consists of homogeneous eosinophilic hyaline thickening of
media → narrowing of lumen can cause ischaemia.
 Small to medium arteries show intimal fibrosis and media SMC
hypertrophy.
 Large muscular and elastic arteries have accelerated
Hyaline arteriosclerosis
atherosclerosis.

Malignant Hypertension (5%) is rapidly progressive and is of severe

degree (DBP>120mmHg). Associated with renal failure, retinal
haemorrhages and optic disc swelling.
 Arterioles undergo hyperplastic arteriosclerosis. Characterised
by concentric proliferation of SMCs with onion skin appearance
→ narrowing of lumen.
 Hyperplastic changes are accompanied by fibrinoid necrosis,
particularly in kidney (see renal notes). Hyperplastic arteriosclerosis

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.
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) 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 Ruptured
Aortic Aneurysm
rupture α size of aneurysm, >5cm serious.
 Occlusion of a branch vessel (iliac, renal, mesenteric, vertebral arteries) → ischaemic damage.
 Embolism from atheroma or mural thrombus.
 Impingement on adjacent structure (eg. compression of ureter, erosion of vertebrae).

Syphilitic Aneurysm
Pathogenesis:
 Late complication of syphilis, whereby T. pallidum affects the vasa vasorum in the Vasa Vasorum
aortic adventitia, causing ‘obliterative endarteritis’ (endothelium inflammation). Arterial network
supplying larger
 Affected vessels show luminal narrowing and obliteration. Scarring of vessel wall
blood vessels.
with surrounding inflammation (lymphocytes and plasma cells).
 Lumen narrowing of vasa vasorum causes ischaemic injury of aortic media → loss of elastic
fibres and muscle cells (destruction and weakening of media) → dilation (aneurysm).

Complications:
 Contraction of fibrous scarring leads to wrinkling of aortic intima, resembles tree bark.
 Associated atherosclerosis of aortic root can obstruct coronary ostia, can cause MI.
 Weakening of aortic root dilates valvular annulus → valvular insufficiency → volume overload
(eccentric) hypertrophy of LV – “cor bovinum” (cow’s heart).
 Most patients with syphilitic aneurysms die of heart failure induced by valvular incompetence.
Aortic Dissection
Blood dissects aortic wall and tracks along luminal planes of the media. Forms a blood-filled channel
within the aortic wall. Occur in mainly in men aged 40-60 with hypertension.

Pathogenesis: main risk factor is hypertension, but the pathways of how

Marfan’s Syndrome
this damages the media is still not known. An autosomal dominant disease of
 Unknown trigger for intimal tearing activated. Intimal tearing then fibrillin, an ECM scaffolding protein
occurs, most frequently in ascending aorta. required for normal elastic tissue
 Once tear has occurred, blood under high systemic pressure synthesis.
penetrates the media forming a medial haematoma. Causes long features, high arch
 Smaller percentage related to CT disorders (Marfan most palate, aortic regurge etc.
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).
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, Raynaud’s Phenomenon
Extremities change from red (proximal
with secondary vein and nerve involvement.
vasodilation), white (central vasoconstriction)
 Pathology: direct toxicity to endothelium by tobacco
and blue (distal cyanosis).
products, or idiosyncratic immune response to same
 Primary: exaggerated central and local
products. vasomotor responses to cold or
 Clinical: superficial nodular phlebitis, Raynaud’s emotion. No pathological changes early.
phenomenon, pain in feet during exercise (in step Common in young women.
claudication), severe pain at rest (neural involvement),  Secondary: vascular insufficiency of
ulceration of extremities (gangrene). extremities due to other disease
 Occurs in heavy cigarette smokers, usually before processes eg. atherosclerosis, SLE,
35yrs. Smoking cessation in early stages decreases Buerger disease, scleroderma.
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.
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 Congestive Splenomegaly
(elongated and crescentic). Diagnosis on prep with reducing Occurs mostly in young children due to
agent (metabisulfate) of Hb electrophoresis. infarction in spleen from microvascular
 Clinical: sickle cells are removed by splenic phagocytes obstruction. Causes scarring, shrinkage
producing a chronic normocytic anaemia. Widespread and loss of function (autosplenectomy).
microvascular obstruction due to sickle aggregates can Functional asplenia leaves patients
cause acute pain crisis and tissue infarction. 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, Warm antibody: functions at body
idiopathic or secondary to malignancy, infection or drug use. temperature, is usually IgG.
 Pathology: antibodies bind and opsonise RBCs. Phagocytosis in Eg. malignancy (CLL), drugs (penicillin,
spleen or complement fixation with intravascular haemolysis. quinidine), SLE.
Warm and cold antibodies, each associated with different Cold antibody: functions below body
underlying diseases/infections. temperature, is usually IgM.
 Diagnosis: Coombs test measures antibodies on RBCs (direct) Eg. Mycoplasma infection,
or antibody in serum (indirect). mononucleosis, B-cell malignancy.

Other Haemolytic Anaemias

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

Anaemia of Diminished Erythropoiesis

Megaloblastic Anaemias large immature RBCs in bone marrow due to vit B12 or folate deficiency.
 Pathology: deficiencies cause impaired DNA synthesis. Results in destruction of immature RBC
within the bone marrow (ineffective erythropoiesis), as well as extra-medullary haemolysis.
 Morphology: large, oval, immature RBC (megaloblasts) with large, hypersegmented neutrophils
found in peripheral blood.
 Vitamin B12 deficiency has profound neurological and Perinicious Anaemia
haematological sequelae. Results from dietary deficiency, Gastritis where auto-antibodies destroy
malabsorption, competitive tapeworm uptake, bacterial gastric parietal cells. Results in absence
overgrowth, pregnancy, hyperthyroidism or cancer. of intrinsic factor and hence Vit B12
NB: bodies B12 stores are large, takes years to develop impaired absorption. Most common
cause of adult Vit B12 deficiency.
deficiency after absorption stops)
 Folate deficiency produces anaemia without neurological changes. Results from deficient intake
(poor diet, alcoholism, malabsorption), increased need (pregnancy, malignancy, inc.
Haematopoiesis) or impaired use (antimetabolic drugs).
 Iron Deficiency Anaemia chronic anaemia exhibiting hypochromic and microcytic cells
 Causes: Fe deficiency is very common, caused by blood loss (GIT, genitourinary tract most
common), poor diet, malabsorption and pregnancy.
 Pathology: inadequate intake of iron results in insufficient haemoglobin synthesis and
hypochromic and microcytic red cells.
 Clinical: low serum iron and ferritin, low transferrin saturation (high TIBC).

Aplastic Anaemia aplasia renders bone marrow incapable of

replenishing blood cells.
 Causes: multiple causes that lead to bone marrow
failure, most cases are idiopathic.
 Pathology: multipotent myeloid stem cells are
suppressed leading to bone marrow failure and
pancytopaenia (anaemia, neutropaenia,
thrombocytopaenia ie. myeloid cells).
 Clinical: Prognosis is poor, bone marrow transplant
may be curative. Hypocellular blood (peripheral
smear) and bone marrow (biopsy). RBCs are
normocytic and normochromic.
Bone Marrow Failure
Defined as inadequate blood cell production.
Has multiple aetiologies, all causing
decreased cell production:
 Chronic renal failure (low erythropoietin).
 Alkylating drugs, radiation, chemotherapy
 Infections and other inflammations
 Endocrine disorders, liver disease
 Congenital abnormalities (Fanconi anaemia)
 Invasive neoplasms or granulomas
 Myelofibrosis

Spherocytosis Sickle Cell Megaloblastic Iron Deficiency

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.
 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.

Idiopathic/Immune Thrombocytopaenic Purpura (ITP) Thrombotic Thrombocytopaenic Purpura (TTP)

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

Disorders of Excess Platelets

Thrombocytosis is a reactive disorder of increased platelets resulting from bleeding, haemolysis,
inflammation, malignancy, iron deficiency, stress or post splenectomy.

Essential thrombocythaemia is a primary myeloproliferative disorder associated with JAK-2 mutations.

Also a prominent feature of chronic myeloid leukaemia (CML). May lead to diffuse thrombosis.

Platelet Function Defects

These disorders can be congenital or acquired, resulting
in prolongation of bleeding time in the presence of
normal platelet count. Classified as follows:
 Defects of adhesion (von Willebrand disease,
Bernard-Soulier disease).
 Defects of primary aggregation (thrombasthenia).
 Defects of secondary aggregation and release
(aspirin, storage pool disease).
Von Willebrand Disease
Autosomal dominant defect in von Willebrand factor
resulting in impaired adhesion of platelets to collagen.
 Also results in low factor VIII levels and activity
(vWF is carrier molecule for Factor VIII) →
prolonged partial thromboplastin time (PTT).
 Characterised by spontaneous haemorrhage from
mucous membranes, wounds and excessive
menstrual bleeding.

Clotting Factor Deficiencies

Acquired Disorders
Vitamin K Deficiency a fat soluble vitamin produced by bacterial metabolism of ingested nutrients within
the large intestine.
 Involved in post translational modification of factors II, VII, IX and X, protein C and S.
 Deficiency may result from fat malabsorption, diarrhoea, dietary deficiency, antibiotics, some
anticoagulant drugs (warfarin).
Liver Disease can result in the failure to synthesis factors II, V, VII, IX, X, XI and XII.
Hereditary Deficiencies
Disorders resulting in low factor counts. Include haemophilia A (factor Factor VIII Deficiency
VIII) and B (factor IX). (Haemophilia A)
 Signs and symptoms include haemarthrosis (most common), X-linked recessive disorder
soft tissue haematomas, genitourinary bleeding, bleeding in resulting in defective Factor VIII or
CNS and neck (life threatening). impaired conversion of precursor
 Severity related to factor level: <1% severe (spontaneous to Factor VIII. Incidence of 1/10
000 in males.
bleeding), 1-5% moderate (bleeding with mild injury), 5-25%
mild (bleeding with surgery or trauma).
Factor IX Deficiency
 Since both Haemophilia A/B have prolonged PTT, must be
(Haemophilia B)
distinguished by specific factor assays.
X-linked recessive disorder
 Treated by factor replacements (either plasma derived or resulting in inactive or inadequate
recombinant). Factor IX. Affects 1/50 000 males.

Disseminated Intravascular Coagulation (DIC)

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

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

Hereditary Bleeding Disorders Acquired Bleeding Disorders

Haemophilia A and B: X-linked disorders of Liver disease or vit K deficiency: reduced factor
Summary

inadequate factors VIII and IX. synthesis/modification.

Von Willebrand's disease: defect in vWF resulting ITP: causes immune platelet destruction.
in impaired platelet adhesion. TTP: platelet aggregation due to vWF accumulation.
Essential thrombocythaemia: primary disorder of DIC: systemic clotting, followed by factor depletion
excess platelet production. and bleeding.
 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) Reactive Leukocytosis (Secondary)

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.
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 Meylodysplasia

production: Group of myeloid tumours (often
 Myelodysplasia is disordered and ineffective haematopoiesis. benign) characterised by disordered
 Myelofibrosis, marrow infiltration by fibrous tissue. and ineffective haematopoiesis. Bone
marrow is still producing cells but
 Infiltrations of bone marrow, secondary to malignancies.
patient develops pancytopaenia. Many
 Infections eg. HIV, hepatitis, dengue, influenza, tuberculosis. progress to AML.
NB: pseudo-leukopaenia can occur during infection due to
marginalisation of leukocytes. Myelofibrosis
 Drugs eg. chemotherapy, radiotherapy, myelosuppressive Abnormal megakaryocytes release
agents and alcohol. growth factors that stimulate reactive
 Vitamin deficiencies in B12 and folate can lead to abnormal marrow fibroblasts to deposit collagen.
DNA production (megaloblastic anaemia). Resulting fibrosis slowly replaces the
marrow space leading to pancytopaenia
 Congenital eg. cyclical neutropaenia.
and extramedullary haematopoiesis.

Or, less commonly, peripheral disorder of increased destruction:

 Splenomegaly/hepatomegaly, increasing sequestration, consumption and destruction.
 Associated immune disorders eg. Felty’s syndrome (rheumatoid with splenomegaly and
neutropaenia), auto-antibodies or some infections.

Non-Specific Lymphadenitis is non-neoplastic inflammation and/or enlargement of lymph nodes. May

be caused by infections, drugs, toxins or other inflammatory stimuli.

Leukaemias
Chronic Myeloid Leukaemia (CML) arises from mutation in a pluripotent myeloid
CML
stem cell, resulting in overproduction and accumulation in blood. Present in
multiple myeloid lineages.
 Pathology: acquired genetic translocation (9;22), producing a BCR-ABL
fusion gene that codes for a tyrosine kinase protein.
o This protein activates transduction pathways to uncontrolled cell
growth, whereas the original ABL gene switches itself off.
o Effects granulocyte precursors most, retain capacity for terminal
differentiation resulting in elevated granulocytes in blood.
 Clinical: chronic phase (slow with non specific symptoms), accelerated phase (symptoms
become severe) and blastic phase (>30% myeloblasts in blood or marrow).
 Diagnosis: bone marrow biopsy with FISH probes to identify BCR-ABL gene. Quantitative PCR.
 Treatment: chemotherapy, drugs (imantinib mesylate), bone marrow transplant.
AML with pallor of
Acute Myeloid Leukaemia (AML) neoplasm comprised of immature myeloid cells. renal substance.
 Pathology: diverse genetic lesions express abnormal transcription factors
that block myeloid cell differentiation. This results in replacement of normal
marrow elements by leukaemic blasts.
o Abnormal cytogenetics found in 60-80% of AMLs.
o Most common is the t(15;17) translocation in Acute Promyelocytic
Leukaemia (APML) resulting in abnormal vitamin A receptors (Tx
with vit A analogue).
  Clinical: makes up 90% of adult and 15% of childhood acute leukaemias. Present with pallor,
purpura and petechiae.
 Diagnosis: chromosome testing most definitive.

Chronic Lymphocytic Leukaemia (CLL) formation of neoplastic B-cells that suppress normal B-cell function.
 Pathology: >95% involve B-cell linage, DNA changes associated with apoptosis (90% have
increased bcl-2 levels).
o Auto antibody production by normal B-cells indicates
breakdown in immune regulation.
o Cell surface characteristics include CD19+ (pan-B marker) (pancreas)
and CD5+ (pan-T marker). CLL of Coeliac LNs,
 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.
Non-Hodgkins
 Small lymphocytic lymphoma (4%) is similar to CLL, only with no or limited Lymphadenopathy
peripheral blood involvement.
 Follicular lymphomas (40%) are lymph node tumours with a nodular appearance.
95% of cases have a t(14;18) translocation leading to increased bcl-2 expression
(anti-apoptotic).
 Burkitt’s lymphoma is associated with t(8;14) translocation and EBV infection. Need
for intensive therapy, including CNS prophylaxis.
 MALT lymphoma is usually a localised, indolent disease. >95% of GIT cases
associated with H. pylori infection, eradication often allows remission.
 Multiple myeloma is malignant growth of mature B-lymphoid cells (plasma cells) which are
normally secretory. Can cause anaemia, infections, bone pains or fractures, and abnormal
monoclonal antibody production (paraprotein).

Hodgkin Lymphomas are neoplasms that arise in a single lymph node and spread in an anatomical
stepwise fashion.
 Characterised by malignant Reed-Sternberg (RS) cells which are derived from B-cells. These are
greatly outnumbered by reactive lymphocytes, macrophages and stromal cells.
 Associated with distinctive clinical features, including systemic features eg. fever.
 Predictable spread allows for localised treatment if detected early, unlike NHLs.
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: ↓Antiprotease:
1. Neutrophils (protease source) are normally 1. Tobacco smoke contains abundant ROS
sequestered capillary periphery. which deplete antioxidant mechanisms in the
2. Smoking induces accumulation of neutrophils lung (oxidant-antioxidant imbalance).
and macrophages in alveoli via nicotine 2. This elicits direct tissue damage but also
(chemoattractant) and ROS (induce IL-8, LT-B4, TNF). inactivates antiproteases, causing a ‘functional
3. Accumulated neutrophils/macrophages are α1-antitrypsin deficiency’ → further protease
activated and release variety of protease granules tissue damage.
(eg. elastin). Results in tissue breakdown.
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 α1-Antitrypsin Deficiency

uniform enlargement of entire acini (resp Hereditary disorder of defective α1-antitrypsin secretion by liver.
bronchiole → alveolar sac). α1-antitrypsin inhibits the destruction of elastin by elastase, a
 More common in the lower lobes. proteolytic enzyme within inflammatory cells.
 Occurs in hereditary α1- Elastase acts on alveolar and hepatocyte walls, hence α1-antitrypsin
antitrypsin deficiency. deficiency results in panacinar emphysema and hepatic cirrhosis.

3. Distal Acinar Emphysema involves the distal part of the acinus, sparing the respiratory bronchioles.
 More prominent adjacent to pleura, septae and the lobular edge.
 More severe in upper lung, esp. following previous injury (adjacent to fibrosis or atelectasis).
 Characteristic enlarged subplueral, cystic air spaces (0.5-2cm) called bullae. Can rupture and
cause pneumothorax (common cause in young people). Not exclusive to distal emphysema.

4. Irregular Emphysema involves non uniform parts of the acinus, often with scarring.
 Often results from healed inflammatory disease (scarring).
 Usually asymptomatic, may be most common form.

Clinical: rarely occurs in pure form, usually as part of COPD with chronic bronchitis.
Signs and symptoms of predominantly emphysema:
 Older patient (>50 yrs), severe dyspnoea and less sputum.
 Weight loss, barrel-chest (hyperinflation), purse-lip breathing, prolonged expiratory time (FEV1).
 ‘Pink puffers’ as hyperventilation may maintain blood oxygenation till late in the disease.
 ↑ Air spaces causes hyper-resonant percussion and low density on X-ray.
Complications may include:
 Respiratory failure with acidosis and coma.
 Right sided heart failure (cor pulmonale). This is due to obliteration of alveolar septal
capillaries/vessels resulting in increased resistance (↑ pulmonary BP).
 Pneumothorax, leading to compression atelectasis.
Chronic Bronchitis
A clinical diagnosis of persistent productive cough for at least 3 months in 2 consecutive years.
Pathogenesis: characterised by chronic irritation causing hypersecretion of mucous (~75mL
sputum/day). Usually due to cigarette smoke, but also SO2, NO2, resulting in:
 Damage to conducting airways with mucous gland hypertrophy in trachea/bronchi.
 Inflammation (CD8+ Tcells, macrophages and neutrophils) with scarring and fibrosis.
Actual airway obstruction occurs in more peripheral airways as a result of:
 Bronchiolitis (small airways disease) induced by Goblet cell metaplasia with mucous plugging of
bronchiolar lumen.
 Coexistent emphysema or bronchospasm (asthmatic bronchitis).

Clinical: affects 10-20% of urban population, even higher in cigarette smokers. Many have COPD.
Signs and symptoms of predominantly chronic bronchitis:
 Younger patient (40-45yrs), milder dyspnoea and plentiful sputum.
 Barrel-chested, hypercapnia, hypoxia (respiratory failure).
 ‘Blue bloaters’ as compensation is rarer resulting in cyanosis in skin and lips.
Complications may include:
Bronchiolitis Obliterans
 Cor pulmonale (right heart failure due to pulmonary hypertension). Mucous plugs are
 Infections don’t usually initiate bronchitis but perpetuate it. Can result permanently fibrosed
in acute infective episodes, causing pneumonia or respiratory failure. which results in complete
 Eventual malignant change in epithelium due to squamous metaplasia. obliteration of the
 May lead to Bronchiolitis obliterans bronchiolar lumen.

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.
TH2 IL-5, eosinophil recruitment (priming or sensitisation).
IL-13, increased mucous production.
 2. Re-exposure results in IgE-mast cell release of mediators (immediate phase, minutes).
o Induce bronchospasm, ↑ vascular permeability, mucous production.
o Mediator effect can be direct or via neuronal reflexes.
3. Mast cell release recruits additional mediator-releasing cells from blood (late phase, hours).
o Eosinophils, neutrophils, basophils and TH2 cells are recruited.
o Release LT-C4/D4/E4, PG-D2, PAF, TNF etc. resulting in further inflammation.
o Eosinophilic major basic protein A can cause epithelial cell damage and
bronchoconstriction.

