MedEd Histopathology Revision Lecture 2013 Part 1 · What is the differential diagnosis for acute onset ... ATHEROSCLEROSIS – RISK FACTORS Key Risk ... MedEd Histopathology Revision

Part 126 th March 2013

HISTOPATHOLOGYICSM MEDED 5TH YEAR REVISION SERIES 2013

MR GUY MARTIN MBBS BSC MRCSCORE SURGICAL TRAINEE

T HE R OYAL LONDON & S T B ARTHOLOMEW ’ S H OSPITAL

� Revision sessions organised and run by The Medical

Education Society

� We are not examiners / lecturers

� These lectures are not formal Imperial College lectures

� No promises about completeness

� General overview, key principles, example questions

� You will require more in depth specific knowledge

� Please fill in the feedback forms!

OVERVIEW

� Why is histopathology important, I want to be a GP?

� You have an exam to pass

� Why do people from Tanzania get squamous cell carcinoma and not

transitional cell carcinoma of the bladder?

� What is Bielschowsky’s stain used for?

� It is very important in day to day clinical practice – the essence of

clinical medicine and surgery

� What is the differential diagnosis for acute onset abdominal pain?

� Why is it important to recognise and treat a CVA as soon as possible?

� 2 sessions - Tuesday 26th and Thursday 28th March

� General principles of histopathology

� System specific histopathology

OVERVIEW

� General principles

� System specific pathology

� Cardiovascular

� Bone and joint

� Connective tissue

� Breast

� Neurological and cerebrovascular

� Respiratory

� GI Tract

� Hepatobiliary and pancreas

� Genitourinary tract

OVERVIEW

GENERAL PRINCIPLES OF

HISTOPATHOLOGY

“While there are several chronic diseases more destruct ive

to l i fe than cancer, none is more feared”

- Charles Mayo 1926

• Transitional cell carcinoma of the bladder

• Melanoma

• Basal cell carcinoma

• Breast cancer

• Colon polyp – tubular adenoma

A. Affects 1:12 women

B. Affects 1:250 women

C. Can be treated with local polyp resection

D. Can only occur in mucous membranes

E. Does not metastasise

F. If malignant, resection is the only treatment

G. Only occurs in the skin

H. Superficial tumour are high grade & associated with poor prognosis

I. Superficial tumours are low grade and associated with good prognosis

EMQ - TUMOURS

• Transitional cell carcinoma of the bladder - I

• Melanoma - D

• Basal cell carcinoma - E

• Breast cancer - A

• Colon polyp – tubular adenoma - C

A. Affects 1:12 women

B. Affects 1:250 women

C. Can be treated with local polyp resection

D. Can only occur in mucous membranes

E. Does not metastasise

F. If malignant, resection is the only treatment

G. Only occurs in the skin

H. Superficial tumour are high grade & associated with poor prognosis

I. Superficial tumours are low grade and associated with good prognosis

EMQ - TUMOURS

� “A specialty concerned with the nature and cause of

disease as expressed by changes in cellular or tissue

structure and function caused by the disease process”

� Histopathology – examination of tissues

� Cytopathology – examination of isolated cells

� “Disease is not something personal and special, but only a

manifestation of life under modified conditions, operating

according to the same laws as apply to the living body at

all times, from the first moment until death”

- Rudolph Virchow

GENERAL PRINCIPLES

� Mechanisms of cellular injury:

� Mechanical disruption

� Failure of cell membrane integrity

� Membrane damage

� Interference with metabolic pathways

� Deficiency of metabolites

� DNA loss or damage

� Outcomes of cellular injury depend upon:

� Nature of injurious agent

� Duration of injury

� Proportion of cell type affected

� Ability to regenerate

CELLULAR INJURY

CELL DEATH - APOPTOSIS VS NECROSIS

� Cell death – “irreversible loss of the cell’s ability to

maintain independence from the environment”

Apoptosis Necrosis

Induction Physiological/pathological Pathological

Extent Single cells Groups of cells

Biochemical

Energy dependent fragmentation

of DNA

Lysosomes intact

Impairment/cessation of ion

homeostasis

Lysosome lytic enzyme release

Cell membrane integrity Preserved Lost

Morphology

Cell shrinkage and apoptosis with

dense chromatin filled apoptotic

bodies

Cell swelling and lysis

Inflammatory response None Usual

Fate of dead cellsPhagocytosed by neighbouring

cells

Phagocytosed by

neutrophils/macrophages

� Regeneration – total healing with restitution of

original tissue structure and function

� Labile cells – good capacity for regeneration

� Stable cells – divide at slow rate under physiological conditions

� Permanent cells – no capacity for regeneration

� Repair – repair via formation of mature connective

tissue; fibrous organisation and scarring

HEALING – REGENERATION VS REPAIR

� Acute inflammation - initial transient reaction to

injury

� 3 principle phases

� Vascular phase: change in vascular caliber and permeability

� Exudative cellular phase: formation cellular exudate

� Outcome: resolution, suppuration, organisation, chronicity

� Macroscopic signs and symptoms

� Rubor (redness)

� Calor (heat)

� Tumour (swelling)

� Dolor (pain)

� Functio laesa (loss of function)

INFLAMMATION - ACUTE

INFLAMMATION - ACUTE

http://callmethedoctor.co.uk/immunology/inflammation/

� Chronic inflammation – prolonged tissue reaction to to

injury with formation of different cellular infiltrate

from acute inflammation

� Lymphocytes, plasma cells, macrophages predominant

� Usually primary, may follow acute inflammation

� Macroscopic appearances:

