Pathology Phase 2a Recap - PowerPoint Presentation

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Pathology

Phase 2a Recap

Olivia Stevens and Judith Scott

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What we’ll cover:

Inflammation

Thrombosis and emboli

Infarction

Cell growth and death

Classification of tumours

Mechanisms of carcinogenesis

Main tumour types

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Inflammation

Acute

Initial response of tissue to injury Early onset (seconds to minutes)

Short duration

(hours to days)

Cells involved = neutrophils and monocytes

Acute Inflammation Steps:

Vascular component: dilation of vessels

Exudative component: vascular leakage of protein-rich fluidNeutrophil polymorph: cells type recruited to tissue

2 types



Acute and Chronic

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Causes

Microbial infections – bacteria, virusesHypersensitivity reactions – parasites

Physical agents – trauma, heat, coldChemicals – corrosives, acids

Bacterial toxins

Tissue necrosis – ischemic infarction

Acute Inflammation

Appearance:

Rubor

– redness; due to dilation of small vessels)Calor – heat; only seen peripherally

Tumor – swelling; results from

oedema

or a physical mass

Dolor - painLoss of function

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Acute Inflammation

Acute Inflammatory Response Process:

Changes in vessel caliber (gets wider)  increased vessel flow

Increased vascular permeability  formation of fluid exudate

Formation of cellular exudate  emigration of neutrophil polymorphs

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Acute Inflammation

Neutrophil Polymorph Emigration:

Migration of neutrophils

Due to increase in plasma viscosity and slowing of flow due to injury, neutrophils migrate to plasmatic zone

Adhesion of neutrophils

Adhesion to the vascular endothelium occurs in venules – called

pavementing

Neutrophil emigration Neutrophils pass through endothelial cells, onto the basal lamina and then the vessel wallDiapedesis RBCs may also escape from vessels, this is a passive process and indicates severe vascular injury

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Acute Inflammation

Outcomes of Acute Inflammation:

Resolution

The complete restoration of tissues to normal

There is minimal cell death and rapid destruction of the causal agent

E.g. acute lobar pneumonia

Suppuration

Formation of pus

This becomes surrounded by a pyogenic membrane, which is the start of healingLeads to scarring Organisation Replacement by granulation tissue

New capillaries grow into the inflammatory exudate, macrophages migrate and fibrosis occurs

Progression

Causative agent is not removed so there is progression to chronic inflammation

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Chronic Inflammation

Subsequent and prolonged response to tissue injury

Cells involved = lymphocytes, macrophages, plasma cells

Longer onset, long last effects

Causes:

Primary Chronic Inflammation

Resistance of infective agent, e.g. TB, leprosy

Endogenous materials, e.g. necrotic tissue

Exogenous materials, e.g. asbestos, silica Autoimmune conditions, e.g. Hashimoto’s, rheumatoid arthritis

Primary granulomatous diseases, e.g. Chron’s, sarcoidosis

Transplant rejection

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Chronic Inflammation

Macroscopic Appearance of Chronic Inflammation:

Chronic ulcer Chronic abscess cavity

Granulomatous inflammation

Fibrosis

Microscopic Appearance of Chronic Inflammation:

Characteristically lymphocytes, plasma cells and macrophages

Exudation is not a common feature

Evidence of continuing destruction Possible tissue necrosis

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Chronic Inflammation

Cellular Cooperation in Chronic Inflammation:

B lymphocytes Transform into plasma cells and produce antibodies

T lymphocytes

Responsible for cell-mediated immunity

Macrophages

Respond to chemotactic stimuli

Produce cytokines: Interferon alpha and beta, IL1, 6, 8, TNF-alpha

GranulomasAn aggregate of epithelioid histocytes TB, leprosy, Chron’s and sarcoidosis cause granulomas to develop

TB is the most common – use a

Ziehl-Neelsen

stain to identify

Granulomas and eosinophil presence indicates a parasite

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Inflammation Summary

Acute Inflammation

Chronic Inflammation

Fast onset, short duration

Slower onset, long duration

Neutrophils

Monocytes

Lymphocytes

MacrophagesPlasma Cells Neutrophil extravasation Cellular infiltrate of lymphocytes, macrophages and plasma cellsPossible granulomas

Rubor

,

calor

, tumor, dolor

Fibrosis, scar tissue

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Thrombosis and Embolism

Thrombosis:

The solidification of blood contents that forms within the vascular system during life

Role of Platelets:

No nucleus, derived from megakaryocytes

Contain alpha granules and dense granules

Alpha granules are involved in platelet adhesion, e.g. fibrinogen

Dense granules cause platelets to aggregate, e.g. ADP

Platelets are activated, releasing their granules when they come into contact with collagen If this happens within an intact vessel, a thrombus is formed