Morphology: histological changes are more diagnostic.

Macroscopic changes: patchy hyperinflation of lungs with
small areas of atelectasis
 Due to occlusion of bronchi/bronchioles by thick
mucus plugs.
Microscopic changes: mucous plugging of bronchi with
airway remodelling*.
 Charcot-Leyden crystals; eosinophils and
membrane protein form crystalloid collections.
 Curschmann spirals; mucus plugs containing shed
epithelium in a spiral configuration.
 Thickening of bronchial basement membrane*.
 Oedema and inflammatory infiltrate in bronchial
walls*.
 Hypertrophy of mucous glands and smooth
muscle in bronchial wall*.

Clinical: main difficulty in asthma lies in expiration. Outcomes of Asthma

 Severe dyspnoea with wheezing upon trigger. -50% childhood cases resolve, mortality 0.2% p.a.
 Hyperinflation due to air trapping. -Status asthmaticus; failure of acute attack to
 Lasts for hours or more until subsides naturally or subside for days or weeks. Can cause resp failure
with treatment (use bronchodilators or and death.

corticosteroids). -Chronic complications in long standing cases (eg.

COPD, pneumonia, cor pulmonale etc.)
 Intervals between attacks usually asymptomatic.

Bronchiectasis Bronchiectasis
Abnormal, permanent dilation of the bronchi and bronchioles due to destruction of their (with emphysema)

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.
 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.
Neonatal Resp. Distress Syndrome
Occurs in premature infants with surfactant
deficiency due to inadequate lecithin
synthesis by immature type II pneumocytes.
Alveoli collapse with resulting hypoxia →
endothelial/epithelial damage → oedema and
fibrin exudation → hyaline membrane
formation.
Increased risks; <2.5kg, <36wks, maternal
diabetes, caesarean section.

Fibrosing Diseases
Disorders with diffuse chronic involvement of pulmonary CT, principally in the alveolar wall.
 Hallmark of these diseases is reduced compliance → lower capacity and dyspnoea.
 Diagnosed clinically or histologically, many have unknown cause.
Pathology: all disorders thought to begin with alveolitis. Interactions of inflammatory cells result in
parenchymal injury and progressive fibrosis.
1. Lung injury from inhaled agents, dust, blood borne toxins, unknown antigens etc.
2. Activation of macrophages which recruit neutrophils (via IL-8, LT-B4).
3. Macrophages/neutrophils release oxidants and proteases which damage type I pneumocytes.
4. Macrophage and type II pneumocyte cytokines lead to fibroblast proliferation → fibrosis.
Idiopathic Pulmonary Fibrosis (IPF) is an interstitial
pneumonitis of unknown aetiology which leads to
interstitial fibrosis (process above). Also called cytogenic
fibrosing alveolitis (CFA).
 Histology: patchy interstitial fibrosis with cystic
spaces forming honeycomb lung.
This pattern is known as usual interstitial
pneumonitis (UIP).
 Clinical: presents with non-productive cough,
progressive dyspnoea and inspiratory crackle.
Cyanosis, cor pulmonale and peripheral oedema in
later stages (median survival <5yrs).
Other Diffuse Fibrosing Diseases
May have similarities with IPF, but can be
distinguished histologically and/or clinically.
 Non-specific interstitial pneumonia (NIP) diagnosis
of elimination, similar to IPF but without
heterogeneity (existence of early and late lesions).
 Cryptogenic organising pneumonia (COP)
unknown aetiology, polypoid plugs of CT in alveoli
and bronchioles.
 Acute-, desquamative-, lymphocytic- interstitial
pneumonitis (AIP, DIP, LIP).
 Pulmonary involvement in CT disorder eg.
rheumatoid arthritis, SLE, collagen diseases.

Pneumoconiosis is pulmonary fibrosis due to inhaled particulates, most commonly mineral dust.
 Also involve macrophages activating inflammatory response leading to fibrotic change
(above).
 Can all cause extensive fibrosis with increasing pulmonary dysfunction, pulmonary
hypertension and cor pulmonale (PMF).
 Smoking increases risk/severity of disease and cancer in all exposure, esp. asbestos. Anthro
 Classified according to causative particulate (may be organic or non-organic). -Silicosis

Coal Workers Pneumoconiosis Asbestosis

Results from repeated exposure to coal. Can range Comes in two forms; stiff amphilobe exposure
from: (↑ disease) or serpantile chrysotyle exposure.
→ Asymptomatic anthracosis
Exposure is linked with six diseases;
→ Simple CWP (coal macules with emphysema)
(i) Interstitial fibrosis (asbestosis)
→ Progressive massive fibrosis (PMF).
(ii) Localised fibrous plaques (sometimes
pleural)
Silicosis
(iii) Pleural effusions
The most common pneumoconiosis in the world,
(iv) Lung carcinoma
usually due to crystalline silica. Ranges from:
(v) Mesothelioma
→ Asymptomatic silicotic nodules
(vi) Laryngeal or colonic carcinoma.
→ Progressive massive fibrosis (PMF).

Granulomatous Diseases
Sarcoidosis multisystem (disseminated) granulomatous disease that can cause restrictive disease in the lung.
Characterised by non-caseating granulomas in many tissues and organs.
 Pathology: idiopathic, likely to be disorder of immune regulation. Antigens, including infectious agents,
with T cell involvement are hypothesised. Diagnosis of elimination.
 Clinical: lung is involved in 90% of patients → granulomas replaced by diffuse interstitial fibrosis
(honeycomb lung) in 5-15%. Additional lymphadenopathy, eye involvement and skin lesions.

Hypersensitivity Pneumonitis is an immune mediated lung disease that primarily affects alveoli (ie. allergic
alveolitis). Restrictive, not obstructive like bronchitic asthma, since in alveoli.
 Pathology: caused by exposure to organic dusts and other antigens. Chronic reaction of type IV
hypersensitivity.
 Clinical: two types, (i) Farmers lung, caused by actinomycetes growing on hay, and (ii) Byssinosis,
caused by cotton, linen or hemp exposure.
PULMONARY 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.

Acute Congestion of lung Chronic Passive Venous Congestion

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

Pulmonary Embolism
Venous emboli travel via IVC into right heart, then impact in pulmonary arterial tree. Massive Pulmonary
 95% arise from the deep veins of the legs eg. femoral, popliteal. Embolism

 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.

Pulmonary Infarction
 60-80% are clinically silent since only small branches affected and
Deep red in colour at
fibrinolytic activity eventually dissolving embolism.
periphery of lung. Wedge
 10% impact end arteries resulting in infarction; infarction rare in other shaped and firm.
cases due to bronchial artery and direct alveolar oxygen supply. Inflammation of overlying
 5% result in major block (>60% block eg. saddle embolism) causing pleura (pleurisy) ± effusion.
instant death by reflex vasoconstriction, acute RHF (acute cor Healing by fibrosis is rapid,
pulmonale) or cardiogenic shock. only small scarring.
 <3% have multiple, recurrent small emboli → chronic cor pulmonale.
NB: 30% of pulmonary embolism sufferers experience recurrences. Paradoxical Emboli
When a patient has foramen
Clinical: risk factor prevention important. ovale/septal defect resulting
 Prolonged bed rest; leg exercises for the immobilised. in emboli passing from right to
left side of heart and into
 Surgery (esp. lower leg), parturition; early ambulation.
systemic circulation.
 CHF, hypercoagulable state; anticoagulants.
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. Plexiform Lesions
 Main elastic arteries: atheroma development.
Different morphology in primary and shunting
 Medium muscular arteries: thickening of muscular wall, hypertensions called plexiform lesions.
smaller lumen.
Vessel wall is thinned and network of
 Smaller arteries/arterioles: medial hypertrophy, capillary like channels replaces part of arterial
thickening of elastic membrane, intimal fibrosis. wall. Fibrinoid necrosis of walls occurs
NB: all increase resistance and progressing hypertension. resulting in irreversible hypertension.

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

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).
Lobar Pneumonia
NB: consolidation = exudate
Bronchopneumonia: foci of inflammatory consolidation in patches throughout one or more lobes.
combining into a firm dense mass.
  Most frequently bilateral, affecting basal areas.
 Intervening areas between isolated consolidation foci are normal.
 Initial infection centred on bronchi and surrounding alveoli, well developed lesion (3-4cms)
→ can coalesce in severe cases, producing the appearance of lobar consolidation.
 Usually secondary infection accompanying other illness (eg. cancer, heart failure, stroke).
 More common at extremes of age.

Lobar vs Bronchopneumonia
The distinction between lobar and
bronchopneumonia is blurry because (i) many
organisms present with either of the two
patterns, and (ii) confluent
bronchopneumonia is hard to distinguish
from lobar pneumonia.
Hence, pneumonias are best classified by
either the specific aetiological agent or by the
clinical setting in which the infection occurs.

Clinical: abrupt onset with fever, chills, productive chest pain, productive mucopurulent cough, haemoptysis
(occasionally).
 Lobar: severe fever and rigors, cough with rusty sputum, dyspnoea, possible pleurisy.
 Bronchopneumonia: septicaemic, high temperature, crackles at affected areas.

Pathogens: S. pneumoniae most common cause, usually via aspiration of pharyngeal flora (oropharyngeal
commensal in 20% of adults).
 Affects young healthy adults, hence usually 10.
 More frequent in those with chronic diseases, immune defects or
decreased splenic function.
 Gram +ve, lancet shaped diplococci on sputum gram stain. Blood
cultures more specific, as may be commensal flora in sputum sample. S. Pneumoniae [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. S. Pneumoniae [blood sample]
 L. pneumophila; organ transplant patients.

Complications: Lung Abscesses

 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.
Localised area of suppurative necrosis within the pulmonary
parenchyma. Will drain (usually into bronchus) leaving a cavity with a
rough ragged wall.
 Usually a result of necrotising bacterial pneumonia (S. aureus, S.
pyogenes, K. pneumoniae). Additional anaerobic bacteria are
almost always present (Prevotella, Bacteroides).
 Organisms usually introduced by aspiration (more common on
right side).
 Clinical: fever, cough, foul smelling sputum, clubbing.
 Complications: rupture (pneumothorax and empyema),
embolisation to brain (meningitis).
 Atypical Community Acquired Pneumonias
Acute non-bacterial infections characterised by patchy inflammatory changes in lungs.
“Atypical” due to moderated amounts of sputum, absence of physical findings of consolidation, moderate
elevation of WBCs and lack of alveolar exudates.

Morphology: patchy, largely confined to the alveolar septa and interstitium.

 Affected areas are reddish-blue and congested. Can be whole lobe, unilateral, bilateral.
 Septa are widened and oedematous, usually containing a mononuclear infiltrate.
 Alveoli spaces are remarkably free of cellular exudate (instead in interstitial space).

Pathogens: Mycoplasma pneumoniae (most common), viruses (influenza A/B, RSV, adenovirus, rhinovirus, rubeola,
varicella) and Chlamydia spp (pneumoniae, psittaci). Pathogen not known in third of cases.

Clinical: acute, nonspecific febrile illness characterised by fever, headache, malaise, cough with minimal sputum.
 Course can vary from a severe URTI that goes undiagnosed as pneumonia, or may present as fulminant,
life threatening infection in the immunocompromised.
 “Walking pneumonia” since lungs with extensive infection may look normal under X-ray.
 Septal alveolocapillary block may cause respiratory distress out of proportion to clinical findings.

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

Nosocomial and Immunocompromised Pneumonia

Nosocomial pneumonias are infections acquired during hospital stay. Common in patients with severe
underlying disease, immune suppression, prolonged antibiotic treatment or on mechanical ventilation.
 Most common pathogens are Enterobacteriaceae, Pseudomonas spp and S. aureus.

Pneumonias in the immunocompromised are caused by opportunistic organisms.

 Cytomegalovirus pneumonia is usually serious pneumonitis, which can progress to full blown acute
respiratory distress syndrome (ARDS). Typical in organ transplant, AIDS patients.
 Pneumocystic pneumonia (PCP); caused by reactivation of P. jiroveci (formally P. carinii). Pneumonia
with intra-alveolar exudate that is foamy and pink staining. Typical in AIDS (60% of deaths), severely
malnourished infants, chemotherapy.

Non-Infectious Pneumonia
Aspiration pneumonia occurs following aspiration of gastric contents, fluid or food.
 Resultant chemical pneumonia (irritant effects) followed by infection.
 Overall similar picture to bronchopneumonia
 If severe can lead to necrosis, abscess formation and even death.
 Often in debilitated patients with abnormal gag and swallowing reflexes (eg. comatose).

Lipoid pneumonia is due to obstruction or aspiration of lipid material.

 Lipid laden foamy macrophages predominate in inflammatory exudate.
 Multinucleate giant cells and interstitial fibrosis.
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).

Cigarette Smoke and Other Carcinogens

Genetic mutations result from cigarette smoking and other environmental stimuli.
Smoking: 90% of lung cancers occur in active smokers, with a linear correlation between lung
cancer frequency and pack-years of cigarette smoking (10-20x risk).
 Cessation of smoking decreases risk of lung cancer over time.
 Females are more susceptible to tobacco carcinogens than men.
 Passive smoking increases risk 20%.
Other environmental stimuli: asbestos (5-90x risk), radioactive ores, arsenic, chromium,
uranium, nickel, vinyl, chloride and mustard gas. Ie. occupational exposure and air pollution.

Morphology: four main histological types that begin as small mucosal lesions. As they develop may undergo
cavitation (necrosis), haemorrhage or dissemination.
Adenocarcinomas (35%) arise from submucosal glands or Atypical Adenomatous Hyperplasia
epithelium, often preceded by ‘atypical adenomatous Precursor lesion with well demarcated foci of
hyperplasia’. Usually peripheral tumours (bronchioles/alveoli). epithelial proliferation, demonstrating cytologic
 Most cases are smokers, but is commonest type in non- change (pleomorphism).
smokers (also women, <45 groups). Broncioalveolar Carcinomas
 Grow slowly, form smaller masses, but metastasise Subtype of adenocarcinomas, only grow along
widely at an earlier stage. pre-existing structures and preserve the alveolar
 Tumours form well circumscribed, grey-white masses architecture.
that rarely cavitate.  Mucinous and non-mucinous types.
 Can project out into alveolar spaces in
 Histologically classified as acinar, papillary or solid.
papillary formations.
o Acinar; well differentiated gland forming
 Well differentiated, tall, columnar-cuboidal
structures, produce mucin.
cells.
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.
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.

Adenocarcinoma Squamous Cell Carcinoma Small Cell Carcinoma Large Cell Carcinoma

Clinical: staging is by size of the tumour, number of affected nodes, and distant metastases (TNM). Lung
cancers are silent, insidious lesions that commonly spread before producing symptoms.
 Early stages: can have chronic cough, sputum or haemoptysis before spread due to intrabronchial
lesions.
 Later stages: of disease can include a wide range of presentations:
a) Nonspecific symptoms only; weight loss, anorexia,
Intrathoracic Dissemination
fatigue, weakness, nausea.
Intrathoracic spread can cause:
b) Intrathoracic spread; invasion/compression of
o Apical neoplasms that invade the brachial
nerves can cause related symptoms, can also
(ulnar nerve pain) or cervical (Horner’s
obstruct blood vessels or oesophagus. syndrome) sympathetic plexuses. Known as
c) Extrathoracic spread; to lymph nodes (mediastinal, ‘Pancoast syndrome’.
clavicular, scalene, Virchow’s nodes), liver, brain, o Phrenic nerve → diaphragmatic damage.
adrenal and bone metastases (most common). o Recurrent laryngeal nerve → hoarseness.
d) Paraneoplastic syndromes; systemic syndromes o Obstruction in SVC → dilation of head/neck
due to ectopic substance (hormone, cytokine) veins, facial swelling, cyanosis.
production. Occurs in 3-10% of lung carcinomas. o Oesophageal obstruction → dysphagia.

Paraneoplastic Syndromes
Ectopic hormone production can cause:
o Hypercalcaemia; PTH secretion (most common in squamous cell carcinomas).
o Cushing syndrome; ACTH production leading to ↑ cortisol from adrenals.
o Syndrome of inappropriate ADH (SIADH) secretion, resulting in fluid overload.
o Neuromuscular syndromes; myasthenia, peripheral neuropathy, poliomyelitis.
o Haematologic/vascular syndromes; anaemia, coagulopathy, DIC, non infectious endocarditis, embolism
(most common with adenocarcinomas).
o Dermatologic signs; dermatomyositis, hyperpigmentation, acanthosis nigricans.
o Skeletal /CT syndromes; hypertrophic pulmonary osteoarthropathy.
NB: apart from hypercalcaemia and haematologic syndromes, most are more common with SCLCs
Treatment: practically split into SCLC/NSCLC for treatment distinctions. 5 year survival around 15%.
 Small Cell Lung Cancers (SMLC) have all metastasised by the time of diagnosis, hence not curable by
surgery, and best treated with chemotherapy ± radiotherapy.
o Median survival with treatment is 1 year.
 Non-Small Cell Lung Cancers (NSCLC) respond poorly to chemotherapy, better treated with surgery
(lobectomy or pneumonectomy) if detected before spread. Better prognosis than SCLCs.
o At diagnosis, 75% have metastasised, inoperable.
o Includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Other Pulmonary Tumours

Remaining 5% primary lung tumours consist of carcinoids, mesenchymal malignancies, lymphomas and some
benign lesions. Secondary lung tumours are much more common.

Carcinoids arise from neuroendocrine (Kulchitsky) cells that line bronchial mucosa. Contain dense
neurosecretory granules but rarely release hormonally active peptides.
 Slow growing malignant tumours that rarely
metastasis (<10%). Typical Carcinoid; small rounded cells with
diffuse chromatin granules, absent/rare mitoses,
 Either obstructs lumen or penetrates bronchiolar
little pleomorphism. 80% 10yr survival.
wall, can be central or peripheral.
Atypical Carcinoid; higher mitotic rate, increased
 Histologically, can be typical or atypical.
pleomorphism, necrosis. 50% 5 yr survival.
 Affects genders similarly, often <40 yrs.

Malignant Mesotheliomas rare cancer of mesothelial cells usually arising in parietal or visceral pleura.
 Cause: related to asbestos exposure (not smoking) with long latent period (25-40yrs). Asbestos not
removed/metabolised → generates ROS → DNA damage → oncogenic mutations.
 Morphology: diffuse lesion, invasion of thoracic structures. Lung is encased by thick layer of grey-pink
tumour. Epithelial, sarcomatoid and biphasic histological types.
 Clinical: chest pain, dyspnoea, pleural effusion. Prognosis is poor (12-14mnths).

Secondary Lung Cancers result from blood-borne metastasis of tumours from other sites. Most often from
breast, colon, stomach, pancreas, kidney (in relative order).