� Chronic ulceration

� Chronic abscess

� Granulomatous inflammation

� Fibrosis

� Thickening of hollow viscus

INFLAMMATION - CHRONIC

� Positive effects

� Dilution of toxins

� Migration/infiltration of immucological cells + Ab’s

� Initiation of coagulation cascade (initiation of fibrin clots)

� Increased delivery of oxygen/nutrients for repair

� Harmful effects

� Damage to local healthy tissue

� Swelling and compression of local structures

� Fibrosis/scarring

� Systemic response - SIRS

� Hypersensitivity

INFLAMMATION

GROWTH, MORPHOGENESIS &

DIFFERENTIATION

http://www.bdbiosciences.com/research/apoptosis/analysis/index.jsp

GROWTH, MORPHOGENESIS &

DIFFERENTIATION

http://www.intechopen.com/books/drug-discovery/anticancer-drug-discovery-from-serendipity-to-rational-design

� Hypertrophy – increase in cell size

� Hyperplasia – increase in cell number

� Atrophy – decrease in size due to loss of cells or

reduction in cell size

� Hypoplasia – failure of an organ to attain normal size

� Aplasia – failure of development of an organ

� Atresia – failure of development of a lumen in a

normally tubular structure

GROWTH – KEY PRINCIPLES

� Genetic factors

� Hormones

� Nutrition

� Blood supply

� Oxygen supply

� Nerve supply

� Growth factors

FACTORS AFFECTING GROWTH

� Process by which a cell develops a specialised function

and structure

� Control of differentiation

� Genes, hormones, growth factors

� Differentiation may be disturbed by environmental

teratogens

� Irradiation, drugs, infections

DIFFERENTIATION

� Metaplasia – reversible transformation of a terminally

differentiated cell into another cell type

� Dysplasia – premalignant condition characterised by

cell growth, cellular atypia and decreased

differentiation

� Neoplasia – abnormal and excessive un-cordinated cell

growth autonomous of normal growth controls

ACQUIRED DISORDERS OF

DIFFERENTIATION

DYSPLASIA

http://en.wikipedia.org/wiki/Dysplasia

� Carcinogenesis – conversion of normal cells to those

capable of forming neoplasms

� Carcinogen – agent known/suspected to participate in

the causation of tumours

� Carcinogenic: cancer causing (malignant)

� Oncogenic: tumour causing (benign + malignant)

� Host factors and carcinogenesis

� Race, diet, inherited pre-disposition, age, gender

CARCINOGENESIS

� Multi-step process

� Latency: causal event followed by latent period

� Initiation: development of irreversible neopalstic potential

� Promotion: event stimulating clonal proliferation

� Persistence: continued growth independent of initiators and

promoters

� Oncogenes – genes whose presence in certain forms

stimulates development of cancer

� Tumour suppressor genes – normal genes whose

absence can lead to development of cancer

CARCINOGENESIS

NEOPLASIA

� Neoplasia – abnormal and excessive un-cordinated cell

growth autonomous of normal growth controls

� Classification

� Behavioural: benign vs malignant

� Histogenetic: cell origin, differentiation

� Major categories

� Epithelial cells – adenoma/papilloma vs

adenocarcinoma/carcinoma

� Mesenchymal cells – -oma va sarcoma

� Lymphoid/haemopoietic cells

NEOPLASIA

Benign Malignant

Slow growing Rapidly growing

Low mitotic rate High mitotic rate

Well differentiated Poorly differentiated

Non-infiltrating Infiltrating

Cells normal Cells abnormal

Never metastasises Frequently metastasises

Often

circumscribed/encapsulatedOften poorly defined/irregular

Rarely undergoes necrosis Commonly undergoes necrosis

Rarely fatal unless local effect e.g.

cerebral tumourAlways fatal unless treatsed

CARDIAC & VASCULAR

PATHOLOGY

“I think the worst t ime to have a heart attack is during a

game of charades”

- Demitri Mart in

� A 46 year old man presents with progressive heart

failure and AF. His previous discharge summaries show

multiple admissions in the last year – Upper GI bleed,

Boxer ’s Fracture, Head Injury. XR – enlarged heart

shadow

a) Restrictive cardiomyopathy

b) Hypertrophic cardiomyopathy

c) Dilated cardiomyopathy

EMQ - CARDIOMYOPATHY

� A 46 year old woman with progressive heart failure. No

cardiac risk factors, is a non smoker and doesn’t drink

alcohol. Arthritis of her MCP joints, and her renal

function has been deteriorating on her last 2 blood

tests. Histology – pale pink amorphous material

between myocardial fibres

a) Restrictive cardiomyopathy

b) Hypertrophic cardiomyopathy

c) Dilated cardiomyopathy

EMQ - CARDIOMYOPATHY

� Thrombosis, embolism & infarction

� Atherosclerosis

� Acute coronary syndrome

� Cardiac failure

� Cardiomyopathy

� Rheumatic fever and endocarditis

� Valvular heart disease

� Hypertension

CARDIAC & VASCULAR PATHOLOGY

KEY PRINCIPLES OF CARDIAC FUNCTION

CARDIAC

OUTPUT

Heart Rate

Stroke Volume

Afterload

Preload

SNS + catecholamines

Vasoconstriction

Peripheral

vascular

resistance

Venous

return

Venoconstriction

Posture

Respiratory

cycle

+

+

+

+

-

+

-

� Thrombosis – “a pathological event when the

haemostatic system is abnormally active”

� Solid mass formed within the circulation

THROMBOSIS

� Embolism – “detached

mass within the

circulation”