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Thrombosis

Thrombosis Formation:

First stage is platelet aggregation, which starts the clotting cascade These both have positive feedback loops

 hard to stop

Thrombosis is caused by 3 major factors  Virchow’s triad

Typically thrombi are formed by 2 of these factors

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Thrombosis

Arterial Thrombosis:

An atheromatous plaque will result in a change in the vessel wall Atheromatous plaque may have a fatty streak

Over time, the plaque grows and protrudes into the lumen causing a degree of turbulence in blood flow

This turbulence results in the loss of intimal cells

Fibrin deposition and platelet clumping occurs

Once this has started, the process is self-perpetuating, leading to the formation of the platelet layer (first layer of thrombus)

This layer allows for the precipitation of a fibrin meshwork in which RBCs get trapped

The structure protrudes further into the lumen causing more turbulence and more platelet deposition Thrombi grow in the direction of blood flow  propagation

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Thrombosis

Venous Thrombosis:

There is lower blood pressure in veins and atheroma do not occur Thrombi begin at valves

Valves produce a degree of turbulence, and can be damaged, e.g. trauma, stasis

When blood pressure falls, flow through the veins slows, allowing for a thrombus to form

Clinical Features:

Arterial thrombi

Loss of pulse distal to thrombus

Area becomes cold, pale and painfulPossible gangreneVenous thrombi

Tender

Area becomes reddened and swollen

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Thrombosis

Fate of Thrombi:

ResolveBest case scenario

Body dissolves and clears it

Organised

Becomes a scar

Results in slight narrowing of the vessel lumen

Recanalisation

Intimal cells may proliferateCapillaries may grow into the thrombus and fuse to form larger vessels Embolus Fragments of the thrombus break off into the circulation

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Thrombosis

Arterial Thrombus

Venous Thrombus

Commonly caused by atheroma

Commonly caused by stasis

High pressure

Low pressure

Mainly made of platelets

Mainly made of RBCsCan lead to MI/stroke

Can lead to DVT/PE

Tx = Anti-platelets, e.g. aspirin

Tx = Anti-coagulants, e.g. warfarin

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Embolism

A mass of material in the vascular system able to lodge in a vessel and block its lumen

Arterial Embolism:

Systemic embolism

Arterial emboli can travel anywhere downstream of its entry point

Mural thrombi in the left ventricle can go anywhere

Cholesterol crystals from an atheromatous plaque in the descending aorta can go to any lower limb or renal artery

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Embolism

Venous Embolism:

Pulmonary embolism In the venous system, emboli travel to the vena cava and lodge in the pulmonary arteries

This results in a PE

Small emboli

May occur unnoticed

Can cause idiopathic pulmonary hypertension

Large emboli

Can result in acute respiratory or cardiac problems Resolve slowlyResult in chest pain and shortness of breathMassive emboliResult in sudden death

Long thrombi derived from the leg veins

Often impacted across the bifurcation of one of the pulmonary arteries

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Ischaemia and Infraction

Ischaemia

is the reduction in blood flow to a tissue or part of the body caused by constriction or blockage of the blood vessels supplying itInfarction is the necrosis of part of the whole of an organ that occurs when the artery supplying it becomes obstructed

Ischaemia

:

Effects can be reversible

Duration of an

ischaemic

attack is briefCardiomyocytes and cerebral neurons are most vulnerable Infarction:

Usually a macroscopic event

Most organs only have a single artery supplying them so they are susceptible to infarcts

The liver, brain and lungs have dual supply

 less susceptible

Reperfusion injury = damage to tissue during re-oxygenation

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Atherosclerosis

Disease characterized by the formation of atherosclerotic plaques in the intima of large and medium-sized arteries, e.g. coronary arteries

Often asymptomatic

The accumulation of lipid, macrophages and smooth muscle cells in intimal plaques

Can cause life-threatening damage if a thrombus forms on a disrupted plaque

Cerebral infraction

Carotid atheroma, leading to TIAs

MI

Aortic aneurysm (can cause sudden death)Peripheral vascular disease

Gangrene

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Atherosclerosis

Formation:

Endothelial cell dysfunction (lots of cholesterol damages wall)High levels of LDL in the blood will begin to accumulate in the arterial wall

Macrophages are attracted to the site of damage and take up lipid to form foam cells (inflammatory response)

Formation of a fatty streak (earliest stage of plaque)

The activated macrophages will release lots of their own products - cytokines and growth factors

Smooth muscle proliferation (to intima) around the lipid core and formation of a fibrous cap (collagen)