Upper Respiratory Tract Tumours don’t bother

Benign: haemangioma, squamous papilloma, juvenile angiofibroma,
Nose and Sinus inflammatory polyps.
Tumours Malignant (sinonasal carcinoma): SCC, transitional, adenocarcinoma
Other: salivary, melanoma, lymphoma
Squamous carcinoma with lymphoid infiltrate
o Leading cause of death in SE Asia
Nasopharyngeal o Associated with EBV, other genetic and environmental links.
Carcinoma o Keratinising (worse) and non-keratinising forms.
o Metastasise to LN, can stimulate large cell carcinoma.
Benign: papilloma (HPV), cysts, laryngeal nodules, amyloidosis.
Laryngeal Malignant: squamous cell carcinoma (SCC) most common.
Tumours o 2% of all male cancers, associated with smoking, alcohol
o Glottic, trans-, supra- and infra- glottic forms
 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.
Hepatic Investigations
 Liver Function Tests
o Enzymes: hepatocellular (AST/ALT) and
cholagiocellular (GGT/Alk Ph)
o Bilirubin
o Synthetic function (albumin and prothrombin)
 Infective agents HAV, HBV, HCV, delta virus etc
o Antibodies to the virus or PCR for viral
DNA/RNA
 Serology: auto-immune markers antiMA,
antiSmM, antiDNA
 Tumour marker: alpha feto protein (levels may go
up with hepatocellular carcinoma)
 Imaging: Xray, Ultrasound, CT scan, MRI
 ERCP cholangiogram, MRI cholangiogram, PTC
 Fine Needle Aspiration
 Liver biopsy histology: diagnosis and
grading/staging of disease
 Iron and copper studies

Clinical Syndromes
Jaundice (Icterus) is excess bilirubin accumulation in the skin and sclerae, producing a yellow discolouration of
these tissues. Bilirubin is the end product of haem degradation and is in excess when >2mg/dl
(hyperbilirubinaemia).
 Unconjugated bilirubin has not yet been made soluble by liver. Jaundice Hereditary
Usually due to excessive haemolysis (haemolytic jaundice). Can be Syndromes
due to ↓hepatic uptake or impaired conjugation. Not excreted in Dubin-Johnson Syndrome -
kidneys, stool still contains pigment (no obstruction). impaired transport of anions.
 Conjugated bilirubin is soluble due to conjugation with glucoronic Gilber Syndrome- relatively
acid. Usually due to impaired bile flow (obstructive jaundice). Can be common mild conjucgation
due to hepatocellular damage. Dark urine (soluble so excreted in disorder.
kidneys), stool is pale as no pigments can reach intestine.

Cirrhosis is a consequence of chronic hepatocellular injury, associated Post-Necrotic Cirrhosis

with diffuse fibrosis and nodular regeneration of the liver. Is usually Is associated with the formation of
either alcohol, inflammatory/necrosis, biliary or haemochromatosis macronodules composed of
related cirrhosis. Cirrhosis can result from chronic infection, chronic regenerating hepatocytes separated
drug reactions, autoimmune reactions, and metabolic abnormalities. by fibrous scars and an inflammatory
infiltrate. Most cases are secondary to
Clinical features include:
chronic active viral hepatitis, others
 Portal Hypertension → ascites (fluid accumulation in the
are due to exposure to hepatotoxins
peritoneal cavity), portocaval shunts forming haemorrhoids, or autoimmune disorders (eg. lupoid).
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.
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.

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). Multiple Hepatic Abscesses
 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

Chronic Hepatitis is chronic inflammation of the liver associated with hepatocyte destruction, cirrhosis and
liver failure. It is more likely to occur in the very young, very old, males, immunocompromised, and dialysis
patients.
 Pathology: characterised by portal infiltrate, necrosis and fibrosis.
o Excessive portal lymphocytic infiltrate that spreads to adjacent parenchyma.
o Piecemeal necrosis: a condensation, fragmentation and phagocytosis of hepatocytes.
o Bridging necrosis: destruction of adjacent hepatocyte lobules.
o Progressive fibrosis → cirrhosis.
 Causes: HBV, HCV, HDV, drug toxicity, alcohol and autoimmune reactions.
Fulminant Hepatitis involves massive hepatic necrosis, progressive hepatic dysfunction and acute liver failure
(mortality 25-90%).
 Cause: hepatitis viruses (A-E), carbon tetrachloride, chloroform, other drugs.
 Morphology: progressive shrinkage of the liver as parenchyma is destroyed. Histologically get
coagulation necrosis followed by liquefactive necrosis → macronodular cirrhosis (if patient survives).

Alcoholic/Drug Induced Liver Disease

Fatty Liver (Steatosis) is a reversible asymptomatic condition resulting from
alcoholism. It is an abnormal accumulation of lipids in cells, resulting in a yellow,
greasy, enlarged liver.
 Pathogenesis: the metabolic breakdown of ethanol produces energy in
the form of NADH → inhibits β-oxidation (breakdown) of fatty acids and
increase fatty acid synthesis → steatosis.
 Histology: fatty vacuoles displacing hepatocellular nuclei in periphery, Steatosis
swollen mitochondria and endoplasmic reticulum.
NB: steatosis → steatohepatitis (alcoholic hepatitis) → cirrhosis → liver failure.

Alcoholic Hepatitis is inflammation of the liver resulting from prolonged alcohol abuse, characterised by
swelling of hepatocytes.
 Followed by necrosis and polymorphonuclear inflammation, formation of alcoholic hyaline (Mallory
bodies) in swollen hepatocytes, cholestasis, and the beginning of fibrosis.

Alcoholic Cirrhosis fibrous tissue replaces fatty swelling, Drug Induced Liver Damage
resulting in nodule formation. Different drugs can damage liver cells through
different mechanisms:
 Early stages of disease: enlarged liver with
1) Hepatotoxins (carbon tetrachloride,
micronodular formation.
methotrexIschaemic Atrophy: due to
 Later stages: small, macronodular liver with a atherosclerosis of pancreatic arteries, usually
‘hobnail’ appearance on its surface. asymptomatic.
2) Obstruction of pancreatic duct: affects
only exocrine pancreas, which becomes small,
Haemodynamic and Vascular Abnormalities fibrous and nodular.
 ate, anabolic steroids).
Portal Hypertension is increased resistance to portal blood flow that may
 Hypersensitivity (drugs can act as haptens).
develop form pre-, intra- or post- hepatic causes. Most dominant cause is
 Metabolic response to drugs (paracetamol,
cirrhosis (intrahepatic). May manifest as ascites (fluid/lymph in peritoneal
phenothiazines, methyldopa, halothane).
cavity), splenomegaly, oesophageal varices and/or hepatic encephalopathy.

Passive Congestion and Central Necrosis are associated with right heart
failure, characterised by congestion of central veins and centrilobular hepatic
sinusoids (‘nutmeg liver’). Clinically manifests as milf hepatomegaly, a
pulsatile liver tender to palpation. Atrophy and necrosis are secondary to
hypoxia and hypoperfusion.

Liver Infarcts are rare due to double blood supply to the liver. Interuption of
the main hepatic artery can be compensated by retrograde accessory vessels
and the portal venous system.
Hepatic-Biliary Tract Disorders
Cholestasis is inability of bile to flow from the liver to the duodenum. Results in retention of bilirubin, bile
acids and cholesterol. Hence get pale stools, dark urine, itching, increased serum lipids.
 Intrahepatic causes: hepatocellular cholestasis seen in viral hepatitis, cirrhosis, drug toxicity.
 Extrahepatic causes: gallstones, cholangitis, cancer of bile ducts and head of the pancreas.

Cholangitis is inflammation of the bile ducts. Usually associated with biliary duct obstruction (gall stones,
carcinoma), which leads to infection with enteric organisms → purulent exudation within the bile ducts, bile
stasis. Clinically manifests as jaundice, fever and upper right quadrant pain (“Charcot Triad”).

Biliary Cirrhosis is the inflammation and fibrosis of bile ducts.

 Primary Biliary Cirrhosis: results from an autoimmune reaction with anti-mitochondrial antibodies, can
cause sclerosing cholangitis (below). Early stages of disease involve inflammation around small portal
bile ducts. Late stages involve fibrosis causing small bile ducts to disappear. There is a female
predominance (middle aged).
 Sclerosing Cholangitis: a chronic fibrosing inflammatory disease of extrahepatic and larger intrahepatic
bile ducts. Progressive stenosis of larger bile ducts → secondary biliary cirrhosis. This condition
predisposes individuals to cholangiocarcinoma.
 Secondary Biliary Cirrhosis: caused by longstanding large bile duct obstruction → stasis of bile →
inflammation, infection and scarring. It presents with jaundice. Histologically, there is dilation of larger
bile ducts ± inflammation.

Metabolic Liver Disease

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

Wilson’s Disease (hepatolenticular degeneration) autosomal recessive disease, characterised by inadequate

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

Hepatic Tumours
Benign Tumours: may be asymptomatic (incidental finding on imaging), a
palpable mass, cause liver dysfunction due to mass effect, or occasionally
haemorrhage or rupture.
 Include nodular hyperplasia, hepatocellular adenoma,
haemangioma, bile duct adenomas and cysts.
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).
Multiple
o Often bile strained and invades vessels. Metastases generally first Metastatic Tumours
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,
Hepato- Carcinoma
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.
Mixed Cholelithiasis
 Pigment Stones small, black, multiple, radiolucent clumps of pigment. Derived (mostly pigment)
from unconjugated bilirubin. Associated with chronic (not acute) haemolytic
disease (eg. hereditary spherocytosis).
 Mixed Stones comprises 80% of all stones and are associated with chronic
cholecystitis.
o Composed of cholesterol and calcium bilirubinate.
o Composition determines colour (yellow → black).
o Those with high calcium are radiopaque.

Clinical: most stones remain in the gall bladder and are asymptomatic. Obstruction of:
 The gall bladder or cystic duct → biliary colic, acute cholecystitis, and mucocele formation.
 Common bile duct → obstructive jaundice, ascending cholangitis.
 Ampulla of Vater (→ pancreatitis) or distal small bowel (→ gallstone ileus).
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 Acute Calculous
with oedema and fibrosis. Microscopically, has acute inflammatory infiltrate Cholecystitis
with mucosal ulceration, erosion and necrosis/haemorrhage.
 Clinical: typically acute onset upper right quadrant pain, fever, tenderness and
leukocytosis. Most resolve with medical management.
 Complications: secondary bacterial infection. Can progress to empyema (lumen
filled with pus), gangrenous necrosis, or rupture. These cases require
cholecystectomy.

Acute Non-Calculous Cholecystitis cholecystitis without gallstones. It is associated with congenital anomalies,
diabetes, infections, polyarteritis nordosa, burns, trauma and surgery.

Chronic Cholecystitis is chronic inflammation of the gallbladder of unknown aetiology. It is probably due to
chemical injury from supersaturated bile, and not due to irritation by stones.
 Gallbladder wall is thickened by fibrosis.
 Rokitansky-Aschoff’ sinuses; penetrations of the mucosa through the muscularis, with chronic
inflammation.

Gallbladder Tumours
Benign Tumours: Papillomas, Adenenomas and Adenomyomas.

Malignant Tumours: typically adenocarcinomas with variable differentiation. Usually asymptomatic

adenocarcinomas until advanced stages, poor prognosis (3% 5 yr survival).
 Gallbladder Carcinoma rare tumours, typically involve the fundus and
neck of the gallbladder.
o Risk factors include cholelithiasis, cholecystitis, and porcelain
gallbladder (due to calcium deposition in the wall).
o Serum alpha feto protein raised in 60-75% of cases.
o Pre-metastatic diagnosis depends on detection of co-existent
abnormalities eg. gallstones. Gallbladder Carcinoma

 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.
PANCREATIC PATHOLOGY [Note: disorders of endocrine pancreas
discussed in Endocrine 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
Acute Pancreatitis
microvascular leakage (oedema).

Clinical: full-blown acute pancreatitis is a medical emergency.

 Symptoms: painful rigid abdomen radiating to upper back Psuedocysts
due to digestive enzymes. DIC, shock and multiorgan These lesions are sequelae of pancreatitis
failure due to response (inflammatory, clotting). or trauma, formed by the localisation of
 Signs: ‘Grey Turner Sign’ (bluish discolouration of the fluid which can be suppurative,
flanks) and the ‘Cullen Sign’ (periumbilical discolouration) haemorrhagic, or necrotic debris.
indicate extensive damage.  Usually 5-10cm in diameter with fibrous
capsule, but no epithelial lining.
 Treatment: supportive, no oral intake, nasogastric
 Present as abdominal mass, often with
suction, IV fluids.
pain
 Complications: infection, abscess formation, pseudocysts  Rupture causes peritonitis.
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.
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. Carcinoma of pancreas,
spread to humerus
 Diffuse pancreatic carcinoma (5%)

Clinical: usually asymptomatic until late in its course, prognosis very poor.
 If resectable, <5% 5yr survival, death usually within 6 months of symptoms.
 Jaundice in half with carcinomas of head of pancreas. Painless jaundice with a palpable gall bladder is
suggestive of pancreatic cancer.

Cystic Fibrosis in Pancreas

This is an autosomal recessive systemic disorder of exocrine
gland secretion, associated with a defect in the Cystic
Fibrosis Transporter Gene (CFTG) on Ch 7.
Defective chloride channels → secretion of very thick mucus
→ mucous plugging of the pancreatic ducts → cystic
dilations, fibrous proliferation and obstructive atrophy of
the pancreas.
Pancreatic Atrophy
 Ischaemic Atrophy: due to atherosclerosis of pancreatic
arteries, usually asymptomatic.
 Obstruction of pancreatic duct: affects only exocrine
pancreas, which becomes small, fibrous and nodular.
 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)

Barrett’s Oesophagus
Barrett's oesophagus is generally defined as intestinal metaplasia (the replacement of one adult cell type by
another adult or mature cell) of the squamous epithelium lining the oesophagus. This process is reversible, and
represents adaptive substitution of squamous epithelial cells that are sensitive to stress (ie: acid reflux) by
secretory columnar epithelium with Goblet cells that are more stress resistant. In some patients, Barrett's
oesophagus progresses through low and high grade dysplasia to adenocarcinoma.

Dysplasia: A premalignant state involving disordered cell characteristics or abnormal cell growth. This usually
occurs in epithelium and is characterised by cytological (pleomorphism, enlarged hyperchromatic nuclei, abnormal
mitotic activity) and/or architectural changes (loss of nuclear polarity, nuclear stratification, gland crowding and
cribiform arrangements).

Regular surveillance by endoscopy and biopsy is recommended for patients with Barrett's oesophagus. Patients
with low grade dysplasia are followed by short interval surveillance and treated with acid suppressing agents. The
finding of high grade dysplasia is an indication for oesophagectomy.
.

Corrosive Oesophagitis
Caused by ingestion of acid or alkaline material. This leads to mucosal injury of the mouth, pharynx,
oesophagus and stomach. Severity is dose dependent and in severe forms leads to full thickness mucosal
necrosis, ulceration and even perforation. It heals by fibrous stricture formation.

Infectious Oesophagitis
Rare in immunocompetent individuals, but is more common in the immunocompromised (eg: AIDS and
transplant patients). Common infectious agents include:
1. Candida species – colonise the squamous epithelium, giving rise to white plaques and hyperkeratosis
with an inflammatory infiltrate.
2. Herpes Simplex Virus – infects squamous epithelial cells resulting in blisters and superficial ulcers.
Infected cells are typically multinucleated with intranuclear viral inclusions which have a glassy
basophilic appearance.
 3. Cytomegalovirus (CMV-. Infects both endothelial and squamous epithelial cells. Infected cells appear
enlarged with prominent intranuclear inclusions, with or without basophilic intracytoplasmic
inclusions.

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

Oesophageal Squamous Cell Carcinoma

Squamous cell carcinoma is most common worldwide but its incidence is decreasing in western countries. Iran,
Central China and South Africa have the highest incidence. Blacks are at higher risk than whites.
Adenocarcinoma is showing comparable incidence rate.
Aetiology: involves a combination of dietary, genetic and environmental factors:
• Dietary factors: vitamin deficiencies (Vit A, C, Thiamine etc), deficiencies in trace elements (zinc) and
fungal contamination of food.
• Life style: Smoking and tobacco use, alcohol, hot beverages
• Oesophageal disorders: long standing oesophagitis, Plummer-Vinson syndrome, achalasia
• Racial and genetic predisposition: coeliac disease, ectodermal dysplasia

Oesophageal adenocarcinoma
Usually arises in the distal oesophagus is often reflux induced.
• Acid reflux causes intestinal metaplasia (Barrett’s oesophagus)
• Further genetic alteration of the metaplastic mucosa may lead to low-grade dysplasia, high-grade
dysplasia and in-situ and invasive carcinoma
The life time risk of developing adenocarcinoma from Barrett's oesophagus is approximately 10%.

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.
Gastric and Duodenal Ulcers (Peptic Ulcer Disease)
Peptic ulcers are deep mucosal lesions occuring within the
duodenal or gastric mucosa that is exposed to gastric acid. This is
caused when there is imbalance between mucosal defence
mechanisms and the damaging forces (NB: hyperacidity is not a
pre-requisite for peptic ulceration). Helicobacter infection is a
major factor in the pathogenesis of peptic ulcer disease and is
present in almost all duodenal ulcers and up to 70% of gastric
ulcers.
 The majority of duodenal ulcers occur in the proximal
region of the duodenum
 Gastric ulcers often occur in the lesser curvature and
around the transition zone between antrum and body.
Complications include bleeding, perforation and stricture
formation/obstruction.

Complications: gastric and duodenal ulcers, gastric carcinoma, gastric lymphoma.

Treatment: combination of antibiotics and suppression of gastric acid production (via Proton Pump Inhibitors)
• Omeprazole 20mg twice/day
• Amoxacillin 1000mg twice/day
• Clarithromycin 500mg twice/day

Gastric Tumours
Gastric Adenocarcinoma (>90%)
Most common primary malignancy in the stomach (90-95%). 50% arise in the antrum and pylorus, 25% in the
gastric cardia. Metastases is frequently present at the time of diagnoses (symptoms develop late). Very high
incidence in Japan, Chile, China and Russia, with relatively lower incidence include Australia, New Zealand, US,
UK, and Canada.
Predisposing factors:
• Helicobacter infection causing chronic gastritis, gland atrophy and intestinal metaplasia. This may
evolve to dysplasia and carcinoma.
• Autoimmune gastritis, which often is associated with gland atrophy and intestinal metaplasia, can
progress to gastric carcinoma.
• Diet (eg: preservatives, salted and smoked foods)
• Genetic alterations and susceptibility.
Types of gastric carcinoma
• Diffuse type (Signet Ring Cell Type)- not associated with chronic gastritis. Composed of gastric type
mucous cells that doesn’t form glands but permeates the mucosa as signet cells. Diffuse infiltration of
the gastric wall causes the stomach to have a gross leather bottle appearance, also known as “linitis
plastic”. Female predominance at a younger age.
• Intestinal type- associated with chronic gastritis caused by H.pylori infection, with gastric atrophy and
intestinal metaplasia. Composed of malignant cells forming glands. Male predominance, usually >50.
Clinical:
 Spread; penetration of serosa lymph nodes (Virchow’s node), and in females spread to ovaries
(Krukenberg tumours).
 Prognosis; depends on the depth of invasion. Early gastric cancer has better prognosis and those
advanced (invasion beyond submucosa) have poor prognosis with five year survival rate less than 15%.

Gastric Lymphoma
Lymphoma accounts for less than 5% of gastric tumours. Nearly all gastric lymphomas arise
from B-cells. The most common type of gastric lymphoma is MALT (Mucosa Associated Lymphoid Tissue)
lymphoma.
• Majority are associated with chronic Helicobacter gastritis (NB: some MALT lymphomas regress
after H.pylori eradication).
• Characterised by atypical lymphoid cell infiltration of the mucosa.
• If not treated, progression to a higher-grade diffuse large B-cell lymphoma is possible.