� Thrombus

� Gas

� Fat

� Tumour

� Amniotic fluid

� Foreign body

� Therapeutic

EMBOLISM

� Ischaemia – “inadequate supply of oxygenated blood

to tissues or organs for its metabolic needs”

� General – shock

� Local – arterial, venous or small vessel obstruction

� Severity – speed of onset, extent of obstruction, presence of

collateral supply, metabolic requirements of tissues

� Infarction – “necrosis of tissue due to irreparable

ischaemic damage”

� White infarct: arterial

� Red infarct: venous

� Low-flow infarction: relative ischaemia

ISCHAEMIA & INFARCTION

� Atherosclerosis – “chronic

inflammation of the intima of

large arteries characterised by

plaque deposition, wall

thickening and loss of elasticity”

� Arterioloscelerosis: small/medium

vessels

� Calcific sclerosis: calcification of

small/medium vessels

� Responsible for more deaths

worldwide than all forms of

cancer

ATHEROSCLEROSIS

ATHEROSCLEROSIS - PLAQUES

http://circres.ahajournals.org/content/111/2/245/F1.large.jpg

http://en.wikipedia.org/wiki/File:Endo_dysfunction_Athero.PNG

ATHEROSCLEROSIS – RISK FACTORS

Key Risk Factors

Smoking

Hypertension

Diabetes

Hyperlipidaemia

Sedentary lifestyle

Age

Family history

� Key risk factors

� Modifiable vs non-modifiable

� Sheer stress

� Sideways force on endothelium

� Modulates endothelial function

� High laminar flow protective

� Low turbulent flow atherogenic

ATHEROSCLEROSIS - HYPERLIPIDAEMIA

� Low density lipoprotein (LDL)� “bad” – carries

cholesterol from liver to tissues

� Oxidised LDL principal agent in atherosclerosis

� High density lipoprotein (HDL)� “good” – carries

cholesterol from tissues to liver

� Converted to bile acids and catabolised in the liver

� Under negative feedback

ATHEROSCLEROSIS - COMPLICATIONS

� Complications of atherosclerotic plaques

� Stenosis

� Plaque rupture

� Aneurysmal disease

http://circ.ahajournals.org/content/vol122/21_MeetingAbstracts/images/medium/g21176_1.gif

ACUTE CORONARY SYNDROME

ACUTE CORONARY SYNDROME

Clinical features suggestive of ACS

ECG

STEMI

Unstable Angina NSTEMI

Cardiac

Enzymes

ST-elevation / LBBB

/ Posterior MI

ECG changes

+ve-ve

Risk Stratification

- ST elevation >1mm in >2 limb leads

- ST elevation >2mm in >2 chest leads

- LBBB

- Posterior ST depression + R-waves V1-V3

Morphine + Oxygen

Nitrates

Aspirin 300mg

Clopidogrel 300/600mg

+/- LMWH – fondaparinux/enoxaparin

http://eurheartj.oxfordjournals.org/content/28/13/1598/F14.expansion

ACS- ENZYMES

http://www.bpac.org.nz/resources/bt/2009/december.asp

PATHOLOGICAL EVOLUTION OF AN MI

Weeks – young scar

Days – necrosis & PMNsHours – necrosis

Months – established scar

� Sudden death

� Cardiac dysrhythmias

� Re-perfusion dysrythmias (flutter, VT)

� Cardiogenic shock

� LVF / RVF

� Myomalacia cordis

� Intra-ventricular septum rupture (pan-systolic murmur)

� Papillary muscle rupture (valvular dysfunction)

� LV wall ruputure (tamponade)

� Dressler’s Syndrome (rare: post-MI pericarditis)

COMPLICATIONS OF MI

� CO inadequate for the body’s requirements

� Poor prognosis: 25-50% 5yr mortality

� 1-3% of population. 10% elderly population

� Systolic vs diastolic

� Right vs left

� Low output vs high output

� Acute vs chronic

� NYHA Classification

� I-IV

CARDIAC FAILURE

CARDIAC FAILURE

http://www.mc.uky.edu/pharmacology/instruction/pha824hf/pha824hf.html

LVF VS RVF

Right Ventricular Failure Left Ventricular Failure

Causes

LVF, pulmonary stenosis,

chronic lung disease (COPD,

PAH, fibrosis)

IHD, HTN, valvular disease, MI

Symptoms

Portal, systemic and

peripheral congestion

(pulmonary oedema, ascites,

facial engorgement), TR

Dyspnoea, reduced ET,

fatigue, PND, orthopnoea,

pulmonary oedema, cardiac

asthma, cool peripheries,

muscle wasting

� Key principles of management:

� Treat the cause + exacerbating factors

� Diuretics + ACE-i + β-blockers + spironolactove

� Intrinsic disease of heart

muscle

� Classification

� Physiological abnormality

� Underlying cause

� Clinical features:

� Sudden death / palpitations

� IHD symptoms

� Cardiac failure

CARDIOMYOPATHY

� Left ventricular hypertrophy (HOCM)

� Heavy muscular hypertrophy with poor compliance

� 0.2-0.5% population

� Enlargement of sarcomeres with disruption of alignment

� 50% familial (autosomal dominant, variable penetrance)

� Reduced LV outflow tract

� Presentation

� Arrhythmias

� LV outflow obstruction

� Cardiac failure

� Sudden death

HYPERTROPHIC CARDIOMYOPATHY

� 4 chamber dilatation and hypertrophy

� Progressive loss of myocytes

� Dilation + heart failure + arrhythmias

� 0.2% population

� 40% mortality at 2yrs

� Common causes

� Idiopathic – most common

� Genetic – autosomal dominant most common

� Infective – viral myocarditis

� Toxic – alcohol, chemotherapy (doxrubacin, herceptin), iron

DILATED CARDIOMYOPATHY

� Restriction of ventricular filling and myocardial

fibrosis

� Rare

� Features of RVF predominate

� Causes:

� Amyloidosis

� Haemachromatosis

� Sarcoidosis

� Loffler’s eosinophilic endocarditis

RESTRICTIVE CARDIOMYOPATHY

� A young Portuguese gentleman presents very unwell

with a high fever and fulminant TR. Blood cultures grow

Staph Aureus. Echo – large irregular vegetations

extending to the chordae

A. Acute Rheumatic Fever

B. Chronic Rheumatic fever

C. Acute Infective Endocarditis

D. Sub-acute Infective Endocarditis

E. Non-infective Endocarditis

F. Libman Sacks Endocarditis.

EMQ – VALVULAR PATHOLOGY

� A young woman presents with joint pains, a malar rash

and mitral regurgitation. ASOT negative. Blood cultures

negative. Echo shows small warty vegetations found

along the lines of closure.






F. Libman Sacks Endocarditis


� A young woman presents with joint pains and a rash.

The rash is geographical, has raised red edges and a

clear centre. She also has mitral regurgitation. ASOT

positive. Blood cultures negative. Echo shows small

warty vegetations. Histology – Sterile vegetations.






F. Libman Sacks Endocarditis


� Systemic infection

� Group-A β-haemolytic streptococci pharyngitis

� Ab cross-reactivity to valvular tissue (2-4/52 in 2% population)

� Modified Jones Criteria

� Evidence strep infection + 2 major / 1 major + 2 minor

RHEUMATIC FEVER

Evidence Group-A Strep

InfectionMajor Criteria Minor Criteria

Positive throat culture Carditis Fever

Rapid strep Ag test +ve Arthritis Raised CRP/ESR

Elevated strep Ab titre Subcutaneous nodules Arthralgia

Recent scarlet fever Erythema marginatum Prolonged PR interval

Sydenham’s chorea Previous rheumatic fever

� Aschoff bodies: acute foci of fibrinoid necrosis

� MacCalllum plaques - chronic subendocardial Aschoff collections

� 60% develop chronic rheumatic heart disease

� Thickening valve leaflet, thickening/shortening chordae tendinae

� MV (70%), AV (40%), TV (10%) PV (2%)

RHEUMATIC FEVER

� Fever + new murmur = endocarditis until proven

otherwise

� Infective

� Acute / sub-acute,

� Bacterial / fungal

� Non-infective – Libman-Sacks (SLE), Marantic (non-bacterial

thrombotic), verrucous (acute rheumatic fever)

ENDOCARDIDITIS

Acute Sub-acute

Staph aureus Strep viridans (>35% all cases)

Very virulent with acute course

5-50% mortality in weeks (age / embolic events)

Chronic, sub-acute course

Mortality in months

Previously normal valves Prosthetic valves / pre-existing valve damage

IV drug users / instrumentation Linked with dental infection

� Duke Criteria

� 2 major

� 1 major + 3 minor

� All 5 minor

ENDOCARDITIS

Major Criteria Minor Criteria

Positive blood culture

- Typical organism in >2 cultures

- 3x positive cultures >12hrs apart

Predisposition

Fever >38°c

Endocardium involvement

- Positive echo (vegetation, abscess,

dehiscence prosthetic valve)

- New valvular regurgitation

Vascular/immunological signs

+ve culture not major criteria

+ve echo not major criteria

� Cardiac complications

� Perforation of cusp/leaflet

� Rupture of chordae tendinae

� Abscess

� Fistula

� Outflow tract obstruction

� Most common cause of death is cardiac failure

� Abx prophylaxis is not recommended

� No proven association between intervention and endocarditis

� Risk of adverse reaction greater than endocarditis risk

ENDOCARDIDITS

� Aortic stenosis

� Aortic regurgitation

� Mitral stenosis

� Mitral regurgitation

� Common aetiologies

� Congenital

� Bicuspid valve

� Connective tissue disorders

� Acquired

� Infective - rheumatic fever / endocarditis

� Degenerative – calcification, MI

� Functional – HTN, PHTN

VALVULAR DISEASE

� Aortic stenosis

� Incomplete opening / narrowing of valve

� Valve area - mild (>1.5cm2), Critical (<0.5cm2)

� Pressure gradient (ventricular pressure > aortic pressure)

� Mild (<25mmHg), Critical (>80mmHg)

� Common causes

� Acquired – rheumatic fever

� Degenerative – calcification of valve cusps

� Congenital – bicuspid valve

� Classical triad – angina, syncope, heart failure

AORTIC VALVE DISEASE - STENOSIS

� Aortic regurgitation

� Valve incompetence

� Common causes:

� Acute – infective endocarditis, aortic dissection, trauma

� Chronic – congenital, connective tissue disorders, rheumatic fever,

vasculitis, rheumatoid arthritis, SLE, HTN

� Reduce systolic HTN

� Valve replacement prior to LV dysfuction

AORTIC VALVE DISEASE - REGURGITATION

� Mitral stenosis:

� Incomplete opening / narrowing of valve

� Valve area - <2cm2 (normal = 4-6cm2)

� Presentation: dyspnoea, fatigue, palpitations, chronic bronchitis

like picture

� Common causes:

� Rheumatic fever, congenital

� Complications

� PHTN, embolic disease, local mass effects

MITRAL VALVE DISEASE - STENOSIS

� Mitral regurgitation

� Valve incompetence

� Common causes:

� Functional - LV dilation

� Acquired - rheumatic fever, infective endocarditis, papillary

muscle/chordae tendinae rupture/damage

� Degenerative - annular calcification

� Congenital - connective tissue disorders, congenital defects

� Control AF, fluid offload, valve replacement

MITRAL VALVE DISEASE - REGURGITATION

� “Blood pressure at which benefit of treatment

outweighs the risk”

� 140/90 (additional risk factors) OR 160/100 (absolute)

� Thickening of intima/elastic lamina due to arteriosclerosis –

chronic low grade ischaemia

� Primary

� Idiopathic / essential = 95%

� Secondary

� Renal disease, endocrine drisease (Conn’s, phaeochromocytoma,

hyperthyroidism, Cushing’s)

� Pregnancy

� Drugs

HYPERTENSION

HTN – DIAGNOSIS / MANGEMENT

CBPM ≥160/100 mmHg

& ABPM/HBPM

≥ 150/95 mmHg

Stage 2 hypertension

Consider specialist referral

Offer antihypertensive drug treatment

Offer lifestyle interventions

If younger than 40 years

If target organ damage present or 10-

year cardiovascular risk > 20%

Offer annual review of care to monitor blood pressure, provide support and discuss lifestyle, symptoms and medication

Offer patient education and interventions to support adherence to treatment

CBPM ≥140/90 mmHg &

ABPM/HBPM

≥ 135/85 mmHg

Stage 1 hypertension

HTN TREATMENT ALGORITHM

Aged over 55 years or

black person of

African or Caribbean

family origin of any

age

Aged under

55 years

C2A

A + C2

A + C + D

Resistant hypertension

A + C + D + consider further diuretic or

alpha- or beta-blocker

Consider specialist referral

Key

A – ACE inhibitor or low-cost

angiotensin II receptor blocker

(ARB)1

C – Calcium-channel blocker

(CCB)

D – Thiazide-like diuretic

HYPERTENSION

RESPIRATORY TRACT DISEASE

“Asthma is a disease that has pract ical ly the same symptoms

as passion except that with asthma it lasts longer ”

- Anonymous JAMA 1964

� 17yr presents with a cough that wakes her at night. CXR normal.

Peripheral eosinophilia. Histo – smooth muscle hyperplasia

� 35yr with CF. Cough with purulent sputum on most days. He also

c/o decreasing exercise tolerance. O/E he is clubbed and has

bilateral coarse crackles. HRCT gives you the diagnosis

� A 60 year old non-smoker with progressive SOB of several

months duration. O/E clubbed + BL fine end-inspiratory crackles.

HRCT – honeycomb fibrosis

EMQ – COUGH

a) Cryptogenic fibrosingalveolitis

b) Extrinsic allergic alveolitis

c) Pneumonia

d) Asthma

e) Bronchiectasis

f) Occupational Lung disease

� 17yr presents with a cough that wakes her at night. CXR normal.

Peripheral eosinophilia. Histo – smooth muscle hyperplasia - D

� 35yr with CF. Cough with purulent sputum on most days. He also

c/o decreasing exercise tolerance. O/E he is clubbed and has

bilateral coarse crackles. HRCT gives you the diagnosis - E

� A 60 year old non-smoker with progressive SOB of several

months duration. O/E clubbed + BL fine end-inspiratory crackles.

HRCT – honeycomb fibrosis - A

a) Cryptogenic fibrosingalveolitis

b) Extrinsic allergic alveolitis

c) Pneumonia

d) Asthma

e) Bronchiectasis

f) Occupational Lung disease

EMQ – COUGH

� The end point for all respiratory disease

� Type I respiratory failure

� PaO2 <8kPa

� V/Q mismatch

� Pneumonia, PE, asthma, fibrosis, LVF

� Type II respiratory failure

� PaO2 <8kPa + PCO2 >6kPa

� Alveolar hypoventilation +/- V/Q mismatch

� COPD, neuromuscular disease, reduced drive, severe acute

asthma

RESPIRATORY FAILURE

� 95% embolic from deep veins of the legs/pelvis

� Large – massive PE often fatal / right heart failure

� Medium – symptomatic + pulmonary haemorrhage + respiratory

failure

� Small – clinically silent

� Multiple small PE a common cause of pulmonary HTN

� Key signs and symptoms

� SOB, pleuritic chest pain, haemoptysis, syncope

� Pyrexia, tachycardia, tachypnoea, hypotension, raised JVP, pleural

effusion, respiratory failure

� D-dimer, ECG (SI, QIII, TIII or tachycardia/RBBB), CXR, CTPA, V/Q

scan

PULMONARY VASCULAR DISEASE –

PULMONARY EMBOLISM


PULMONARY EMBOLISM

� Primary pulmonary hypertension

� Idiopathic

� PA pressure >25mmHg at rest

� Young women

� Secondary pulmonary hypertension

� Chronic lung disease, pulmonary vascular disease, thoracic cage

abnormalities, neuromuscular disease, hypoventilation

� Right heart failure – cor pulmonale

� 50% 5yr mortality


PULMONARY HYPERTENSION

RESPIRATORY AIRWAYS DISEASE

http://www.frca.co.uk/article.aspx?articleid=100023

RESPIRATORY AIRWAYS DISEASE

http://www.frca.co.uk/article.aspx?articleid=100023

� Remember the key points

� Kids > adults

� Chronic airways inflammation that is usually reversible

� Part of atopic trait

� Can be severe and life threatening

� Pathology

� Macroscopic – overinflated, patchy atelectasis, mucus plugs

� Microscopic – oedema, inflammatory pulmonary infiltrates,

smooth muscle and mucosal gland hypertrophy

RESPIRATORY AIRWAYS DISEASE -

ASTHMA

� COPD – bronchitis + emphysema

� Bronchitis

� “chronic cough with production of sputum most days, for a least 3 months in 2 consecutive years.”