Gastrointestinal Stromal Tumours (GISTs) (1-3%)

• Majority occur in the stomach (70%) 20% in small intestine and 10% in the esophagus.
• Patients present with dysphagia, GI harmorrage and metastases to liver.
• They arise from the interstitial cells of Cajal
• Arise beneath the mucosa and usually protrude into the lumen
• The overlying mucosa either remains intact or focally ulcerates causing blood loss.
• Histology: spectrum of appearances, with cells characteristically overexpressing a c-kit oncogene
(CD117) (also a useful diagnostic test).
• Most have low malignant potential (however, size, necrosis, cellularity, mitotic rate and
pleomorphism may indicate malignant behaviour).
• Treatment: Surgical resection, presence of the c-kit oncogene overexpression indicates likely
tumour response to Glivec.
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 Subacute
• Severe acute abdominal pain and tenderness • Non-specific symptoms, episodes of bloody
• Nausea & vomiting diarrhoea blood loss, sepsis
• Bloody diarrhoea
• Loss of bowel sounds, abdominal rigidity Chronic
• Shock, vascular collapse • episodes of bloody diarrhoea
Morphology:
 Macroscopic: Variably demarcated, congested (purple/red), haemorrhagic (due to blood reflow into
damaged area), edema (thick rubbery wall), thinning of the wall and perforation.
 Microscopic: Exudate (neutrophils and fibrin), mucosal infarction/necrosis and sloughing, oedema,
haemorrhage, ulceration with granulation tissue, vascular thrombi with haemosiderin, fading of
muscle details.
Treatment: Surgery

Idiopathic Inflammatory Bowel Disease

A group of inflammatory conditions including Crohn’s Disease and Ulcerative Colitis. It is associated with
immune-mediated inflammation and tissue destruction. Both have unknown aetiology (infectious and
autoimmune causes have been proposed) although there is a genetic predisposition. Extraintestinal
manifestations indicates that IBD is a systemic illness (eg: U/C predominantly colonic but may also cause liver
or biliary tract disease, arthritis, uveitis, pyoderma gangrenosum, and Wegeners granulomatosis).
 Crohn’s Disease (Regional enteritis)
Any age after late childhood (20-40yo)
Symptoms/Signs
♦ Abdominal pain
♦ Diarrhoea
♦ Rectal bleeding, less common than U/C
♦ Abdominal mass
Pathology
♦ Any part of the intestine to anus (terminal ileum 40%
or colon 30% or both 30%)
♦ Preferentially right sided (rectal sparing)
♦ High incidence of anal lesions
♦ Sharp demarcation, continuous or skip lesions
Macroscopic
♦ Mucosal cobblestone appearance
♦ Deep fissuring linear ulceration- fistula formation
♦ Transmural inflammation
♦ Intestinal wall thickened - oedema, inflammation,
fibrosis, muscle hypertrophy
♦ Stricturing
Microscopic
• Variable between fragments and sites
• Transmural changes
• Mucosal inflammation
• mainly chronic, some acute
• Ulceration – classically “rose thorn”
• Non-caseating granulomas (40-60% of cases)
• Architectural distortion - cycles of destruction and
regeneration, paneth cell metaplasia
• Retention of mucus production
• Submucosal fibrosis
• Hypertrophy of the muscularis
• Serosal thickening due to fibrosis, creeping fat
Complications
• Toxic megacolon with perforation
• Stricture with obstruction
• Fistula - bowel, bladder vagina, peritoneal cavity,
perianal skin
• Iliitis - malabsorption, protein losing enteropathy,
pernicious anaemia (vitamin B12), steatorrhoea (bile
salts)
• Carcinoma colon
Treatment
♦ Supportive therapy
♦ Immunosuppression – local/systemic
♦ Surgery – total colectomy, reconnection depends on
the presence of perianal disease
♦ Surveillance for malignancy
Ulcerative Colitis
Any age, peaks at 20-30 and 70-80 years (M=F)
Symptoms/Signs
♦ Pain and cramps relieved by defecation
♦ Episodic if mild, continuous if severe, can be fulminant
♦ Attacks of bloody mucoid diarrhoea days/months
♦ Occasionally constipation
♦ Abate with or without treatment
♦ Flare ups precipitated by stress
Pathology
♦ Characteristically left sided disease (rectosigmoid) but
extends proximally (pancolitis in 40%)
♦ Continuous – no skip lesions
Macroscopic
♦ Blood and mucus in lumen
♦ Hyperaemia, granularity, friability
♦ Broad based ulceration (not linear) with pseudopolyps
of regenerating mucosa
♦ Muscularis propria and serosa normal
Microscopic
• Continuous and relatively uniform
• Mucosa and submucosa
• Lymphoplasmacytic inflammation in the lamina
propria
• Ulceration (flask shaped) confined to the
mucosa/submucosa with granulation tissue
• No granulomas
• Mucosal acute inflammation with cyptitis and crypt
abcesses
• Goblet cell depletion
• Pseudopolyps of granulation tissue
• Architectural damage - regeneration, fibrosis, gland
disarray/atrophy, paneth cell metaplasia
Complications
• Toxic megacolon – perforation – peritonitis/abcess
• Strictures rarely
• Loss of blood or fluid and electrolytes – anaemia,
malnutrition
• Carcinoma (20-30x risk in pancolitis for 10+ years)
Treatment
• Supportive therapy
• Immunosuppression –
local/systemic
• Surgery – total colectomy
• Surveillance for malignancy
Large Intestine Tumours
Investigations:
- Clinical examination, faecal occult blood test (FOBT)
- Imaging (plain films, barium studies)
- Endoscopy, Colonoscopy
- Pathology: cytology, fine needle aspiration, brushings, fluids, biopsy, resection.

Polyps (Adenomas)
Polyps are abnormal epithelial growths projecting from the mucosa (smooth, discrete and round
elevations). Two main types of polyps are:
1) Hyperplastic polyps (90%)- non-neoplastic lesions, occurring mostly in the rectosigmoid colon.
2) Adenomatous polyps- true neoplasms, which are precursor lesions for adenocarcinoma. There is
a higher incidence of cancer in higher grade, larger polyps, and those containing a greater
proportion of villous growth:
a. Tubular adenomas (pedunculated)- 75%. Familial Adenomatous Polyposis
Can be sporadic of familial. Male to A genetically inherited (autosomal dominant)
female ratio of 2:1. Average age is 60. condition associated with a mutation in the APC
Mostly occur in the left colon. gene on chromosome 5. This predisposes to
multiple (hundreds) of colonic adenomas starting in
b. Villous adenomas (usually sessile)-
the rectosigmoid area, and eventually covering the
largest, least common polyp. 33% are
entire colon. This occurs during adolescence and
cancerous. Characteristic “cauliflower- early adulthood. Benign polyps undergo malignant
like” growth (1-10cm diameter). transformation usually in the 30s and 40s.
c. Tubulovillous adenomas Treatment is by total colectomy.

Morphology: The mucosal lining of adenomatous polyps show increasing architectural complexity and
cytologic atypia (ie: low and high grade dysplasia).

Adenocarcinoma
This malignancy accounts for 98% of all colon cancers. There is a high incidence in urban, Western
societies. It is the 3rd most common tumour in men and women. Most colorectal adenocarcinomas
appear to arise from villous adenomas, but are also associated with ulcerative colitis, Crohn’s disease,
and familial polyposis.

Risk factors include: age, prior colorectal carcinoma, familial/genetic predisposition and diet (low dietary
fibre, high fat and red meat).

Morphology:
 Macroscopic: tumours can be polypoid (protruding into the lumen), ulcerating (eroding into
surrounding structures) or infiltrative (spread within colonic wall). 75% occur in the rectum
or sigmoid colon.
 Microscopic: variable differentiation. Usually irregular glandular structures lined by atypical
columnar epithelium.
Spread:
 Direct invasion is usually into the mesentery and if the surface is breached, can involve adjacent
structures (small bowel, female genital tract, bladder)
 Lymphovascular invasion is common with metastasis to mesenteric lymph nodes followed by
the liver, lungs and bones.
Clinical features:
 May be clinically silent and rarely presents as an abdominal mass
 Rectal bleeding
 Change in bowel habits (constipation/diarrhoea)
 Obstruction - more common with left sided tumours; lumen is smaller and faeces more solid
 Perforation with peritonitis
 Fistula formation (eg: rectovaginal)
 Systemic symptoms related to malignancy – anorexia, malaise, weight loss, weakness.

Screening: Faecal Occult Blood Testing (FOBT) and subsequent colonoscopy/biopsy with patients that
test positive. This allows for early detection of precursor adenomas or early stage adenocarcinomas,
possibly improving the overall outcome.

Treatment:
 Surgical excision.
 Chemotherapy and radiotherapy: have a role to play, either before surgery to down size the
tumour or after surgery to decrease the likelihood of or palliate any recurrence.

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).

Acute Pyogenic
Morphology:
Pyelonephritis
 Macroscopic: kidneys have discrete yellowish and raised abscesses on their
surfaces. Often hyperaemic, usually unilateral.
 Microscopic: suppurative necrosis or abscess formation within the renal
parenchyma. Large masses of intratubular neutrophils.

Clinical: typical sudden onset pain at costovertebral angle. Chills, fever, malaise.
 Pyuria and bacteriuria, urethral irritation causes dysuria, frequency, urgency.
 Disease tends to be benign and self limiting even without antibiotic treatment.
 Predisposed by: obstruction, instrumentation, pre-existing lesion or VUR, females, pregnancy,
older males (prostatitis), immunosuppression.
 Diagnosis: finding leukocytes by urinalysis and urine culture.
Chronic Pyelonephritis
A clinical entity whereby interstitial inflammation leads to grossly visible scarring and deformity of renal
parenchyma and the pelvicalyceal system. Associated with urinary obstruction or reflux.

Pathology: divided into two forms based on cause.

 Chronic Obstructive Pyelonephritis: obstruction predisposes to recurrent infections → recurrent
bouts of inflammation and scarring → chronic pyelonephritis. Can be bilateral (eg. congenital
anomalies of urethra) or unilateral (eg. obstructive lesions such as calculi).
 Chronic Reflux Associated Pyelonephritis (reflux nephropathy): results from superimposition of
a UTI on congenital vesicoureteral reflux (VUR) and intrarenal reflux. Is more common, can be
unilateral or bilateral.
Chronic
Pyelonephritis
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.
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
Multifocal Renal Infarction
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.
Thrombotic Microangiopathies
Disorders characterised by fibrin thrombi in glomeruli and small vessels resulting in renal failure.
Common diseases causing these lesions include; childhood/classic haemolytic uraemic syndrome (HUS),
adult HUS (various forms), and thrombotic thrombocytopaenic purpura (TTP).

TTP HUS
Caused by defects in von Willebrand caused by endothelial injury by an E. coli toxin
factor (vWF) leading to excessive → activation and intravascular thrombosis.
thrombosis with platelet production (see  This disease is one the main causes of acute
cardio notes). Multiple thrombi renal failure in children.
throughout vasculature, including  25% of children eventually develop renal
kidney, result. insufficiency due to 20 scarring.

CYSTIC DISEASES OF THE KIDNEY

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

Autosomal Dominant (Adult) Polycystic Kidney Disease

Autosomal dominant disease characterised by multiple cysts in both kidneys that ultimately destroy the
intervening parenchyma. Accounts for 10% of chronic renal failure.

Pathology: mutations in polycystin molecule which is involved in cell-cell and cell-matrix

adhesion. It is thought that defects in cell-matrix interactions may lead to alterations in
tubular epithelial cells, and to cyst formation.
 Polycystin 1; PKD1 on Ch 16, accounts for 85-90% of mutations.
 Polycystin 2; PKD2 gene on Ch 4, implicated in 10-15% of cases.

Morphology: kidneys increase in size and are palpable abdominally.

 Cysts may arise at any level of the nephron, from tubules to the collecting ducts.
 Cysts are filled with fluid, which may be clear, cloudy or haemorrhagic. Adult ADPKD

Clinical: small cysts start to develop during adolescence, asymptomatic until around age 40yr.
 Most common presenting complaint is flank pain or a heavy dragging sensation.
 Typically leads to intermittent haematuria, hypertension and urinary infection.
 Complications: saccular aneurysms in Circle of Willis (10-30%), end stage renal failure (50yrs),
death usually results from uraemia or hypertensive complications.
Autosomal Recessive (Childhood) Polycystic Kidney Disease
Rare developmental defect of the kidney that is autosomal recessive.
 Pathology: caused by mutations in the PKHD1 gene coding for a membrane
receptor protein called fibrocystin.
 Morphology: many small cysts in the cortex and medulla giving the kidney a
spongelike appearance. Cysts originate from the collective tubules, nearly
always accompanied by cysts in the liver.
 Clinical: serious manifestations usually present at birth. Infants can due
quickly from hepatic and renal failure. Survivors develop liver cirrhosis.
Child ARPKD

Medullary Cystic Disease

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

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
Causes of Calcium Stones
by hypercalciuria but can be due to other metabolic abnormality,
Hypercalcuria (60%); ↑ gut absorption,
or even idiopathic. Favoured by ↑pH. ↓ renal reabsorption, hypercalcaemia
 Struvite (Magnesium Ammonium Phosphate) (15%) occur in (↑PTH, vit D etc).
persons with persistently alkaline urine due to UTIs. Urea splitting
Hyperuricosuria (20%); ↑ uric acid in
bacteria (eg. P. Vulgaris, Staph) predisposes persons to stones.
urine, promoting Ca deposition.
 Uric Acid Stones (6%) gout and diseases involving rapid cell
Hyperoxaluria (5%); hereditary ↑ in
turnover (eg. leukemia) lead to high uric acid levels in the urine
oxalate in urine.
and the possibility of the uric acid stones. Favoured by ↓pH.
 Cystine stones (1-2%) genetic defect in the renal transport of No known metabolic problem (15%)
cystine (AA) forming yellow, soft stone. Favoured by ↓pH.

Morphology: unilateral in 80% of cases, commonly in the renal pelvis, calyces, and bladder.
 Usually small (2-3mm), however progressive accretion of salts can lead to branching.
 Staghorn calculi; development of branching structures which create a cast of the renal
pelvicalyceal system.

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

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.
Hydronephrosis
 Polyuria (rather than oliguria) in bilateral incomplete obstruction due to
defects in tubular concentrating mechanisms.
 Return of normal function if obstruction is removed within a few weeks.

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

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

Nephroblastoma (Wilms Tumour)

Congenital malignant neoplasm derived from the mesoderm, 5% of renal cancers, major in children.

Pathology: involves mutations in Wilm’s tumour (WT) 1 and 2 genes on chromosome 7.

 Familial associations include WAGR syndrome (WT1), Denys-Drash Syndrome (WT1) and
Beckwith-Wiedemann Syndrome (WT2).
 Sporadic mutations in WT1 causes around 5% of Wilm’s tumours.

Morphology: begins in renal cortex and replaces entire kidney.

 Macroscopic: tan-grey, large and soft. Usually solitary well circumscribed mass.
 Microscopic: classic triphasic combination of blastema (small round blue cells), epithelial cells
and stromal/SM cells.

Clinical: palpable asymptomatic abdominal mass.

 Prognosis generally good with combination of nephrectomy and chemotherapy.
 If anaplasia is diffuse with extrarenal spread, prognosis is less favourable.

Other Renal Tumours

Urothelial Carcinoma of Renal Pelvis located in renal pelvis, 5-10% of renal cancers. May be multiple,
increased incidence with analgesic nephropathy. High grade infiltrative tumours (5 year survival of 10%).

Secondary kidney tumours have metastasised from other sites. Most common primary sites are lung,
skin, contralateral kidney, GIT and gonadal tumours.

Benign Kidney Tumours present in 25-50% of patients with tuberous sclerosis. May include renal
papillary adenoma, renal fibroma/hamartoma or angiomyolipoma.
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 Transitional Cell Carcinoma
metastases.
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 Inflammation of inner surface of prepuce (posthitis) usually accompanied by
(balanitis) inflammation of adjacent surface of glans penis (balanitis).
o Often associated with a tight prepuce (phimosis).
o Due to secondary infection of smegma by pyogenic bacteria.
NB: smegma is cheesy substance (exfoliatd epithelial cells, skin oils and moisture) that
can accumulate under male foreskin (prepuce) or vulva in females.
Phimosis Prepuce unable to be retracted, tightening up.
o Commonest medical indication for male circumcision.
Paraphimosis Tight prepuce retracted behind glans.
o Obstructs venous return → oedema
Balantis Involves thickened white plaques and fissures on glans and prepuce.
Xerotica o Non retractile prepuce or discharge.
Obliterans o Treated with circumcision.
(BXO) o Histology similar to lichen sclerosus of vulval skin.
o Usually 30-50yrs
Infections
Genital Herpes Is caused by HSV types 1 and 2, most genital tract lesions due to type 2 as STI.
o Itching followed by appearance of closely grouped vesicles surrounded by
erythema.
o Becomes latent for life and reactivates intermittently.
Genital warts Condyloma acuminatum lesion is caused by HPV.
o Commonest urogenital lesion.
o Infection with HPV types 6 and 11 (unlike warts
types 1, 2 and 4 in other parts of body)
o Histology: epidermis shows papillomatous
hyperplasia. Cytoplasmic vacuolation and
kiolocytes (keratinocyte squamous cell with
irregular and enlarged nuclei). Cytoplasmic
clearing at the periphery. Condyloma Acuminatum
NB: condyloma acuminatum is wart like growth with stalk base (planum is flat).
Found around anus, vulva, glans penis.
Syphilis Is caused by T. pallidum, with three distinct stages.
o Primary stage: chancre on penis, a painless ulcerated nodule with firm raised
boarders. Endarteritis with lymphocytes and associated lymphadenitis.
o Secondary stage: condyloma lata, generalised lymphadenitis.
o Tertiary stage: gumma (destructive granulomatous lesions), often in testis.
NB: second/tertiary stages not commonly seen due to antibiotic treatments when
detected.
Tumours of the Penis
Intraepidermal Carcinoma is full thickness dysplasia of epidermis with no stromal invasion.
 Carcinoma in situ with strong association with HPV infection.
 A sharply delineated red patch with moist keratotic patch (“erythroplasia of Queyrat” on glans).
 Significant risk of progression to invasive SCC.

Invasive Squamous Cell Carcinoma is a well differentiated, invasive tumour.

 Usually in the glans or inner aspect of prepuce → forms indurated nodule/plaque that later
ulcerates. Rarely develops on the outer surface of prepuce or shaft.
 Alost exclusively in uncircumcised men, HPV infection important cause.
 Rare in western countries, common in Africa/Eastern Asia.
 Invades corpus cavernosum, metastasises to inguinal lymph nodes.
NB: genitals drain to inguinal nodes, testis to para-aortic nodes

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 Characteristic classic triad of large tumour cells (with
Seminomas cytoplasmic clearing), fibrous tissue and lymphocytes
o The most common germ cell tumours (50% of all cases).
o May present with painless mass, 15% normal on
examination.
o 30% have metastasised at presentation, but rarely have
symptoms from these metastases.
o Serum AFP (alpha fetoprotein) normal, 10-20% have
↑ β-HCG (human chorionic gonadotropin).
Spermatocytic Occur only in testes (2% of germ cell tumours).
Seminomas o Consist of small, intermediate and large cells.
o Patients in their 50s and present with a mass.
o Very rarely metastasise.
o Usually cured with orchidectomy.
Non-Seminomatous Germ Cell Tumours (NSGCT)
Group of tumours which may arise from IGCN or seminomas.
Embryonal Ill-defined invasive masses with foci of haemorrhage and
Carcinoma necrosis.
o Second most common germ cell tumour (20% of cases)
and present in the majority of mixed GCT.
o Mostly 20-30yr men with testicular mass, very rare in
children and older men.
o >2/3 have metastasis, but only 10% symptomatic.
o Serum AFP normal, 60% have ↑ β-HCG.
Yolk Sac Tumour ‘Endodermal sinus tumour’ with multitude of histological patterns.
o Children: most common testicular cancer in children where
it occurs in pure form. Is usually diagnosed before
24months age.
o Adults: pure form rare, but found in 50% of mixed GCT.
o Usually presents with a mass, ↑ Serum AFP
o In children orchidectomy alone is curative in 90%.

Teratoma Tumour of all three embryonic layers (endo-, ecto-, meso- derms).
o Adults and children present with a testicular mass.
o Children: 2nd most common GCT in children, occurs in pure form, diagnosed
around 20months. Metastases don’t occur in children.
o Adults: component of mixed GCT, is identified in >50% of mixed tumours,
however still treated like a pure NSGCT. Metastasis occurs in adults.
Choriocarcinoma Very unusual pure form (<1% of germ cell tumours) which is bright red tumour
(highly vascular) and contains trophoblastic cells with nuclear atypia.
o Found in 15% of mixed GCT.
o Many patients present with symptoms related to metastases to lungs or
brain. ↑ serum β-HCG
o Does not develop in children.
o Poorer prognosis but tumour is chemosensitive.
Mixed Germ Cell Tumours (Mixed GCT)
Lesions composed of two or more germ cell tumour types. Comprises 33% of all GCT. Often consists of
seminoma and non-seminomatous components.
NB: Non-germ cell tumours are uncommon but include sex-cord stromal tumours (sertoli or leydig cell),
mixed tumours, haematopoietic tumours and secondary (metastasised) tumours.

Testicular Cancer Staging and Treatment

Staging is by common TNM classification, especially metastases; stage 1 (no
lymph nodes), stage 2 (lymph nodes), stage 3 (distant metastases). Those with
extratesticular extension are considered bulky (16% of cases, mostly at hilum).

Treatment depends on type and staging of tumours. All involve orchidectomy.

 Seminoma S1, non-bulky S2→ LN radiation. 90-95% cure rate.
Seminoma bulky S2, S3→ radiation, chemotherapy. 80% survival rate.
 NSGCT S1→ LN dissection. 90-95% survive, 10% relapse.
NSGCT S2 non-bulky→ LN dissection, chemo. Cure 90%.
NSGCT S2 bulky→ chemo and resection residual masses. Cure 70-80%.
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. CZ/TZ- Hyperplasia,
PZ- Carcinomas
 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).
Benign Prostatic Hypertension
o Begins in periurethral glands, compresses them.
o Multinodular proliferation surrounded by compressed
prostatic tissue (psuedocapsule).
o Nodules vary in appearance according to composition
(often cystic).
 Microscopic: hyperplasia may be glandular, muscular, fibrous or
mixed.
o Cystic dilation often prominent, containing secretions ±
corpora amylacea (calcified amyloid material in ducts).
o Often secondary inflammation, infarction (25%) or
squamous metaplasia.
o Glands have double epithelial lining; in carcinoma it’s single.

Clinical: prostatism which involves poor urinary stream, dribbling, frequency, nocturia etc.
 Rectal examination shows enlarged, nodular, soft, boggy gland.
 Late manifestations relate to urethral obstruction with urinary retention and infection.
 Very common, esp >50 (80% at 80 yrs). Common in Australia, USA, Europe but not in Asian
countries.
Tumours of the Prostate
Nearly all prostatic neoplasms are adenocarcinomas. Others are very rare, including transition cell
carcinomas, squamous cell carcinomas, sarcomas and lymphomas.
 Mostly >50yrs (average 75, 10-80% by 80 depending on definition).
 Incidence and death rate increasing (aging population, better diagnosis). Over 1000 new
cases/yr in WA. 2nd highest cause of cancer death in men.
 Common in developed countries, low in Asia.

Pathology:
Prostatic Adenocarcinoma
 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 Cancer Staging Prostatic Cancer Grading Prostate Specific Antigen

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

Benign Cervical Processes

Benign Reactive Processes are common with uterine prolapse.
 Hyperkeratosis: is abnormal epithelial keratin
formation. Can also be parakeratosis (keratosis with
maintained nuclei).
 Cervicitis: may be noninfectious or infectious which are
difficult to distinguish due to commensal
microorganisms normally in vagina.
 Tubule metaplasia/endometriosis: result in uterine like
endometrial glands or stroma in the cervix.
Benign Lesions these can be polypoid, papillary or cysts.
- Endocervical/Endometrial Polyps: surface projections
which may bleed
- Nabothian Cysts: endocervical crypts get blocked
leading to a buildup of mucous, form a cyst-like dilation
in the endocervix.
- Condyloma Accuminatum: stalk based papillary lesion
caused by HPV infection.
Infectious Cervicitis
May occur due to a number of organisms:
 Human Papilloma Virus (HPV) is most
important due to carcinogenic effects.
 Other causes are Candida, Trichomonas,
Neisseria, Gardnarella, Chlamydia, HSV,
CMV and Tuberculosis.
Condylomatous Lesions
Caused by HPV infection.
 Condyloma Accuminatum: benign papillary
lesions with fingerlike projections in the
cervix (also vagina, vulva). Seen on
colposcopy. Generally self limiting.
→ HPV 6 or 11
 Condyloma Planum: flat wart with
oncogenic potential for cervical carcinoma
(if HPV 16 or 18).
→ HPV 6, 11 or 16, 18 (more).

Carcinomas of the Cervix

Cervical cancer is the commonest cause of cancer death in women in 3rd world countries.
 Highest rates in Africa, South America, Southeast Asia and Aborigines.
 Becoming ‘rare’ in countries with long established cervical/papsmear screening.
 Mean age of 52 years, 20% of cases <35 years.
Pathology: human papilloma virus (HPV) is responsible for all (>99%) HPV-Cervical Cancer Relationship
cases of cervical carcinoma. The virus works by triggering alterations
HPV is a papillovirus of a large family
in cervical epithelial cells → cervical intraepithelial neoplasia (CIN) → with around 150 identified types.
cervical cancer. These can cause warts, or lead to the
 E6 and E7 are the principle ‘transforming’ genes of HPV development of cancer. Cancer is only
causing neoplastic cellular changes. associated with HPV 16, 18, 31, 33
o E7 interacts with the tumour suppressor Rb gene, (HPV HR).
blocks proliferation-inhibitory function of cervical cells However, despite HPV HR being the
(↑p16, ↓p21). strongest risk factor for cancer, these
o E6 interacts with p53 tumour suppressor gene to infections are extremely common and
enhance E7’s effect. are usually self limiting (80% disappear
within a year). Higher risk is associated
 Cervical carcinomas are associated with latent HPV of ‘high
with persistent infection with HPV.
risk’ (HPV HR), most commonly HPV 16, 18 (90%), 31, 33.
Ie. Most women with HPV HR don’t
 Other risk factors include smoking, immunosuppression (more
get cancer, but most cervical cancers
prone to persistent infection), number of sexual partners,
are caused HPV HR.
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.

Precursor Identification and Management

 Pap Smear: an effective screening test. It
identifies abnormal lesions and grades. Low Grade
lesions → monitor with repeated pap smear.
Detection of high grade lesions → colposcopy and
biopsy.
 Colposcopy: a magnified visual inspection of
cervix aided by using acetic acid (vinegar) solution
to highlight abnormal cells. Identifies exact site
and extent of lesion.
 Directed Punch Biopsy: produces an exact
diagnosis. Confirmed high grade lesions →
LLETZ/cone biopsy.
 LLETZ (Large Loop Excision of the Transformation
Zone): removal of high grade cervical dysplasia.
 Cone Biospy: removal of larger abnormal areas of
cervical epithelium.
Invasive Cervical Carcinoma: invariably result from HSIL.
 Squamous Cell Carcinoma (60-80%) are microinvasive
lesions (<5mm into stroma) with various distinctive
patterns. Most common, well controlled by papsmears.
 Adenocarcinomas (20%) and Adenosquamous Carcinomas
(5%) have precursor/in situ stages (AIS). Most are HPV
related but papsmears have not been an effective control,
hence increasing in relative frequency.
 Small Cell Carcinomas are high grade, aggressive
neuroendocrine lesions with metastases to endometrium,
Squamous CC Adenocarcinoma
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 Staging and Prognosis

vaccination. Staging (FIGO) is rated 0-4, with
 Pap Smear: associated with ↓ 70% in 25yrs. Can potentially prognosis given in 5 yr survival %.
0- In situ, CIN 3 (100%)
prevent 90% of cancers.
1- Confined to cervix (90-95%)
 HPV DNA Vaccine (Gardasil): for HPV 6,11,16,18. Effective
2- Uterus, not pelvic wall (50-70%)
before infection with HPV and is suitable for young girls/women. 3- Pelvic wall, lower vagina (30%)
4- Distant metastases (20%)

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.
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. Adenomyosis

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 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. Endometrial Carcinoma

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.
 Endometrial Cancer Staging
Clinical: usually in post menopausal women (although it can occur at
Stage 1: confined to uterus
any age). Often confined to the uterus at diagnosis, with
(subdivided according to depth of
 Treatment: hysterectomy ± bilateral salpingo-oophorectomy
myometrial invasion).
(removal of ovaries and fallopian tubes). Lymph node
Stage 2: extension to cervix.
dissection ± omental sampling in high risk cases.
Stage 3: Invasion of serosa, adnexae
→ postoperative radiotherapy/chemotherapy.
or positive peritoneal cytology.
 Prognosis: depends on staging, however overall good
Stage 4: bladder/bowel invasion or
prognosis, 80-90% 5 yr survival.
distant metastases.

Mesenchymal Tumours
Refers to several malignancies arising from the stromal components, which are usually benign.

Smooth Muscle Tumours are very common, and mostly benign.

 Leiomyomas (fibroid) are benign lesions, vast majority of uterine SMT.
Often multiple and typically hormone dependent, tend to grow in
reproductive age group.
 Leiomyosarcomas are malignant lesions, <1-2% of uterine SMT.
Aggressive tumours with rapid growth, especially post-menopausal.
Characterised by increased cellular atypia, mitotic activity and tumour
necrosis. Not responsive to therapy (<50% 5 year survival). Leiomyoma

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%).
Ovarian Tumours
Tumours of the ovary are amazingly diverse, attributable to the diverse cell types. Ovarian tumours are
classified into three groups based on these different cell types; (i) surface epithelial, (ii) germ cell and (iii)
sex cord stromal tumours.

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

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). Benign Cystic Teratoma
3. Sex Cord Stromal Tumours: (5-10%) relatively uncommon stromal tumours that are mostly benign.
 Thecoma-fibroma consist of solid grey fibrous cells to yellow (lipid laden) thecal cells.
 Granulosa-thecal cell tumours consist of granulosa and thecal cells with cystic spaces.
o 3-5% of ovarian malignancies, usually post menopausal. Often with oestrogenic
release (can lead to endometrial/breast cancer).
o Late metastases common.
 Sertoli-Leydig cell tumours (androblastomas) result in androgen
production and virilism.
 Many are low grade (granulosa and sertoli tumours) and may present
with effects of hormone secretion. Androblastoma

Clinical Presentation of Primary Tumours

Clinical presentation of all ovarian tumours is similar despite their morphological diversity,
Usually asymptomatic until large enough to cause local pressure problems.
-Exception: functioning neoplasms with hormonal effects (eg. granulosa-thecal tumour).
Patients can present with palpable abdominal/pelvic mass, abdominal swelling (tumour,
ascites), GIT symptoms (diarrhoea, constipation), vascular obstruction (DVT, oedema) or distant
metastases.

NB: although germ cell/stromal cell tumours make up around 30% of tumours, they are only
responsible for <10% of malignant tumours as most are benign.

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

Fallopian Tube Pathology

Salpingitis is usually due to ascending infection of the genital tract.
 Can be acute or chronic with variable microbiology.
 Inflammatory infiltrate and fibrosis can lead to serosal adhesions distorting the fallopian tubes
→ adhesions can cause hydrosalpinx, due to obstruction → infertility.
Ectopic Pregnancy is very common (1/80), with the fallopian tubes being the most common site.
 Signs/symptoms include pain, post vaginal bleed, and positive pregnancy test.
 Increased risk with tubule abnormality (salpingitis, endometriosis)
 Ultrasound diagnosis, may be surgical emergency due to acute bleeding into peritoneal cavity.

Tumours of Fallopian Tube are uncommon, malignancies rarer, but incidence depends on definition.
 Some ovarian and peritoneal carcinomas may arise in the fallopian tube (and perhaps previous
ovarian primaries are instead secondary to fallopian carcinoma).
 Increased risk with BRCA 1 patients.
 Usually serous carcinomas, may spread even when in-situ.

Tumours of the Peritoneum most are metastatic (GI, biliary, cervical, uterus etc), primary malignancies
include mesotheliomas and carcinomas.
 Most primary carcinomas are high grade serous carcinomas (similar appearance, behaviour and
treatment similar to ovarian serous carcinoma).
 Diagnosis of exclusion, increased risk in BRCA 1 mutation
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.
Fibro-cystic Change

Epithelial Hyperplasia proliferative lesions within the ductules, terminal ducts and lobules. Can be typical
or atypical (similar to ductal carcinoma in-situ).
 Lumen filled with heterogenous cells of different morphologies, with irregular slit-like
fenestrations, esp at periphery.
 Atypical hyperplasia is associated with 5x risk of carcinoma (10x with family history).

Sclerosing Adenosis lesion with proliferation of ductule and acini cells, aggregation of proliferating
ductules (adenosis), and marked intralobular fibrosis (sclerosing).
 Can be clinically and morphologically similar to invasive ductal carcinoma.
 Hard, rubbery consistency similar to cancer, associated with 1.5-2x risk of carcinoma.

Normal Duct Epithelial Hyperplasia Sclerosing Adenosis

Inflammations
Inflammations of the breast are uncommon, causing pain and tenderness in the involved areas during
the acute stages. Not all inflammations increase risk of cancer.

Acute Mastitis develops when bacteria gains access to the breast tissue through ducts.
 Can occur when there is; thickening of secretions, fissures in the nipples (nursing), or various
forms of dermatitis involving the nipple.
 Usually Staphylococcus, can induce abscess formations which heal with scarring (hardened areas
within breast).
 Rarely due to Streptococcus, which causes a spread out infection of entire breast, with pain,
swelling and tenderness.

Mammary Duct Ectasia (periductal or plasma cell mastitis) is a non-bacterial chronic inflammation of the
breast. Associated with thickening of breast secretions in the main excretory ducts.
 Ductal dilation with rupture leads to inflammatory changes in the
surrounding breast tissue.
 Characterised by lymphocytic/plasma cell infiltration and granulomas in
periductal stroma.
 Uncommon, generally occurring in 40s and 50s.
 Lesions cause hardening on the breast and retraction of the skin and
nipple, mimicking changes caused by carcinomas. Mammary Duct Ectasia

Traumatic Fat Necrosis is an uncommon and innocuous lesion producing a mass, often associated with
preceding trauma to the breast.
 Lesions are small (<2cm), tender and sharply localised. Have central focus of necrotic fat cells
surrounded by neutrophils and lipid filled macrophages.
 Focus replaced by scar tissue or debris encysted in scar capsule. Calcification may then develop.

Benign Tumours
Fibroadenoma most common neoplasm of female breast, composed of fibrous and glandular tissue.
Usually occurs in young females.
 Lesions are discrete, firm, freely moving nodules (1-10cm).
 Usually solitary, but can be multiple/bilateral.
 Development of these lesions is associated with an increase in oestrogen.

Phyllodes Tumor much less common, thought to arise from periductal stroma and not from pre-existing
fibroadenomas.
 Lesions may be small, but many grow very large, distending the breast.
 Usually benign, localised and cured by excision.
 Malignant lesions usually remain localised, except the most malignant (15%) do metastasise.

Intraductal Papilloma a solitary neoplastic papillary growth within a lactiferous duct/sinus.

 Intraductal papilloma presents clinically as (i) serous or bloody nipple discharge, (ii) presence of
small subareolar tumour, or (iii) nipple retraction (rare).
 Intraductal Papillomatosis involves multiple papillomas in several ducts, sometimes malignant.
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).
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.

Hormonal Influences
Hormonal imbalance plays a significant role. Oestrogen stimulates growth factor production by
epithelial cells. If epithelial cells are neoplastic, this production can be exaggerated, leading to an
autocrine mechanism of tumour development.
 Increased exposure to oestrogen peaks during the menstrual cycle.
o Long duration of reproductive life (menarche to menopause), late age of pregnancy, and
nulliparity (no previous pregnancy).
 Prolonged exposure to exogenous postmenopausal oestrogens (ie. HRT)

Environmental Influences
 Age: rare under 30, however risk increases with age and plateaus after menopause.
 Geography: risk much greater in Western countries, due to environmental factors such as diet,
reproductive patterns, and nursing habits.
 Previous Breast Lesions: in order of risk; proliferative lesions, atypical proliferative lesions,
ductal/lobular carcinoma in situ.
 Ionising Radiation: to the chest increases risk depending on dose and duration. Only women
irradiated before 30, during breast development, seem to be affected.
 Lifestyle Factors: obesity, alcohol, high fat diet; are all less well established factors.
Morphology: Breast cancers are classified into those that have not yet penetrated the limiting basement
membrane (non-invasive) and those that have (invasive).
Non-Invasive Carcinomas
Two types of breast cancers both of which arise from the terminal duct lobular unit.
 Ductal Carcinoma In-Situ (DCIS) is a neoplastic epithelial
Paget’s Disease of the Nipple
proliferation, precursor to invasive ductal carcinoma. Is
Caused by the extension of DCIS up to
typically found on mammographic examination as
the lactiferous ducts and adjacent to
calcifications or a mass. the skin of the nipple. Presents as a
o Classified by growing pattern (solid, cremedo, unilateral crusting exudate over the
cribiform, papillary, micropapillary) nipple and the areolar skin. An
o Graded as low (monotonous nuclei) or high underlying invasive carcinoma may be
(pleomorphic) grade. present, and prognosis is based on the
o Risk and rate of DCIS progression is thought to be underlying carcinoma.
proportional to grade (ie. low grade DCIS → slower
progressing, low grade IDC).
o Prognosis is very good (>97% survival with
mastectomy ± radiation therapy, Tamoxifen).
o When invasive cancer develops, it is usually in the
Paget’s Disease
same breast and of ductal histology.

 Lobular Carcinoma In-Situ (LCIS) is an expansion of the lobules by discohesive, bland neoplastic
cells. This lesion is frequently an incidental finding and doesn’t form masses or calcification.
o Approximately 1/3 of women with LCIS will develop invasive carcinoma.
o When invasive carcinomas develop, it occurs in either breast with the same frequency,
and may be lobular or ductal carcinoma.

Invasive (Infiltrating) Carcinomas

 Invasive Ductal Carcinoma (IDC) (80%) replaces normal breast fat,
forming a hard palpable mass with abundant fibrous stroma (hence
also called ‘Scirrhous carcinoma’).
o Usually associated with DCIS, rarely LCIS
o Invasion of lympho-vascular spaces along nerves.
o 2/3 express ER and PR, 1/3 over-express HER2.

 Invasive Lobular Carcinoma (LCIS) (10%) consist of cells

Ductal Carcinoma Breast Carcinoma
morphologically identical to cells of LCIS.
o Metastasize to CSF, serosal surfaces, GIT, ovary, uterus, Inflammatory Carcinoma
and bone marrow. A clinical presentation of an
enlarged, swollen and
o Mainly multicentric and bilateral. Express ER/PR receptors.
erythematous breast, usually
 Others: there are some relatively uncommon special types of without a palpable mass.
invasive carcinoma, most being rare variants of IDC . o Clinical appearance is due to
o Invasive tubular carcinoma small palpable masses (<1cm) blockage of dermal lymphocytic
seen on mammogram. Well formed tubules. spaces by carcinoma.
o Medullary Carcinoma sheets of large anaplastic cells, may o Underlying carcinoma is
generally poorly differentiated
be mistaken for fibroadenomas.
and diffusely invades the breast
o Colloid (Mucinous) Carcinoma produce abundant
parenchyma.
quantities of extracellular mucin which invades stroma. o Distant metastasis → poor
o Metaplastic and squamous carcinomas (poor prognosis). prognosis.
Clinical: the most important clinical consequence is lymphatic and Tumour Locations
haematogenous spread. Breast cancers affect the left breast
 Outer quadrants and centrally located lesions typically slightly more. About 4% of women
spread first to the axillary nodes. with breast cancer have bilateral
primary tumours or sequential lesions
 Inner quadrants often involve the lymph node along in the same breast. Locations of the
internal mammary arteries. tumours within the breast are:
 Metastases can occur in any organ, but most common in  Upper outer quadrant (50%)
lung, bone marrow, liver, adrenals and (less commonly) the  Central Portion (20%)
brain and spleen.  Lower outer quadrant (10%)
 Metastases may appear many years after apparent  Upper inner quadrant (10%)
therapeutic control of the primary lesion (decades).  Lower inner quadrant (10%)

Prognosis: 20% mortality which is influenced by the following variables.

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

Male Breast
Gynocomastia enlarged male breast which may occur in response to oestrogen excess.
 Associated with liver cirrhosis (inability of liver to metabolise oestrogen), oestrogen secreting
tumours, oestrogen Therapy, and anabolic steroids
 Physiologic gynocomastia often occurs in puberty and old age.