� Blue bloaters – chronic hypoxia

� Emphysema

� “destruction/dilatation of the lung parenchyma distal to the terminal bronchioles.”

� Pink puffer – increased respiratory effort

� Smokers / A1AT

RESPIRATORY AIRWAYS DISEASE - COPD

� Emphysema

� Panacinar – affects whole lobule

� A1AT deficiency

� Centrolobular– part of lobule

� Upper respiratory tree

� Smokers

� Complications

� Bullae formation

� Pneumothorax

� Cor-pulmonale



� Permanent abnormal dilation of bronchi associated

with inflammation and secondary weakening

� Congenital – CF, severe immune deficiency

� Post-infectious – viral, bacterial, fungal

� Bronchial obstruction – tumour, foreign body

� Ciliary dysfunction – smoking, Kartagener’s syndrome

� Traction bronchiectasis – contraction of fibrous scar tissue

� Complications

� Chronic infection – H.influenzae

� Secondary infection – s.aureus, pseudomonas, moraxela

� RVF


BRONCHIECTASIS


BRONCHIECTASIS

� Wide group of conditions affecting the lung

parenchyma diffusely

� Characterised by chronic inflammation +/- progressive fibrosis

� SOBOE, cyanosis, non-productive cough, abnormal CXR, restrictive

picture on spirometry, clubbing, fine end inspiratory crackles

� Classification:

� Known cause – occupational, drug, hypersensitivty, infectious

� Associated with systemic disorders – sarcoid, RA, SLE, UC

� Idiopathic – IPF, cryptogenic fibrosing alveolitis, cryptogenic

organising pneumonia, lymphocytic interstital pneumonia

INTERSTITIAL LUNG DISEASE



Upper ZoneTB

Extrinsic allergic alveolitis

Ankylosing spondylitis

Radiotherapy

Sarcoidosis / Histoplasmosis

Middle ZoneProgressive massive fibrosis

Lower ZoneIdiopathic pulmonary fibrosis

Asbestosis

� Idiopathic/Cryptogenic fibrosing alveolitis

� Idiopathic diffuse pulmonary fibrosis

� Persistent fibroblast proliferation and fibrosis

� Dry cough, exertional dyspnoea, malaise, weight loss

� Right heart failure and increased risk malignancy

� Extrinsic allergic alveolitis

� Hypersensitivity pneumonitis – inhalation antigens

� Farmer’s lung – thermophilic actinomycetes

� Bird fancier’s lung – avaian proteins

� Pathology – interstitial pneumonitis + non-caseating gramulomas

PULMONARY FIBROSIS – 5 IMPORTANT

CAUSES

� Pneumoconioses

� Inflammatory lung disease due to mineral dust inhalation

� Coal dust – lung nodules (coal macules) + massive fibrosis

� Silicosis – nodular fibrosis

� Asbestosis – diffuse fibrosis

� Auto-immune disease

� Sarcoidosis – non-caseating granulomas + multi-system disease

� RA / SLE / systemic sclerosis / ankylosing spondylitis

� Drugs

� Potentially reversible pneumonitis � fibrosis

� Bleomycin, amiodarone, nitrofurantoin

PULMONARY FIBROSIS – 5 IMPORTANT

CAUSES

� Asbestosis – family of silicates

� Chrysotile (serpentines) – white

� Crocidolite (straight) – blue

� Amosite – brown

� Asbestos related lung disease:

� Pleural plaques – marker of exposure

� Asbestosis – pulmonary fibrosis

� Adenocarcinoma

� Synergistic effect with smoking

� Mesothelioma

� Cancer of mesothelial lining (pleural, pericardial, peritoneal)

� Estimated peak of disease 2020

� Any exposure – no threshold

ASBESTOSIS

INTRA-ALVEOLAR DISEASE – PULMONARY

OEDEMA / EFFUSION

� Hydrostatic/oncotic imbalance �� transudates

� Vessel permeability �� exudates

INTRA-ALVEOLAR DISEASE – PULMONARY

OEDEMA / EFFUSION

Transudates (<25g/L) Exudates (>25g/L)

Cardiac failure

Liver cirrhosis

Hypoalbuminaemia

SVC obstruction

Constrictive

pericarditis

Malignancy

Infection

Inflammation

� Acute Respiratory Distress Syndrome (ARDS)