Male Breast Carcinoma is uncommon, 120x less likely than females, mostly in the elderly.
 Associated with BRCA2 mutations, Klinefelter syndrome, excess oestrogen, obesity, and
testicular abnormalities.
 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 Intracellular edema of keratinocytes, often seen in viral infections.
(ballooning)
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
 Lichen planus and variants
 Lichenoid drug reactions
 Lichenoid keratosis
 Erythema multiforme, FDE
 GvHD
 Lupis erythematosus
 Dermatomyositis
 Pityriasis lichenoides
Psoriasiform
 Psoriasis
 Lichen simplex chronicus
 Pityriasis rubra pilaris
 Parapsoriasis
 Mycosis fungoides (T cell
lymphoma)
 Secondary to infections
 etc
Reaction Histology
 Characterised by epidermal basal layer Lichen planus
damage  Hyperkeratosis
 Basal vacuolar change or cell death  Epidermal hyperplasia: saw tooth pattern
 Accompanying inflammatory infiltrate  Wedge shape hypergranulosis
o Lymphocytes  Band like lichenoid inflammatory infiltrate
o Histiocytes  Basal vacuolar change with Civatte bodies
o Eosinophils  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
 Regular epidermal hyperplasia with Psoriasis
elongation of the rete ridges  Regular epidermal hyperplasia (acanthosis – thickening)
 Increase mitotic activity  Elongated club-shaped rete ridges
 Accompanying inflammatory infiltrate  Parakeratosis (scale)
o Lymphocytes  Mild spongiosis
o Histiocytes  Superficial dermal perivascular lymphocytic infiltrate
o Polymorphs  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
Vesiculobullous
 Pemphigus foliaceus
 Spongiotic vesicular disease
 Pemphigus vulgaris
 Bullous pemphigoid
 Epidermolysis bullosa
 Erythema multiforme
 Dermatitis herpetiformis
 Subcorneal pustular dermatosis
 Porphyria cutanea tarda (PCT)
 Intraepidermal and intercellular oedema
 ‘eczematous reaction’
 Associated inflammatory infiltrate
 Intracorneal and subcorneal
 Intraepidermal
 Suprabasilar
 Subepidermal
o subclassified according to the
inflammatory infiltrate
 Miscellaneous
dermatitis
 Intracellular oedema within epidermis (spongiosis)
 Lymphocytic exocytosis
 Intra-epidermal collections of langerhans cells
 Superficial perivascular lymphocytic infiltrate with some eosinophils
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  Chronic dermal inflammation with Granuloma annulare
 Necrobiosis lipoidica histiocytes or epithelioid histiocytes  Dermal necrobiotic granulomatous reaction
 Sarcoidosis o Sarcoidal, TB granulomas  Well circumscribed foci of necrobiosis surrounded by palisade of
 TB, leprosy, syphilis o Necrobiotic granulomas epithelioid histiocytes and multinucleated histiocytes and patchy
 Fungal infections o Suppurative granulomas lymphocytic infiltrate
 Foreign bodies etc o Foreign body granulomas 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  Non-inflammatory purpuras Leukoclastic vasculitis
 Disseminated intravascular  Vascular occlusive diseases  AKA hypersensitivity vasculitis
coagulation  Uticarias  Affects small vessels in the superficial dermis
 Uticaria  Vasculitidies  Fibrinoid necrosis
 Vasculitidies (leukoclastic,  Neutrophilic dermatoses  Swollen endothelium
lymphocytic)  others  Perivascular lymphocytic infiltrate, nuclear dust and RBC extravasation
 Sweet’s syndrome Hereditary angioedema
 Hypersensitivity  Decreased of dysfunctional esterase inhibitor leads to increased kinin
 Henoch Scholein purpura 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 Neurofibromatosis:
 Hemangioma  NF1 (classic) 1:4000 Chr 17
 Neural tumours  NF 2 (central acoustic) 1:50 000 Chr 22
 Lipomas  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  Most common skin tumour  Sun exposure (UV-B)  Multifocal superficial
carcinoma  70% all skin malignancies  Radiation, X-ray exposure  Nodular
 BCC:SCC = 5:1  Thermal burns  Infiltrating
 Sun exposed skin of fair individuals  Pre-existing organoid naevi, epidermal naevi  Morphoeic
 80% head and neck  BCC naevus syndrome  Mixed
 Male, older patient  Xeroderma pigmentosum  Other
 Most slow growing (some  Arsenic poisoning  (Tumour cells can resemble epidermal
aggressive)  Stasis dermatitis of the legs basal layer)
 Metastasis rare  PUVA therapy for psoriasis
 Transplant, AIDS and immunosuppressed
Squamous cell  Second most common skin  Sun exposure (UV-B)  Similar to SCC from other sites
carcinoma malignancy  Chronic ulceration  Malignant squamous cells with dermal
 Sun exposed areas of fair skinned  Trauma, Burns, Frostbite invasion
individuals  Fistula tracts, pilonidal sinus  Dyskeratosis, acantholysis
 Most arise in the head and neck,  Hidradenitis suppurativa  Spindle cell, verrucous, adenosquamous
dorsum of hands, vermillion  Marjolin’s ulcer variants
border  Dystrophic epidermolysis bullosa
 Lichen sclerosus etc
Malignant  Malignant melanoma of  Increased sun sensitivity (pale skin, blond/red hair,  Lentigo maligna melanoma (5-15%)
melanoma melanocytes freckles, poor tan  Superficial spreading melanoma (50-70%)
 Qld highest rate in world  History of painful or blistering sunburns during  Nodular melanoma (15-35%)
55.8/100000 childhood or adolescence (2 or more before 20)  Acral lentigonous melanoma (5-10%)
 Lifetime risk 1/87  Intermittent intense sun exposure  Desmoplastic, neutropaenic melanoma
 4.6% male mortality  Dysplastic naevi  Unclassified histo types
 Others- genetics, PVC, xeroderma pigmentosum
  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  Measures tumour volume  SIZE mm  5 year survival %
thickness according to the  Vertical measure from the granular layer of the epidermis to the  < 0.76  98
method of Breslow, deepest part of melanoma  0.76-1.49  96
measured to the nearest  One dimensional estimate of the tumour bulk or tumour volume  1.5-2.99  86
0.1mm  Most accurate yet imprecise guide to the behaviour of some  3.0-3.99  79
melanomas (thin melanomas that metastasise  4<  58
Clark level of invasion  anatomical compartment LEVEL Level of invasion
 Provides useful prognostic information in melanoma arising in very I Intraepidermal in situ
thick or very thin skin and in thin melanomas II Invasion of papillary dermis
III Invasion/expansion of papillary dermis
IV Invasion of reticular dermis
V Invasion of subcutaneous layer
Completeness of excision  Entire tumour must be thoroughly sampled
 Margins examined for the presence of invasive melanoma, in situ
melanoma and other atypical melanocytic lesions
Microscopic measurement
of margins of excision
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 Hypogonadism
or menstrual irregularities
TSH Very rare – causes hyperthyroidism Hypothyroidism
Plurihormonal GH + PRL with other combos – probably Panhypopituitarism (Simmond’s disease
common eg. Sheehans syndrome)
ADH Inappropriate ADH secretion Diabetes insipidus
Pathological Hyperplasia (primary or secondary to Surgery, tumour destruction of >75% of
Lesion ectopic promoters of secretion), gland, ischaemia (eg. Sheehans
Neoplasia syndrome), inflammation, hypothalamic
lesions etc.

Anterior Hyperpituitarism
Pituitary Adenomas
Most common cause of hyperpituitarism is an isolated adenoma in the anterior
lobe (3% are associated with MEN-1). Found in 20% of population post-mortem,
represent about 15% of all intracranial neoplasms, most non-functioning and
benign. Mutation of the GNAS1 gene, which results in continual activation of Gs-
protein is a common cause. Pituitary Adenoma
They are classified on basis of cell type, function and size:
 Cell type: based on immunohistochemical stains of hormone(s) produced by neoplastic cells.
 Function: can be clinically functional (clinical symptoms due to hormone excess), silent
(hormone production demonstrated without clinical manifestations) or hormone negative (no
hormone specific differentiation demonstrated, rare).
 Size: microadenoma (<1cm) or macroadenoma (>1cm). Note that silent/hormone negative
adenomas tend to be larger when diagnosed as they usually come to clinical attention at a later
stage (eg. after mechanical symptoms).
Most functional pituitary adenomas consist of one cell type and produce one hormone, although there
are exceptions. Clinical symptoms vary according to type of cells involved:
Type of Adenoma Clinical Manifestations
Prolactinoma -Most common hyperfunctioning pituitary adenoma resulting in
amenorrhea, galactorrhea, loss of libido and infertility.
-Often composed of chromophobe cells (lack of granules/staining).
-Stalk effect; condition can be caused by compression of stalk which
prevents dopamine from inhibiting prolactin release
GH-producing -Somatotroph adenomas are second most common, often plurihormonal
Adenoma with prolactin.
-Gigantism occurs when excess secretion occurs before epiphyses close
resulting in hepatic secretion of ILGF-I and hence increased body size with
disproportionate long arms and legs.
 -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 -Excess ACTH results in Cushing’s disease (hypercortisolism) which can
Adenoma occur from other sources (see below).
Thyrotroph Adenoma -Rare cause of hyperthyroidism (see below)
Gonadotroph -Difficult to recognise due to lack of clinical syndrome.
Adenoma -Usually detected later when mass (eg. impaired vision, headaches) or
hypopituitary effects (pressure invasion) occur.
Non-functioning and -Usually detected later when mass (eg. impaired vision, headaches) or
Hormone negative hypopituitary effects (pressure invasion) occur.

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

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

Posterior Pituitary Syndromes

Abnormal oxytocin synthesis and release has not been associated with any significant clinical
abnormalities. Important syndromes of the posterior pituitary involve ADH production.
 Syndrome of inappropriate ADH (SIADH) secretion is ADH
Diabetes Insipidus
excess caused by local injury to hypothalamus or extracranial diseases
Diabetes insipidus is an ADH
(usually ectopic production in the lung). Results in hyponatraemia and
related disorder that causes
diabetes like symptoms cerebral oedema (neurologic dysfunction). No peripheral oedema.
(polyuria, polydipsia).  ADH deficiency (diabetes insipidus) can occur from damage to
Central form is a result of ADH pituitary by trauma, infection/inflammation, surgery or tumours. 30%
deficiency due to various causes. of cases are familial. Loss of ADH causes failure of water resorption by
Nephrogenic form is caused by the renal tubules resulting in abundant dilute urine (polyuria),
renal tubular unresponsiveness excessive thirst (polydipsia) and increase serum sodium/osmolality.
to ADH.
THYROID GLAND PATHOLOGY
Hyperthyroidism
Hyperthyroidism is the most common cause of thyrotoxicosis (increased T3/T4) although the terms are
used interchangeably.

Grave’s Disease (Primary Hyperplasia/Goitre)

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)
The most common cause of hyperthyroidism (85%),
especially in young females with HLA-B8 and –DR3 gene
haplotypes (define which antigens detected by Tcells).
Pathology: It is an autoimmune disorder caused by IgG
antibodies (TSI, TGI, TBII are also immunoglobulins) that bind
the TSH receptor and mimic TSH action resulting in diffuse
hyperplasia/hypertrophy of follicles and lymphoid infiltrates.
Clinically: triad of thyrotoxicosis (follicle hyperplasia),
opthalmopathy (exophthalmos, lid lag) and dermopathy
(pretibial myxoedema).

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

Hypothyroidism Thyroid Atrophy

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).

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).
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.
 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.
Benign
Note: haemorrhage, cysts, scarring and calcification in nodular goitre. Multinodular Goitre

Causes: often endemic iodine deficiency, goitrogens (cabbage, turnips, CaCl2, cyanates, iodides etc.),
metabolic defect or Grave’s disease (see above).

Clinical Manifestations: dominant symptoms caused by mass effects (eg. airway obstruction, dysphagia,
vessel compression, cosmetic problems).
 If goitre is insufficiently compensating for iodine deficiency hypothyroidism will result.
 Other goitres are hyperfunctioning (toxic) resulting in hyperthyroidism.

Thyroiditis
Thyroiditis encompasses a diverse group of disorders characterised by some form of thyroid
inflammation.
Hashimoto’s Disease
Chronic lymphocytic (Hashimoto) thyroiditis is most
common cause in populations with sufficient iodine. It
occurs at any age, being more common in females.
Pathology: HLA-DR5 and HLA-DR3 associations (define
Tcell antigen recognition). Deficient suppressor Tcells
permit development of variety of auto-antibodies.
Overall effect is depletion of thyroid epithelial cells and
mononuclear cell replacement (Hurthle cells). Rare
atrophy and fibrosis.
Clinically: usually hypothyroidism, however may be
hyper (transient) or euthyroidism. Associated painless
enlargement. Slight increase risk of lymphoma,
carcinoma.
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.
Non Specific Forms
 Infective thyroiditis: invasion results in
acute illness with severe thyroid pain.
 Palpation thyroiditis: caused by vigorous
clinical palpation of gland resulting in follicular
disruption associated with chronic inflammation
(however no abnormalities).
Specific Forms
 Hashimoto disease:
autoimmune disease, most common
cause in populations with sufficient
iodine.
 De Quervain’s disease: self
limiting disease, probably secondary
Hashimotos Disease
to viral infection.
 Reidel’s struma: rare idiopathic (likely
autoimmune) disease with extensive fibroses
involving the thyroid and neck structures. Thyroid
becomes hard and fixed.
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.

Thyroid Carcinoma
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.
 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.
Parathyroid Adenomas Parathyroid Hyperplasia Parathyroid
Typically solitary (if multinodular, Primary hyperplasia typically involves Carcinomas
hyperplasia suspected). Most in all glands. Very rare with variable
inferior glands (may be ectopic sizes. Diagnosis is
Pathology: mainly chief cells with
and hard to locate). difficult as it requires
nodular pattern (polyclonal origin).
Pathology: usually chief cell type Hyperplastic chief cells completely evidence of invasion ±
with monoclonal origin. Most are replace fatty tissue normally preset in metastasis. Normally
sporadic, 25% of these have adult parathyroid. May be familial slowly progressive.
similar Ch11 mutation to familial (associated with familial Ch11 gene
forms. Rarely associated MEN 1. loss and MEN 1).

 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
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 -Combination of peripheral resistance to
the progressive destruction of islet β-cells insulin and inadequate pancreatic
in pancreas response (β-cell dysfunction)
-Leads to “absolute insulin deficiency” -Leads to “relative insulin deficiency”
Clinical -Accounts for 10% of cases -Accounts for 80-90% of cases
-Early onset (<20yr) -Late onset (>30yr)
-Normal weight -Obese (part of metabolic syndrome)
Biochemical -Insulin levels low -Insulin can be normal (high early)
-Antibodies to islet cells -No islet auto-antibodies
-Ketoacidosis common -Ketoacidosis rare
-Association with HLA-DR3/4 -Polygenic inheritance
Pathology -Non specific T-cell/cytokine insulates -Variety of genetic defects and obesity
often with auto-antibodies against β- contribute to insulin resistance.
cells. -β-cell dysfunction means inability to
-Later atrophy, fibrosis and β-cell adapt to peripheral resistance.
depletion/degranulation. -Islet amyloidosis and degeneration at
later stages.

A variety of monogenic and secondary causes make up the remaining causes of diabetes:
 Diseases of the pancreas; haemochromatosis, pancreatitis, neoplasms
 Endocrine diseases; Cushing’s, Acromegaly, hyperthyroidism, phaeochromocytoma
 Others; genetic defects, infections, carcinoid syndrome, drug-induced, gestational
Clinical Manifestations
The clinical manifestations of diabetes include;
 Polyuria; glycosuria induces osmotic
dieresis
 Polydipsia; renal water loss combined with
hyperosmolarity
 Polyphagia; increased protein and fat
metabolism
 Weight loss (without appetite loss),
 Fatiguability
 Clinical signs of diabetes related
complications (see below).
Diagnosis
If a patient is suspected of diabetes from such
clinical signs then a diagnosis is confirmed
based on blood glucose tests:
 Random blood glucose conc. >11mmol/L,
with classical signs/symptoms
 Fasting glucose conc. >7mmol/L, on more
than one occasion
 OGTT with glucose conc. >11mmol/L, 2hrs
after carbohydrate load on more than one
occasion

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

Adrenocrotical Adenoma Metastatic Adrenal

(arrow is remaining tissue) Adrenocrotical Carcinoma Adrenal Carcinoma Necrosis (bilateral)

Adrenocortical Hyperfunction (Hyperadrenalism) Cushing Disease

Hypercortisolism (Cushing Syndrome) Specific form of Cushing syndrome
Conditions that cause excess glucocorticoid levels: (hypercortisolism) which is secondary
 Exogenous/ iatrogenic administration is most common cause to primary hypothalamic-pituitary
 Cushing disease (secondary to pituitary disease) is most disease.
common endogenous cause In majority of cases the pituitary gland
contains ACTH producing adenoma. In
 Primary adrenal hyperplasia, adenoma, carcinoma (ACTH
remaining patients corticotroph
independent hypercortisolism)
hyperplasia is the cause.
 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.
Adrenogenital Syndromes
Conditions that cause excess release of androgens from adrenal cortex. This can occur as a pure
syndrome or as a component of Cushing disease. The adrenal causes of androgen excess include:
 Adrenocortical neoplasms, usually carcinomas
 Congenital adrenal hyperplasia (CAH), a group of congenital disorders that result in enzyme
defects which affect steroid biosynthesis (mainly cortisol).
Note: With reduced cortisol, compensatory increase in ACTH release results in secondary
hyperplasia of adrenal cortex (bilateral).

Symptoms; are most commonly associated with virilism (excess androgen causing signs of masculinity in
females).

Adrenocortical Insufficiency (Hypoadrenalism)

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

Waterhouse-Friderichsen Syndrome Addison’s Disease

Massive haemorrhage due to Primary chronic adrenocortical
overwhelming septicaemia, especially insufficiency usually caused by
seen in infants. autoimmune adrenalitis. Other main
Associated with meningococcal sepsis causes include tuberculosis, AIDS and
and DIC. non functioning malignancies.

Clinical Manifestations: can vary between primary and secondary cases.

 Patients typically present with fatigue, weakness and gastrointestinal symptoms.
 Primary disease can also cause hyperkalaemia, hyponatraemia with resulting hypotension and
cardiac arrhythmias due to reduced aldosterone.
 Primary disease also causes hyperpigmentation due to MSH release.

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.
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 -Loss of tumour suppressor
-Pancreas (40%), endocrine neoplasms (usually gene at Ch11q13.
metastatic) or less commonly gastrinomas -Unknown mechanism of
-Pituitary (30%), mostly prolactin or GH secreting action.
MEN-2a -Thyroid, medullary carcinoma in virtually all cases -Inheritance of RET proto-
-Adrenal medulla (50%), phaeochromocytomas oncogene on Ch10q11.
-Parathyroid (30%), primary hyperplasia -Multiple tyrosine kinase
MEN-2b -Thyroid and adrenal medulla disease similar as 2a mutations.
-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 Osteomyelitis
infection. of Femur

Morphology: suppurative exudate in bone marrow, neutrophil polymorphs, RBC’s, fibrin and debris.
Osteoclast activity at necrotic margins. Can have granulation tissue or abscess depending on stage.

Outcome: determined by the anatomic location, the host response (resistance), the number and relative
virulence of the pathogens, and the effectiveness of therapy.
 Ideal outcome; with resolution and repair, the sequestrum is resolved, the organisms are dealt
with by the immune response and the defect fills with granulation tissue.
 Ultimately undergoes intramembranous ossification and healing.

Clinical: local pain and fever, especially in children. May be difficult to distinguish from a neoplasm.
 X-rays often normal for first 14days, inflammation and reactive bone seen with time.
 Intense uptake isotope scans can be used, but MRI imaging will often reveal
infection/abnormality the earliest.
 Conclusive diagnosis either by blood cultures (may be -ve) or from the lesion itself.

Chronic Osteomyeltis Tuberculous Osteomyelitis

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

Pott’s Disease
Kyphotic deformity of thoracic spine during tuberculous
osteomyelitis.
 Destruction of anterior vertebral end plates → spreads to IV discs
→ involves adjoining vertebral bodies.
 Large, cold abscesses filled with necrotic gaseous material may
form in the soft tissues eg. the paravertebral/psoas musculature.
 Can also cause spinal cord compression, meningitis and/or
ankylosis (fixation). Pott’s Disease
Joint Infection
Acute septic arthritis is the invasion of the joints by pathogenic microorganisms which trigger an
immune response and degradation of the cartilage. Infection of joint may occur by:
 Haematogenous dissemination to synovium.
 Extension from adjacent focus of osteomyelitis or soft tissue infection.
 Direct implantation of organisms via trauma or operative intervention.

Pathogens: S. aureus is most common.

 In neonates/infants can also be due to Strep, H. Influenzae and gram –ve rods. Most often
affecting single hip, knee or ankle joint.
 Adults prone to developing septic arthritis are individuals with chronic inflammatory arthridities.
Non-gonococcal causes are a medical emergency, gonococcus is often easily treated with
antibiotics alone. Fungal causes usually only in immunocompromised.

Pathology: presence of pathogens incites an acute inflammatory reaction within the joint capsule and
synovium, with swelling and effusion.
 Inflammatory response causes degradation of the cartilage, esp articular cartilage.
 Cellulitis and suppurative exudates may extend beyond the joint capsule → complete joint
disruption into soft tissues with sinus formation.

Morphology: hallmarks evident within the synovial tissues where there is dense, mixed inflammatory
cell infiltrate. Patchy fibrinous exudate at synovial surface which may be eroded in some areas. Synovial
blood vessels are congested and prominent.

Clinical: clinical course determined by the pathogens involved, host response and therapy. Early
recognition, diagnosis and treatment is critical due to rapid cartilage damage.
 Often present with a swollen, red, warm and painful joint. Associated fever and ↑WCC.
 Purulent material may be recovered on joint aspiration.
 Diagnosis by aspiration and synovial fluid examined for the crystals and microorganisms.
 Treatment by surgical incision, drainage, immobilisation and antibiotic therapy

Tuberculous arthritis most often involves large joints, as a result of haematogenous colonisation within
the synovium. Cases chronic granulomatous inflammation throughout the joint cavity.
 Destroys the articular cartilage and also infiltrates and destroys subchondral bone.
 Joint destruction is often followed by the formation of fibrous scars, ie. fibrous ankylosis.
 Early manifestations of chronic swelling and effusion, with few acute signs of inflammation.
 With progression there is loss of range of motion of the joint, which may be accompanied by the
formation of draining sinuses.
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
Osteoarthritis Process
include trauma, metabolic conditions, infection, 1. ↑ chondrocyte activity due to various stimuli (eg.
avascular necrosis, other forms of arthritis, congenital trauma)
alterations etc. 2. Abnormal quantity and quality of proteoglycan
 Result in damaged cartilage and alteration in and collagen production.
shape of the articular surfaces. 3. Joint may maintain normal function for years but
 Articular cartilage exhibits fibrillation and clefting. eventually, the arrangement and size of collagen
Variable loss and thinning can expose underlying fibres are altered.
4. Proteoglycans begin to break down faster than
bone (eburnation).
they can be synthesized resulting in degenerative
 Subchondral bone reveals sclerosis, cystic change,
cartilage (pieces can fragment into joint).
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

Charcot joint is an extreme form of osteoarthritis seen in

patients with neurological dysfunction. There is rapidly
destructive osteoarthritis, production of loose bodies, severe
subluxation and even dislocation of the joint.
Osteonecrosis (Avascular Necrosis) is necrosis of bone and bone marrow in absence of infective cause.
 Pathology: a relatively common disorder with vast majority of cases
are secondary to trauma. Collapse and fracture of the necrotic
subchonral bone disturbs joint anatomy and function.
Non-traumatic AVN occurs primarily in younger adults, and is often
bilateral. Has been linked to corticosteroid use, alcoholism,
infections and embolism, however, a large number of cases have no
obvious aetiologic factor. Avascular Necrosis
 Morphology: necrotic bone is recognised by the absence of osteocytes from lacunar spaces. The
marrow space is also necrotic. May be evidence of osteoblastic and osteoclastic activity.
 Clinical: significant cause of joint pain and disability. Clinical signs and symptoms similar to OA,
though usually sudden onset and younger patient.

Spondylosis is osteoarthritis of the spine, including degenerative disc disease (osteochondrosis).

Associated with vertebral osteophytes, ligamentous disease, facet joint changes and neurological
complications.
 Spinal changes: most often in cervical and lumbar spine. Degenerative spondylolisthesis
Osteophytes from facet joint degeneration can impinge on is a displacement of the
intervertebral foramina. Can cause vascular congestion, vertebral vertebral body on the one
artery insufficiency and nerve root irritation. directly below it. It is
associated with degeneration
 Vertebral disc changes: can displace in any direction. If posteriolly
of the facet joints and can
can potentially impinge on nerve roots and if anteriorly on the
result in spinal stenosis.
contents of the spinal canal.

Rheumatoid Arthritis
Rheumatoid arthritis is a chronic systemic disorder of unknown aetiology, which effects females more
often than males. The peak age of onset is in the fourth to sixth decade.

Pathology: although the cause is unclear, 70% to 80% of affected individuals test
positive for histocompatibility antigen DW4 and there are some familial cases.
 It is clear that there is a immunological reaction and increased formation of
degradative enzymes within the joint.
 Rheumatoid factors (RF) are immunoglobulins that complex with IgG.
Approximately 70% of patients are RF +ve.
Synovium from
Morphology: joint destruction with little reparative activity. The synovium joint with RA
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 Rheumatoid
ankylosis. nodule from elbow
 Extra-Articular RA Manifestations
There are numerous extra-articular manifestations of
Rheumatoid Arthritis (Rheumatoid Disease).
 Subcutaneous rheumatoid nodules occur in
approximately one third of cases, usually on support
structures of the joint.
 Weakness/skeletal muscle atrophy is common.
 Limited forms of vasculitis can occur and manifest as
cutaneous vasculitis, peripheral neuropathies, ischaemic
leg ulcers etc. Rarely serious.
 Pleuritis, pleural effusion most common in lung.
 Ocular disease includes episcleritis and scleritis
 Cardiac and neurological disease are uncommon may
occur as a result of vascular compromise.
Spondylarphropathies (RA Variants)
Group of conditions in which RF is usually –ve but involve
inflammation in the spine and peripheral joints.
 Anklyosing Spondylitis; low back pain and stiffness due
to synovial inflammatory changes. Eventual fusion.
 Psoriatic Arthritis; psoriasis usually precedes the onset
of arthritis but may follow or accompany it.
 Enteropathic Arthritis/Spondylitis; patients with chronic
colitis, can develop peripheral arthritis/spondylitis.
 Reactive Arthritis; infection of GIT, followed weeks later
by a sterile synovitis. Reiter’s syndrome is an example.
All these diseases exhibit: enthesopathy, synovitis,
dactylitis, sacroileitis, spondylitis, extra-articular
inflammation (eg. GIT), family history, antigen HLA - B27.

Metabolic/Crystal Arthropathies
Gout is characterised by episodic acute attacks of inflammatory arthritis, and chronic deposition of urate
crystals around affected joints. May occur sporadically or as a hereditary condition.

Pathology: can be due to inherited (primary) or acquired (secondary)

metabolic defects that cause hyperuricamia.
 Uric acid in the end product of the catabolism of purines and is
excreted by kidneys.
Gout of Big Toe
 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
Gout of 2nd Digit
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).
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.
METABOLIC BONE DISEASE
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
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 Osteoporosis with crush
(involutional) or secondary. fracture and kyphosis

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

Osteomalacia occurs in adults, resulting in osteopenia (reduced overall skeletal mass). May clinically be
asymptomatic or have various features underlying the disorder.
 Soft bone (deformity), fragile (fractures), bone pain/tenderness (back, hips, generalised),
proximal muscle weakness (hypocalcaemia).
 Multiple bilateral and symmetric lucencies may be seen on X-rays, altered calcium, phosphorus
and vit D in serum tests.

Rickets is when the growing skeleton is involved, including both bone and the cartilage matrix of the
growth plates. Results in inadequate endochondral ossification, and a variety of distinctive skeletal
abnormalities may develop.
 Reduced bone length, prone to deformities/fractures, deranged bone growth and development,
weakness and hypotonia.
 Microscopically, excessive osteoid, islands of cartilage, fibrosis and widened diameter.

Hyperparathyroidism
Hyperparathyroidism is a surplus of PTH released from chief cells of the parathyroid gland.
Pathology: excess PTH has various effects on bone, also resulting in hypercalcaemia.
 Increased bone resorption (↑ osteoclastic activity) resulting in mobilisation of Ca2+/PO42-.
 Cysts (macro or micro) or rarer brown tumours (large localised areas of resorption).
 Marrow fibrosis, resulting in ‘osteitis fibrosa cystica’.
Classification: occurs in two major forms, primary and secondary.
Primary hyperparathyroidism uncontrolled production of parathyroid hormone from neoplastic or
hyperplastic parathyroid tissue. In most cases (>95%) is caused by sporadic parathyroid adenoma or
hyperplasia, rarely carcinoma or familial MEN syndromes.
 Patients may be asymptomatic (biochemical abnormality
detected incidentally) NB: many other causes of
 Present with signs and symptoms related to hypercalcaemia hypercalcaemia eg. vit D
intoxication, familial condition,
(abdominal cramps, constipation, muscle fatigue, peptic
sarcoidosis. Doesn’t have to be
ulceration, renal calculi, cardiac valve calcification etc.).
hyperparathyroidism.
 Have bone related disease (only 10%).
Secondary hyperparathyroidism results from chronic parathyroid
Tertiary Hyperparathyroidism
stimulation by low serum calcium (occasionally associated with other
Represents autonomous and
disease processes). The clinical features are usually dominated by those
continuing PTH secretion in the
of chronic renal failure, vit D deficiency and malabsorption. In general,
absence of low serum calcium.
the osseous pathology is less severe than that seen in primary
hyperparathyroidism.

Clinical/Morphology: primary and secondary bone changes are essentially identical.

 Macroscopic: X-ray may reveal diffuse osteopaenia and/or circumscribed areas of lucency (esp
in the phalanges). These reflect resorption of cortical bone.
 Microscopic: increased osteoclast activity, with increased bone resorption and a characteristic
tunnelling or dissecting pattern. Mesenchymal cells and fibrous tissue replaces lost bone.

Paget’s Disease of Bone

Pagets disease of bone is an idiopathic disorder that represents derangement of bone remodelling and
turnover. May involve one bone (monostotic) or multiple bones (polyostotic). Mostly commonly
involves the pelvis and skull but virtually any bone may potentially be affected.

Pathology: extensive bone remodelling that evolves in three phases:

1. Osteolytic phase; acceleration of resorption.
2. Mixed lytic/blastic phase; efforts at bone replacement by appositional
formation, whilst bone resorption continues.
3. Osteoblastic/sclerotic phase; continuing bone formation with diminished
resorption.
Results in thick, soft, porous bone that is prone to compression and deformity. Normal
bone architecture is lost.

Morphology: remodelling is disordered and purposeless resulting in thickened bone with mosaic
patterns of cement lines.

Clinical: relatively common in late adult life with greatly variable presentation
depending upon site, extent of disease and presence of complications.
 Signs: often asymptomatic or patients present with pain, increasing bone
size, deformity or fracture.
 Diagnosis: raised alkaline phosphatase as a result of osteoblastic activity
or radiological changes (bone deformity, thickening, coarseness).
 Complications: stress, fracture, high output heart failure, sarcoma. Paget’s disease in clavaria
Renal Osteodystrophy
Refers to a range of skeletal abnormalities seen in association with chronic renal disease and
haemodialysis. Associated with phosphate retention, hypocalcaemia, decreased vit D and sometimes a
metabolic acidosis. The clinical and pathological manifestations of renal osteodystrophy are variable.
 Hypocalcaemia may trigger secondary hyperparathyroidism
 Acidosis promotes osteoporosis/osteopenia.
 Various manifestations eg. osteomalacia, osteosclerosis and OFC can occur in combination.

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 Less common, aggressive benign lesion, classically located in epiphysis with 80%
Tumour skeletally mature. Majority are at articular end of a long bone.
Osteogenic Most common primary malignant tumour of bone (not marrow) yet still rare, 0.2%
Sarcoma 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 Metastasis to bone is the most common bone malignancy, and location for
Disease metastases with virtually every malignancy being able to invade bone.
 Spread: metastatic deposits reach bone via vascular systems,
lymphatics are less likely. The most common sites of
involvement are bones of the axial skeleton though virtually
any bone can be affected. Most common sources include
breast, prostate, lungs, kidney, thyroid.
 Morphology: metastasis may produce combinations of
osteoblastic and osteoclastic activity, and as such may be
lytic, blastic or mixed in appearance. Most are osteoclastic,
however prostatic and breast carcinomas become typically
blastic. Typically have destructive changes with moth eaten
appearances. Extension into soft tissue and periosteal
reaction can be present.
 Clinical: presentation is with pain, swelling or tenderness.
Acute presentation may result from fracture, mass effect or
hypercalcaemia. Identification of the primary site of origin is
important, as it may influence therapeutic decisions.
Primary Marrow Neoplasms
Multiple Malignant plasma cell proliferation with osteolytic lesions. Is most common primary
Myeloma malignant neoplasm of bone. Most often located in vertebral bodies, ribs, pelvis and
skull. The neoplastic cells are characterized by production of a single homogenous
immunoglobulin product .
 Morphology: spectrum of differentiation may be seen.
 Clinical: can cause hypercalcaemia, anaemia, renal failure, amyloidosis.
Radiology reveals lytic, punched out, little areas of periosteal reaction and
destruction. Bone scans are typically negative.
Lymphomas, Discussed with the haematological system.
leukaemias.

Clinical Aspects of Bone and Soft Tissue Neoplasms

Presentation: musculoskeletal tumours may present in a number of generally non-specific ways. Depends on
anatomical location, rate of growth, size attained and secondary changes (eg. necrosis, haemorrhage). Local
effects (pain, swelling) reflect mass effect and impingement on surroundings. Systemic effects are less common.
 Benign inactive lesions may asymptomatic and discovered incidentally. Aggressive benign lesions are
usually symptomatic, grow rapidly and permeate surrounding structures.
 Low grade sarcomas tend to have a relatively indolent course. High grade sarcomas tend to have a
relatively rapid growth extra-compartmental and metastatic spread.

Diagnosis: management decisions in rest upon tissue diagnosis from biopsy. Must obtain sufficient sample (for
accurate diagnosis and classification), but consider possible procedure complications. Without careful planning,
biopsies may lead to adverse effects (20%) on treatment and outcome as a result of misdiagnosis or procedural
complications.
The radiological assessment of neoplasms of bone also plays an invaluable role. Plain X-rays reflect growth
patterns outlined above, while more sophisticated imaging (CT, MRI, PET) enhances the diagnostic work-up.

Staging: musculoskeletal and soft tissue neoplasms use the Enneking system (not haematopoietic or metastatic
neoplasms).
 Grade of biological aggressiveness: G0 (benign), G1 (low grade malignant), G2 (high grade malignant).
 Site: T0 (confined by capsule), T1 (extracapsular, intracompartmental), T2 (extracompartmental)
 Metastases: M0 (local), M1 (metastasised).
 Soft Tissue Neoplasms
Soft tissues are those which are non- epithelial, reticuloendothelial, CNS and skeletal. They are of
mesodermal and neuroectodermal origin, including fibrous CT, smooth muscle, skeletal muscle, fat,
peripheral nerves and blood/lymphatic vessels.
 Soft tissue tumours are complex and highly heterogenous. They may be classified as benign,
borderline, malignant or pseudoneoplastic (appear as tumours, but are not).
 The vast majority of tumours have unknown patho-aetiology. Associated with radiation,
carcinogens, trauma and inherited/familial disorders.
 Growth pattern is affected by its proliferative, matrix forming and destructive characteristics,
also influenced by response in surrounding tissues.
 Generally non-specific symptoms. Depends on anatomical location, rate of growth, size attained
and secondary changes (eg. necrosis, haemorrhage). Local effects (pain, swelling) reflect mass
effect and impingement on surroundings.
 Incidence of 3 per 1000, with most being benign (100:1). Could be many more as many benign
neoplasms are not biopsied.

Classified by pattern of soft tissue differentiation and cell origin type. This histogenesis is
disputed/uncertain in some tumours. Can present in any cell population of soft tissue.
Vascular Neoplasms Benign: haemangioma Rhabdomyosarcoma
Intermediate: haemangioendothelioma of forearm
Malignant: angiosarcoma
Adipose Tissue Benign: lipoma
Neoplasms Malignant: liposarcoma
Smooth Muscle Benign: leiomyoma
Tumours Malignant: leiomyosarcoma Fibrosarcoma
Skeletal Muscle Benign: rhabdomyoma of thigh
Tumours Malignant: rhabdomyosarcoma
Mesenchyme (CT) Benign: fibroma
Tumours Malignant: fibrosarcoma

Benign Soft Tissue Tumours

Are often, but not invariably, <5cm, superficial to deep fascia, soft, moveable and non-tender. May have
static or intermittent growth. Can be active, inactive or aggressive.
 Inactive tumours are asymptomatic (discovered incidentally), remain intracompartmental
(completely encapsulated) and seldom deform/distort surrounding tissue eg. ganglion cyst.
 Active tumours are benign lesions that grow steadily and expand by defoeming/distorting
surrounding tissue boundaries. Remains encapsulated eg. tenosynovial giant cell tumour.
 Aggressive benign tumours are usually symptomatic, grow rapidly, permeate and infiltrate
surrounding structures eg. deep fibromatosis.

Ganglion Cysts develop by myxoid Tenosynovial Giant Cell Fibromatosis is fibroblastic

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.
Tumours are a localised type of proliferation forming collagen.
giant cell tumour in tendon Aggressive clinical behaviour,
sheaths. Diffuse- pigmented infiltrative. Repeated local
villonodular synovitis (PVNS). recurrence, but no metastases.
Locally aggressive, non -Deep: muscle, abdominal.
metastasising neoplastic -Superficial: palmar, plantar,
process. penile, infancy.
Malignant Sarcomas
Are often, but not invariably, >5cm, deep to deep fascia, firm, fixed and tender. Progressively increases
in size and symptomatic. Grow locally, compressing adjacent tissue, form a pseudocapsule (ie.
unencapsulated). Common haematogenous metastases.
 Low grade sarcomas have relatively indolent course and gradual local expansion. Ultimately may
have extracompartmental spread, low rate of metastatic spread eg. myxoid liposarcoma.
 High grade sarcomas have relatively rapid growth, extracompartmental spread and metastatic
spread. Often involve neurovascular bundles eg. synovial sarcoma.

Myxoid 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.

SKELETAL MUSCLE DISEASE [Original notes by Ben H.]

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) Acute: symmetric difficulty using large Eg. Guillain Barre (motor unit),
Myopathies muscles of the hip and shoulder. Myasthenia Gravis (NM junction)
Chronic: lifelong slowly progressing Eg. congenital myopathies,
disorders. muscular dystrophies
Distal Predominant Symmetrical distal weakness of Eg. Charcot-Marie Tooth
Myopathies hand/foot, no sensory involvement.
Channelopathies Episodic weakness, due to defective Cl, Eg. potassium imbalances (Na,
(Episodic Weakness) Na, Ca etc channels (↓ AP, contractility). Ca), congenital myotonias (Cl)
Exercise-Induced Rare painful weakness with cramping and Eg. metabolic myopathies of
Myopathies myoglobinuria. 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 Clinical Signs of Duchenne’s
two disorders as there is an absence of dystrophin  Kids have a very characteristic way of
completely. Has early onset, manifesting when child getting from lying to standing
starts walking and relentlessly progresses till death (Gower’s maneuver with lordosis).
(usually around 20yr).  Waddling decompensation of gait as
 Becker’s Muscular Dystrophy is a milder form since muscle function deteriorates.
dystrophin is made, but it is in altered quality and/or  Large calves due to fatty
quantity. Has later onset, often in late childhood/early replacement (pseudohypertrophy).
adolescence, and slower, progression. more clinical  Abnormal posture due to progressive
weakness → wheelchair bound.
variability and overlap makes it harder to prognosticate.
Genetics: X-linked mutations (mostly deletions in Ch Xp21) hence manifests mostly in males.
 Females are usually just carriers, however they can express phenotype depending on how much
of the X-chromosome is inactivated.
 Very large gene so there’s lots of room for abnormalities (hence the variation in Becker’s).
 2/3 are familial, other 1/3 are sporadic new mutations.