� Acute respiratory failure + non-cardiogenic pulmonary oedema �

reduced lung compliance + refractory hypoxaemia

� Respiratory component of SIRS / MOF

� Discrete histopathological stages

� Inflammatory/exudative phase – 24hrs

� Massive inflammatory response

� Formation of non-cardiogenic pulmonary oedema

� Type II pneumocyte dysfunction – reduced surfactant production

� Proliferative phase – 5-10 days

� Proliferation type II pneumocytes + fibroblasts

� Progressive interstitial fibrosis

ARDS

NEOPLASTIC LUNG DISEASE

� The most common primary malignancy in the world

� 7-10% 5yr survival - ¼ all male cancer deaths in UK

� Benign tumours

� Rare - <10%

� Hamartomas, clear cell tumours, papillomas, gland adenomas

� Commonly asymptomatic

� Malignant tumours

� Non-small cell (adenocarcinoma, large cell carcinoma, SCC) – 80%

� Small cell (neuroendocrine) – 20%

NEOPLASTIC LUNG DISEASE

� Clearly defined risk factors

� Smoking - >75% cases

� Progressive squamous metaplasia � dysplasia � neoplasia

� Abnormal cells proportional to exposure

� Asbestosis – 50x increased risk

� Synergistic with tobacco smoke exposure

� Environmental agents

� Ionising radiation

� Infection

� Cryptogenic fibrosing alveolitis

NEOPLASTIC LUNG DISEASE -

PATHOGENESIS

� Squamous cell carcinoma

� 25-40% all lung cancers

� Closely associated with smoking

� Commonly central tumour arising from bronchial epithelium

� Significant early hilar LN spread, metastasises late

� Squamous cell differentiation

� Frequently haemorrhagic with cavitating necrosis

NEOPLASTIC LUNG DISEASE –

SQUAMOUS CELL CARCINOMA

� Adenocarcinoma

� 25-40% of all lung cancers

� Arises from glandular cells – e.g. mucus goblet cells

� P53 – 30% of adenomatous hyperplasia

� More common in far east, females and non-smokers

� Commonly peripheral and multi-centric

� Associated with pulmonary fibrosis/asbestosis

� Metastasises late – 80% at diagnosis


ADENOCARCINOMA

� Large cell carcinoma

� Central and highly aggressive/destructiove

� Haemorrhage and necrosis common

� Un-differentiated

� Poor prognosis

� Small cell carcinoma (Oat cell)

� 20-25% of all lung cancers

� Often central and arising from near main brinchi

� 80% present with advanced disease

� Paraneoplastic syndrome common

� Metastasise early

� Histologically hyperchromatic nuclei and indistinct nucleoli


LARGE CELL / SMALL CELL CARCINOMA

� Local effects

� Bronchial obstruction

� Impaired mucus clearance

� Local invasion

� Distant effects

� Peptide production – ACTH, ADH, PTH (SCC)