Pathology: dystrophin is at periphery muscle cells and is responsible for transducing the contractile
force of intracellular sarcomere to extracellular CT matrix → shortens muscle causing contraction.
 In dystrophin deficiency there is sarcolemma instability and the work of the
sarcomere is not manifest in muscle movement.
 Membrane is then ‘ripped apart’ when contraction occurs and there is a
degeneration of muscle fibres (inflammatory response) → chronic
necrotizing myopathy.
 Results in CK release (↑ serum CK), fibrous regeneration/repair and
hypertrophy of the remaining fibres.
 Eventually there is a failure of regeneration and existing fibres atrophy →
Duchenne’s
replaced by connective tissue and fat.
NB: dystrophin isoforms may play a role in the CNS causing abnormalities and mild mental retardation.
Can also affect myocardium and this with respiratory failure is usually the cause of death.

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.
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.
Communicating Hydrocephalus Non-Communicating Hydrocephalus

Results from impaired resorption of CSF or during Results from obstruction of CSF pathways within
obstruction of CSF pathways in subarachnoid ventricular system. Ventricular system behind
CH
space (not ventricular system). This is a general point of obstruction becomes dilated.
condition where all the ventricular system is
Can be caused by congenital malformations,
enlarged.
tumours, inflammation or haemorrhage.
Can be caused by inflammation (meningitis),
Commonly in intraventricular foramen (Monro)
subarachnoid haemorrhage or tumour (meningeal
NCH and cerebral aqueduct (Sylvius).
carcinomatosis).

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

Cerebral Herniation
Cerebral herniation occurs when ICP causes displacement of soft tissue of the brain through available
openings. An increase in volume in intracranial contents (eg. pathological mass, oedema) results in
increased ICP due to the limited capacity of blood, cerebral tissue and CSF to compress.
 Subfalcine herniation displacement of cingulate gyrus under the edge of the
falx. This can compress on branches of anterior cerebral artery.
 Transtentorial herniation occurs when uncal notch on medial temporal lobe
displaces under the tentorium. This can compress the posterior cerebral
artery, CN III (fixed dilated pupil), midbrain and aqueduct (Sylvius).
 Tonsillar herniation is displacement of cerebellar tonsils through foramen
magnum. Life threatening due to compression of vital centres in the medulla.
 Transcalvarial herniation is external as it is due to a skull defect (surgical or
traumatic).
CEREBROVASCULAR DISEASE
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
Non-Haemorrhagic Infarct
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 Haemorrhagic Infarct
Haemorrhagic Infarct
 Hypotension may precipitate infarct, especially in watershed areas.
 Morphology: depends on interval between occlusion and examination. Lacunar Infarcts
 12-36hrs first well developed changes including slight softening,
Small <1cm infarcts (single or
discolouration and blurred grey/white interface. multiple) due to microvascular disease
 7days tissue becomes soft and friable. or emboli.
 10days liquefactive necrosis is evident.
Most commonly seen in hypertensive
 Later repair results in cystic change and reactive gliosis.
patients and associated with severe
deficits (eg. hemiplegia).
Intracranial Haemorrhage
Parenchymal haemorrhage is mostly caused by rupture of small intraparenchymal vessels. Often
extends into ventricles and less commonly to leptomeninges (pia/arachnoid mater).
 Usually caused by hypertension, also associated with trauma, neoplasms, infection, berry
aneurysm, cerebral amyloid angiopathy and other vascular disease.
 Area affected varies greatly, brain swelling and herniation quite common.
 10% of all strokes, 15% of all hypertension deaths.

Hypertensive Haemorrhage

Pathogenesis: is due to hypertensive weakening of parenchymal arterioles. Overall

effect is hyaline arteriolar sclerosis.

 Replacement of smooth muscle with collagen, fragmentation of elastica.

 Associated with the development of minute aneurysms that may rupture
(Charcot-Bouchard microaneurysms).

Classification: based on type of lesion caused by haemorrhage.

 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.
Hypertensive Haemorrhage
 Petechial haemorrhage occurs in acute hypertensive encephalopathy with
severe neuro symptoms.

Presentation: depends on site and volume, often progressing over hours or days.
Subarachnoid haemorrhage is most frequently
Common due toheadache,
symptoms; rupture vomiting,
of a berryhemiparesis,
aneurysm. hemisensory
Blood seepsloss,
intocoma.
the
subarachnoid space between the pia and arachnoid mater. 15-20% go unnoticed. Other causes include:
 Rupture of other aneurysms (eg. fusiform, giant, infective).
 Vascular malformation (eg. arteriovenous malformation, cerebral amyloid angiopathy), however
these are more likely to cause parenchymal haemorrhage.
 Systemic factors (eg. bleeding diathesis)

Berry Aneurysm

Saccular aneurysm that develops at points of weakness of tunica media of cerebral

arteries. Causes 4.4% of stroke mortality, incidental in 2-3% of autopsies.
Risk Factors: mainly hypertension. Also AVM, fibromuscular dysplasia, collagen
defects, polycystic kidney disease, coarctation of aorta.

Location: most at points of arterial branching. May be multiple.

 85% in anterior part of Circle of Willis,

 10-15% in vertebra-basilar system.
Berry Aneurysm, ruptured Presentation: rupture causes sudden severe headache. May localised symptoms or
cause coma/death within minutes.

 Third die within 72hrs, another third have serious complications

 Half have warning symptoms related to sentinel leak.
Epidural and subdural haemorrhages are often associated with trauma and are considered below with
haematomas caused by CNS trauma.
 Epidural haematoma is blood collected between the clavaria and dura mater. Arterial origin.
 Subdural haematoma is blood collected between dura mater and arachnoid. Venous origin.

Stroke
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. Contusion with Haematoma

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.

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.
Epidural Haematoma

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

Well differentiated tumour with initial The least differentiated form which may evolve from
slowly progressing symptoms. Eventually astrocytoma (via anaplastic degeneration) or be present
anaplastic degeneration occurs leading to from start. Rapidly fatal.
clinical deterioration.
Macroscopic: white matter of hemispheres is variegated
Macroscopic: ill defined infiltrative tumour. (colourful), haemorrhage, necrosis, thrombosed vessels.
It is solid, firm and tough (± cystic). Circumscribed expansion of cerebral tissue.
Microscopic: variable cell morphology, Microscopic: anaplastic astrocytes, endothelial
usually fibrillary and increased nuclei. proliferation, mitotic activity.
 Pilocytic astrocytomas are relatively benign tumours, often cystic. Typically occur in younger
population and located in cerebellum.
 Other special astrocytomas include sub-ependymal and pleomorphic forms.

Oligodendrogliomas (10-15%) are most common in cerebral hemispheres, esp 40-60yrs. Patients may
have several years of neurological complaints (often including seizures), however has better prognosis
than astrocytomas.
Ependymomas (2-6%) are most common in the ependyma-lined ventricular system, esp <20yrs. Most
are infratentorial, children in the fourth ventricle, adults in the spinal cord.

Astrocytoma (glioblastoma) Oligodendroglioma Ependymoma

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).
Medulloblastoma

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.
Meningioma
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). Schawnnoma- bilateral CNVIII

CNS Lymphomas are most common in the immunocompromised, esp AIDS and EBV.
 Primary lesions are uncommon except in Hodgkins. Majority are B-cell high
grade lymphomas.
 Secondary involvement is a late complication of meningeal, nerve root or
epidural lymphoma.
Metastatic Melanoma

Pituitary neoplasms account for 10-15% of intracranial neoplasms (see endocrine notes).
 Symptoms from mass effects or secretory abnormalities.

Metastatic tumours are secondary tumours that comprise of 20-25% of adult CNS tumours.
 Metastases form sharply demarcated, multifocal masses usually at white/grey border.
 Most common primary sites are; lung, breast, skin, kidneys, GIT.
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
Acute Meningitis
nerve palsies and meningoencephalitis may also occur.
(with abscesses)

Aseptic Meningitis is clinical term for meningitis without recognisable organism. In most cases viral
pathogen is eventually found.
 Common Pathogens: echovirus and coxsackie A/B (enteroviruses), HSV2
 Clinical Signs: similar but less fulminant than pyogenic meningitis, usually self limiting.
 Diagnosis: CSF reveals lymphocytosis, moderate protein elevation and normal glucose.

Chronic Meningitis is caused by mycobacteria and spirochetes, often with parenchymal components.
 Tuberculous meningitis causes increased cellularity and protein in the CSF. May result in well
circumscribed parenchymal mass (tuberculoma) or spinal TB (Potts Disease).
 Neurosyphilis is a tertiary stage of syphilis with major meningeal manifestation. Paretic
(progressive mental/physical function loss) and tabes dorsalis (dorsal root damage) forms.
 Neuroborreliosis is nervous system involvement by B. burgdorferi.

Infections of Parenchymal
Brain Abscesses are focal suppuratives infections nearly always caused by bacteria.
Known as cerebritis if no abscess forms. Fungi and parasites are rarer causes.
 Causes: direct implantation of organisms, local extension from adjacent foci
(mastoiditis or sinusitis), or haematogenous spread (primary site from heart,
lungs, bones etc.).
Pyogenic Abscesses
  Morphology: discrete, non invasive, destructive parenchymal lesions.
o Macroscopic: central liquefactive necrosis surrounded by fibrous capsule.
o Microscopic: vascularisation, granulation tissue. Reactive gliosis outside fibrous capsule.
 Clinical Signs: fever ± signs related to focal deficits and raised ICP.
 Complications: rupture can cause ventriculitis, meningitis, venous sinus thrombosis.

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.
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.

Subacute Encephalitis is also mostly viral, however does Progressive Multifocal

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

Other CNS Infections

Epidural and Subdural Infections can involve bacteria or fungi.
 Epidural abscesses are usually a complication of osteomyelitis. Symptoms from mass effects or
spinal cord compression.
 Subdural empyema is accumulation of pus in this potential space as a complication of infection
in sinuses or skull. Symptoms generally from mass effect.

Parasitic Infections mostly due to toxoplasmosis or cysticercus.

 Cysticercus remain dormant for years, eventually degenerate inducing granuloma formation,
focal scarring and calcification. May involve parenchyma, meninges or ventricular system.
 Seizures most common symptom, can cause raised ICP if ventricular.
NEURODEGENERATION 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 Dementia vs Neurodegeneration (ND)
dynamics play a large role in the disease processes. This may include
abnormal protein breakdown, folding or aggregation. These abnormalities ND is a disease process, dementia is a
can render proteins soluble (neurotoxic) or insoluble (filaments/deposits). clinical sign.
This leads to cellular dysfunction and neuronal death.  Not all ND results in dementia eg.
motor ND may only result in
somatic deficit.
Clinical: dementia is the development of memory impairment and other
 Not all dementias are due to ND
cognitive deficits during normal consciousness. It is a clinical sign that is
eg. some dementias are caused by
present in many ND diseases and is not a normal part of aging.
vascular disease.

Subcortical Degenerations
Motor Neuron Disease involves neurodegeneration of upper motor neurons (Betz cells) in the motor
cortex and/or lower motor neurons in the spinal cord, both resulting in weakness.
Clinical: depends on location, sensory systems and cognitive functions are usually unaffected, but
types with dementia do occur. Death within 5 years due to respiratory failure or aspiration.
 UMN loss also results in hyperreflexia, hypertonicity, paresis and +ve Babinski sign.
 LMN loss also results in hyporeflexia, hypotonicity, muscle wasting and fasciculations.
Pathology: most cases are sporadic. Specific forms of degeneration have familial cause eg. 10% of
amyotrophic lateral sclerosis (ALS) are due to a SOD-1 gene mutation.
Morphology: loss of associated motor neurons with shrunken ventral nerve roots. Inclusion bodies in
surviving motor neurons (bunina bodies). Neuronal swelling.

Parkinsonism results from degeneration of dopaminergic neurons of the substantia nigra. Is distinct
from other such conditions by the presence of Lewy bodies. Parkinsonism – substantia
Clinical: classic symptoms of cogwheel rigidity, bradykinesia, resting tremor and nigra pallor.
postural instability. Dementia occurs 40% of the time. Most common ND
movement disorder.
Pathology: most cases are idiopathic and sporadic. Some autosomal forms exist.
Morphology: diagnostic feature is presence of Lewy bodies, an inclusion of 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.
 Pathology: unknown, there is accumulation of tau (protein that stabilises microtubule) within
neurons and glial cells.
Morpholgy: atrophy of midbrain and pallor of substantia nigra. Microscopically there is; inclusions of
tau aggregate, neuronal loss and gliosis.

Huntington’s Chorea is an inherited autosomal dominant disease characterised by progressive

movement disorders and dementia.
Clinical: rapid involuntary movements (chorea), rigidity and cognitive decline (dementia).
Pathology: mutation gene IT-5 gene on Ch 4. Involves >40 repeats of CAG sequence (normally <34).
 Codes for huntingtin (large polyglutamine protein) which aggregates in abnormal tissue.
 The repeats expand in children of affected males (occurs during spermatogenesis).
Morphology: loss of neurons in the form of caudate, putamen and cortical atrophy. Microscopically,
astrocytic gliosis and huntingtin inclusions (in surviving neurons) can be seen.

Cortical Degenerations
Alzheimer’s Disease is the commonest cause of dementia (50-75%) characterised by memory and higher
intellectual impairment.
Clinical: progressive dementia with eventual end stage cachexia, death by bronchopneumonia. 4% in
>75yrs, 40% for >90.
Pathology: neurodegeneration of cortical/subcortical neurons due to the build up of various proteins.
 Amyloid precursor protein (APP) is a transmembrane glycoprotein which when abnormally
cleaved forms Aβ amyloid. This aggregates extracellularly and forms plaques.
 Small Aβ aggregates can alter neurotransmission and can be toxic. Large aggregates lead to
neuronal death and elicit an inflammatory response.
Alzheimer’s – cortical atrophy
 Surviving neurons develop filaments of hyperphosphorylated
tau inclusions. These neurofibrillary tangles (NFT’s) can
cause neuritic plaques.
Morphology: macroscopically shows variable cortical atrophy and
widening of cerebral sulci. Diagnosed by the microscopic presence of
extracellular amyloid plaques and intracellular NFT’s.

Lewy Bodies Dementias are the second most common type of dementias (10-25%). Hallmark of cortical
lewy bodies in deep grey matter.
Clinical: fluctuating cognitive decline can cause recurrent visual hallucinations and spontaneous
motor features of Parkinsonism. These often coexist with Alzheimer’s features.
Pathology: most cases idiopathic and sporadic.
Morphology: mild-moderate fronto-temporal atrophy, pallor of substantia nigra and locus coeruleus.

Pick’s Disease is a fronto-temporal dementia

Pure Dementia Alzheimer’s Pure Motor
with rapid deterioration in personality.
Disease
Morphology: fronto-temporal atrophy is very
severe with ‘knife edge gyri’. Residual swollen Tauopathies Synuclein-

neurons with spherical inclusions (pick opathies

bodies). Filamentous inclusions of tau
eg. Pick’s
protein.
Disease eg. Parkinsonism
Other dementias are either rare or not caused by neurodegeneration. These include ALS- (motor
neuron), corticobasal degeneration-, diffuse frontal- and Ch 17- related dementias. Vascular dementia is
a non-neurodegenerative cause resulting in acquired intellectual impairment.

Prion Disease is the accumulation of abnormal cellular protein

Cruetzfeldt-Jacob Disease (CJD)
called prion protein (PrP).
Prion infection that is due to sporadic
Clinical: no means of treating and body has no immune
change in 85%. It can occur via:
response. Must be prevented by avoiding exposure (right) and
sterilising contaminants.  Spontaneous change in protein
Pathology: PrPc are normal proteins found in cell membranes. structure (1:106).
PrPSc is an infectious folded isoform that is able to convert PrPc  New variant consumption (BSE
in body to PrPSc. contaminated meat).
 PrPSc causes neurodegenerative disease by forming  Canabolism (kuru).
amyloid aggregate within the CNS resulting in  Iatrogenic inoculation (avoided by
holes/vacuoles in neurons, reactive astrogliosis and recombinant tissue).
white matter degeneration. Familial cases make up 15% and are due
Morphology: atrophy in most cases with ventricular to a polymorphism at codon 129. This
enlargement. Spongioform change with neuronal loss and confers susceptibility to spontaneous
astrocytosis. Accumulation of prion protein both intracellularly change in PrPc to PrPSc.
and extracellularly (as amyloid plaques).

DEMYELINATING DISORDERS [Original notes by Ben H.]

Demyelination is the destruction of normal myelin with a relative preservation of axons. This can affect
the CNS and PNS. Various features common to all demyelinating disorders:
NB: Ephaptic transmission
 Demyelination and formation of plaques.
is when two nerves
 Ephatic neurotransmition (ephaptic neurotransmission causes
communicate with each
episodes of pain and spasm). other via an artificial
 Protean symptoms (so variable can suggest other diagnoses). synapse.

Pathogenesis/Morphology: due to an abnormal T-cell mediated autoimmune response to several

myelin proteins, which forms plaques. This is preceded by perivascular inflammation.
1. Active Plaques: activation of inflammatory cells → myelin fragmentation/phagocytosis by
microglia. Some oligodendrocytes (support myelin) are also destroyed.
2. Inactive plaques: inflammation slowly resolves (about 6 wks) and glial cells respond by
proliferating to form a hardened, sclerotic plaque (astrocytosis).
3. Shadow plaques: remaining oligodendrocytes attempt to remyelinate, however form abnormal
grouping of axons → allows short circuits → permanent ephaptic transmission.
NB: if the inflammatory process is arrested early, plaques are partially remyelinated. In advanced
lesions, astrocytosis creates a barrier between oligodendrocytes and their axonal targets.

Morphology: characteristic central vessel surrounded by a zone of demyelination at the periphery. This
zone is filled with lymphocytes and macrophages (microglia).
 Plaques vary in size and shape and can occur anywhere in the white matter, often at angles of
ventricles, white-grey junction and surface of brain stem/spinal cord (forms grey depressions).
 Active early plaques are pink (inflamed), inactive old plaques are grey (sclerosed).
Clinical: signs are highly protean (variable) and depend on site and extent of plaques.
 Cerebellar/brainstem: wide based gait, autonomic dysfunction (eg. BP).
 Spinal cord: weakness, sensory loss, bowel and bladder dysfunction.
 Optic nerve: sudden unilateral blindness which is self limiting lasting 2-3 wks.
NB: ephaptic neurotransmission causes neuralgia and muscle spasms.

Diagnosis: can be asymptomatic so need to use investigations. Best test is MRI as it reveals ‘silent’
plaques. CSF sample (electrophoresis) and evoked response tests (visual/auditory/somatosensory) can
be used to support diagnosis.

Multiple Sclerosis
CNS disease with intermittent and seemingly random neurological symptoms, can occur at any age.
 Manifests as well demarcated area of demyelination which
causes multifocal white matter plaques. There is axonal
preservation, except late in disease.
 White matter is more affected than grey matter as it has a
predominance of myelinated axons.
 In cases of severe demyelination lasting years, cavities form
when axons break down which can mimc infarcts. Demyelination due to MS
 Abnormal Tcell response to several myelin proteins, thought to be precipitated by viral
infection. Other associations with bacteria, defective gliosis, diet, genetic, toxins.

Charcot (Classic) Type has three Acute Fulminant Type is a rare clinical presentation and
clinical patterns; tends to happen as a one off severe episode.

 Relapsing-remitting with attacks  Acute (Marburg Type) occurs in younger people, has
once every 2 years (commonest). a rapid course, large plaques Involves destruction of
 Primary progressive with later myelin and some neuronal loss.
onset and spinal cord  Neuromyelitis Optica (Devic’s Disease) occurs
involvement. especially in Asian populations.
 Secondary progressive.  Concentric Sclerosis (Balo’s Disease)

Acute Disseminated Encephalomyelitis (ADEM)

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

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

LABRATORY TEST INTERPRETATION

Lab

GLOSSARY OF NAMED DISODERS [Written by David H.]

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.
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.