� Paraneoplastic syndromes

� Lambert-Eaton myaesthenic syndrome, acanthosis nigrans

� Metasteses – bone, brain, liver


CLINICAL EFFECTS

� Malignancy of lung pleura – <1% all cancer deaths

� Associated with asbestos exposure

� Long lag to presentation

� M>F

� Nodule � confluent sheet surrounding lung � chest wall invasion

� Poor prognosis - <2yrs

� Histologically – mixed epithelial and spindle cell tumours


MESOTHELIOMA

BONE & JOINT DISEASE

� Principle functions of bone

� Mechanical – support and site of muscle attachment

� Protective – vital organs and bone marrow

� Metabolic – calcium reserve and site of haematopoiesis

� Composition of bone

� Inorganic vs organic

� Bone subtypes

� Cortical bone – long bones, mechanical/protective

� Cancellous bone – axial skeleton, metabolic

BONE – THE BASCIS

BONE – THE BASICS

� Common osteoprogenitor

� Osteoblasts – line endosteal

surfaces and deposit osteoid

� Osteoclasts – multi-nucleate

cells of macrophage family

involved in bone resorption

� Osteocytes – osteoblast cells

trapped within bone matric in

lacunae

� Bone homeostasis

dependent on balance of

deposition/resorption

BONE – THE BASICS

• bone mass + normal mineralization

• Aggressive & malignant tumour of adolescents

• osteoclastic activity + PTH + Ca2+ + normal renal function

• bone mineralization + renal failure/malabsorption

• osteoblast activity + osteoclast activity bone pain with

normal Ca2+ & normal PTH

A. Bony metastasis

B. Chrondrosarcoma

C. Ewing’s sarcoma

D. Gout

E. Osteoarthritis

F. Osteomalacia

G. Osteomyelitis

H. Osteoporosis

I. Osteosarcoma

J. Paget ’s disease

K. 1° hyperparathyroidism

L. Rheumatoid arthritis

M. 2° hyperparathyroidism

N. 3° hyperparathyroidism

EMQ – DISORDERS OF BONE

• bone mass + normal mineralization - H

• Aggressive & malignant tumour of adolescents - C

• osteoclastic activity + PTH + Ca2+ + normal renal function - K

• bone mineralization + renal failure/malabsorption - F

• osteoblast activity + osteoclast activity bone pain with

normal Ca2+ & normal PTH - J

A. Bony metastasis

B. Chrondrosarcoma

C. Ewing’s sarcoma

D. Gout

E. Osteoarthritis

F. Osteomalacia

G. Osteomyelitis

H. Osteoporosis

I. Osteosarcoma

J. Paget ’s disease

K. 1° hyperparathyroidism

L. Rheumatoid arthritis

M. 2° hyperparathyroidism

N. 3° hyperparathyroidism

EMQ – DISORDERS OF BONE

METABOLIC BONE DISEASE

� Disordered bone turnover

� 3 principle categories

� Non-endocrine – e.g. age related osteoporosis

� Endocrine – e.g. Vit D, parathyroid hormone

� Disuse osteopaenia

METABOLIC BONE DISEASE

� Bone – normal quality, reduced density

� Primary – age, post-menopause

� Secondary – drugs, systemic disease

� Generalised vs local

� Key risk factors

� 1/3 women and 1/12 men >50yrs

� Fragility fractures � 50% lose independence, 20% mortality

OSTEOPOROSIS

OSTEOPOROSIS

� Defective bone mineralisation

� Vitamin D deficiency

� Phosphate deficiency

� Bone pain, fractures, proximal weakness, deformity

OSTEOMALACIA / RICKETS

PARATHYROID DISEASE

� Hyperparathyroidism

� Primary - >80% single adenoma

� Secondary – prolonged hypocalcaemia

� Tertiary – autonomous PTH

PARATHYROID DISEASE

� Disorder of bone turnover

� Characterised by lytic/sclerotic lesions

� >40yrs, M=F

� Pain, micro-fractures, nerve compression

� Aetiology unknown

� 1% will neoplastic change - osteosarcoma

PAGET’S DISEASE OF BONE

NEOPLASTIC BONE DISEASE

� Benign tumours

� Primary bone tumours are uncommon

� <30yrs

� Site and age predilication

� Classification based upon cytological appearance and matrix

product

� Diagnosis – symptoms, XR appearance, biopsy

� Secondary bone tumours

� Common

� >50yrs

NEOPLASTIC BONE DISEASE

� Osteochrondroma

� Cartilage capped bony protrubence of metapysis/diaphysis

� Growth plate derived - 10-20yrs, M>F

� Osteochondromatosis may lead to malignant transformation

� Enchondroma

� Sub-periosteal chrondroma

� Radiological appearance of lytic cotton wool calcifcation

� Multiple enchrondromas = Maffucci’s Syndrome

� Significant risk of malignant transformation

BENIGN BONE TUMOURS

� Osteoma (“ivory osteoma”)

� Smooth non tender mound rarely

causing symptoms

� Common on surface of skull vaukt

� Osteoid Osteoma

� Long bones of young males, small <1cm

� Continuous pain worse at night

� Lytic lesion with a central nidus and

sclerotic rim

� Highly vascular and histologically well

defined

BENIGN BONE TUMOURS

PRIMARY BONE TUMOURS

Bone Tumour Age Site Radiology Histology Prognosis

Osteosarcoma<20yr

sLong bones

Lytic changes with

elevated periosteum

(Codman’s triangle)

Mesenchymal

cells

(osteoblastic/cho

ndroblastic)

60% 5yr

Chondrosarcoma>40yr

s

Pelvis, axial

skeleton or

long bones

Lytic destruction with

fluffy calcification

Myxoid/hyaline

cartilage70% 5yr

Ewing’s Sarcoma<20yr

sAny bone

Onion skinning of

periosteum + lytic

changes and sclerosis

Small round cell

tumour75%

� Osteosarcoma > chrondrosarcoma > Ewing’s sarcoma

� Rare – osteosarcoma ≈150/annum in UK

PRIMARY BONE TUMOURS

� Typical primary sites

� Lung, thyroid, breast, prostate,

kidney

� Symptoms

� Pain, fracture, cord compression,

hypercalcaemia, anaemia

� Radiology

� Principally lytic

� Prostate is sclerotic

SECONDARY BONE TUMOURS

• Epigastric pain which is worse lying f lat . An endoscopy and biopsy reveals

squamous inf lammation and basal cel l prol iferation

• 38yr with RA presents with melaena. Endoscopy & biopsy reveals gastric

erosions and a neutrophil inf i ltrate

• 30yr diarrhoea and weight. Duodenal biopsy - cytotoxic T-cel ls

• 60yr with epigastric pain rel ieved by meals and antacids. +ve CLO test

• Biopsy 2cm change to columnar epithel ium in the lower oesophagus

A. Active chronic gastritis

B. Acute gastritis

C. Barrett ’s oesophagus

D. Coeliac disease

E. Duodenal ulcer

F. Gastric ulcer

G. GORD

H. Intestinal metaplasia

I. Streptococcus pneumoniae

J. Normal oesophagus

K. Oesophageal varicies

L. Pernicious anaemia

M. Squamous carcinoma

EMQ – GI DISORDERS

• Epigastric pain which is worse lying f lat . An endoscopy and biopsy reveals

squamous inf lammation and basal cel l prol iferation - G

• 38yr with RA presents with melaena. Endoscopy & biopsy reveals gastric

erosions and a neutrophil inf i ltrate - B

• 30yr diarrhoea and weight. Duodenal biopsy - cytotoxic T-cel ls - D

• 60yr with epigastric pain rel ieved by meals and antacids. +ve CLO test - E

• Biopsy 2cm change to columnar epithel ium in the lower oesophagus - C

EMQ – GI DISORDERS

A. Active chronic gastritis

B. Acute gastritis

C. Barrett ’s oesophagus

D. Coeliac disease

E. Duodenal ulcer

F. Gastric ulcer

G. GORD

H. Intestinal metaplasia

I. Streptococcus pneumoniae

J. Normal oesophagus

K. Oesophageal varicies

L. Pernicious anaemia

M. Squamous carcinoma

� 25yr with weight loss, abdominal pain and PR bleeding.

Endoscopy – transmural inflammation, non-caseating

granulomas, skip lesions

� 24yr with known IBD presents with an itchy perineum. He has

noticed discharge which soils his underwear. Examination shows

a “Pepper pot anus”

a) Crohn’s Disease

b) Ulcerative colitis

c) Both

d) Neither

EMQ – INFLAMMATORY BOWEL DISEASE

� 25yr with weight loss, abdominal pain and PR bleeding.

Endoscopy – transmural inflammation, non-caseating

granulomas, skip lesions - A

� 24yr with known IBD presents with an itchy perineum. He has

noticed discharge which soils his underwear. Examination shows

a “Pepper pot anus” - A

a) Crohn’s Disease

b) Ulcerative colitis

c) Both

d) Neither

EMQ – INFLAMMATORY BOWEL DISEASE

END OF PART 1 – ANY QUESTIONS?

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MedEd Histopathology Revision Lecture 2013 Part 1 · What is the differential diagnosis for acute onset ... ATHEROSCLEROSIS – RISK FACTORS Key Risk ... MedEd Histopathology Revision