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Atherosclerosis

Risk Factors:

Hypercholesterolaemia  most important risk factor

Smoking

Hypertension

Diabetes

Male sex

Increasing age

Preventative Measures:Smoking cessation Blood pressure controlWeight reduction

Low dose aspirin

 inhibits aggregation of platelets

Statins  cholesterol reducing drug

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Apoptosis and Necrosis

Apoptosis is a cellular process in which a defined and programmed sequence of intracellular events leads to the removal of a cell without the release of products harmful to surrounding cells

Regulation of Apoptosis:

Inhibitors

Growth factors

Extracellular cell matrix

Sex steroids

Inducers

GlucocorticoidsFree radicalsIonising radiation

DNA damage

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Apoptosis and Necrosis

Apoptosis Pathways:

Intrinsic:

Uses pro- and anti-apoptotic members of the Blc-2 family

Bax

forms

Bax-Bax

dimers which enhance apoptotic stimuli

The Bcl-2:Bax ratio determines the cell’s susceptibility to apoptotic stimuli Responds to growth factors and biochemical stress p53 gene induces cell cycle arrest and initiates DNA damage repairIf damage is difficult to repair, p53 can induce apoptosis

Extrinsic:

Ligand-binding at death receptors on the cell surface

Receptors include TNFR1 and CD95

Ligand-binding results in the clustering or receptor molecules on the cell surface and the initiation of signal transduction cascade

Caspases are activated, triggering apoptosis

This pathway is used by the immune system to eliminate lymphocytes

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Apoptosis and Necrosis

Apoptosis Pathways:

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Apoptosis and Necrosis

Necrosis is traumatic cell death which indices inflammation and repair

Characterised

by bioenergetic failure and loss of plasma membrane integrity

Coagulative necrosis

Most common type

Can occur in most organs

Cause by

ischaemiaLiquefactive necrosisOccurs in the brain due to its lack of substantial supporting stromaCaseous necrosis

Causes a ‘cheese’ pattern

TB is characterized by this form of necrosis

Gangrene

Necrosis with rotting of the tissue

Affected tissue appears black due to deposition of iron

sulphide

(from degraded

haemoglobin

)

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Cell Growth and Other Tissue Changes

Hypertrophy:

Increase in cell size without cell division Muscle hypertrophy can be seen in athletes due to increased muscle activity

Uterine hypertrophy is seen in pregnancy

Hyperplasia:

Increase in cell number by mitosis

This can only happen in cells that divide



cannot happen in myocardial cells or nerve cellsHyperplasia of bone marrow cells can be seen in those living at high altitudes

Atrophy:

The decrease in the size of an organ or cell be reduction in cell size and/or number

Occurs naturally during the development of the GU tract

Occurs in disease, e.g. muscle atrophy in ALS

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Cell Growth and Other Tissue Changes

Metaplasia:

The change in differentiation of a cell from one fully-differentiated cell type to anotherOccurs in response to alterations in the cellular environment

E.g. Squamous epithelium of the oesophagus can become columnar epithelium in response to stomach acid

 Barrett’s Oesophagus

Dysplasia:

Morphological changes seen in cells in the progression to becoming cancer

Imprecise term

 not cancer, but could become cancer

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Carcinogenesis

The transformation of normal cells into neoplastic cells through permanent genetic alterations or mutations

Neoplasm – A lesions resulting from the autonomous of relatively autonomous abnormal growth of cells

(Neoplasm cannot arise in erythrocytes as they do not have nuclei)

Tumours

– Any abnormal swelling

Carcinogens:

An environmental agent participating in the causation of

tumours

Smoking can cause lung

tumours

B-naphthylamine (dyes and rubber industry) can cause bladder cancerPolycyclic aromatic hydrocarbons (soot exposure) can cause scrotal carcinoma

EBV is linked to Burkitt’s lymphoma

HPV is linked to cervical cancer

UV radiation is linked to skin cancer

Aflatoxins (Mycotoxin) linked to hepatocellular carcinoma

Asbestos has been linked to mesothelioma

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Classification of Tumours

Classification is based on behaviour and histogenesis

Behavioural Classification:

Benign

Malignant

Does not invade the basement membrane

Invades the basement membrane

Exophytic (grows outwards)

Endophytic (grows inwards)

Low mitotic activity

High mitotic activity

Circumscribed

Poorly circumscribed

Necrosis and ulceration rare

Necrosis and ulceration common

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Classification of Tumours

Classification is based on behaviour and histogenesis

Histogenesis Classification:

Based on the specific cell or origin of the tumour

Epithelial cells form carcinomas

Connective tissues form sarcomas

Lymphoid forms lymphomas or leukaemia

Histological grading

Grade is based on the extent to which the tumour resembles its original histology Grade 1 – Well differentiated (most closely resembles parent tissue)Grade 2 – Moderately differentiated

Grade 3 – Poorly differentiated

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Nomenclature of Tumours

Epithelial Tumours:

All have suffix –omaBenign

 Papilloma (non-glandular tissue) or adenoma (secretory tissue)

Malignant

Carcinoma – malignant tumour of epithelial cells

Adenocarcinoma - malignant tumour of glandular epithelium

Connective Tissue Tumours:

BenignLipoma – benign tumour of adipocytes

Rhabdomyoma – benign tumour of satiated muscle

Leiomyoma – benign tumour of smooth muscle cells

Chondroma – benign tumour of cartilage

Osteoma – benign tumour of bone

Malignant

Liposarcoma

– malignant tumour of adipocytes

Rhabdomyosarcoma – malignant tumour of satiated muscle

Leiomyosarcoma – malignant tumour of smooth muscle cells

Chondrosarcoma – malignant tumour of cartilage

Osteosarcoma – malignant tumour of bone

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Invasion and Metastasis

Metastasis:

The process whereby malignant tumours spread from their site of origin to form other tumours at distant sites

Exception: Basal cell carcinoma

never

metastasises

Process:

Detachment of tumour cells from their neighbours

Invasion of the surrounding connective tissue to reach conduits of metastasisIntravasation into the lumen of vesselsEvasion of host defence mechanisms, such as NK cellsAdherence to endothelium at a remote location Extravasation of the cells from the vessel lumen into the surrounding tissue

Tumour cells proliferate in the new environment

Routes of Metastasis:

Bone metastasises from lung, breast, kidney, thyroid, prostate

Lymphatic metastasis is common (secondary tumours in lymph nodes)

Carcinomas prefer lymphatic spread

Sarcomas prefer haematogenous spread

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Invasion and Metastasis

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Tumour Staging

Staging is the extent of a tumours spread

Determined by histopathological examination and clinical examination

TNM Staging:

T - Refers to the primary tumour

N – Refers to lymph node status

M – Refers to metastatic status

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Formative Questions

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Question 1

Which 2 cell types are involved in the response to acute inflammation?

a) Neutrophils and basophilsb) Eosinophils and basophilsc) Neutrophils and monocytesd) Neutrophils and lymphocytese) Lymphocytes and monocytes

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Question 1

Answer = C

Neutrophils (6-24hrs) and monocytes (24-48hrs) are the cells involved in acute inflammation

Neutrophils phagocytose pathogens while monocytes migrate to tissue and become macrophages which secrete chemical mediators for chemotaxis

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Question 2

Which of these is NOT an outcome of acute inflammation?

a) Pus formationb) Destructionc) Organisationd) Resolutione) Progression to chronic inflammation

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Question 2

Answer = B

Pus formation (also known as suppuration) occurs when there is excessive exudate production during acute inflammation, organisation occurs when a tissue is replaced with granulation tissue as part of the healing process, resolution is complete restoration of tissues to normal and progression to chronic inflammation.

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Question 3

Hypertrophy is best described as:

a) Increased size of organ/tissue due to increased number of cellsb) Increased size of organ/tissue due to decreased number of cellsc) Increased cell growth and decreased differentiationd) Increased size of organ/tissue due to increased size of cells

e) Replacement of one differentiated tissue by another

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Question 3

Answer = D

Hypertrophy is an increase in size of organ/tissue due to an increase in the size of cells (this is due to an increase in protein synthesis and an increase in the size of intracellular organelles).

Option a = hyperplasia e.g. uterine enlargement, option b = doesn’t make sense, option c = dysplasia e.g. pre-cancer state, option e = metaplasia e.g. Barrett’s oesophagus

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Question 4

In which pathological process would you expect:

- Organelles to be damaged- Cell lysis- Inflammation- Altered chromatina) Metaplasiab) Apoptosis

c) Dysplasia

d) Hypertrophy

e) Necrosis

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Question 4

Answer = E

This is a description of cell death therefore the only answers can be B or E – apoptosis, however, is programmed cell death

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Question 5

What is a malignant neoplasm of smooth muscle called?

a) Adenocarcinomab) Leiomyomac) Rhabdomyomad) Leiomyosarcomae) Adenoma

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Question 5

Answer = D

An adenocarcinoma is a malignant neoplasm of glandular origin, a leiomyoma is a benign neoplasm of smooth muscle, a rhabdomyoma is a benign neoplasm of striated muscle and an adenoma is a benign neoplasm of glandular origin.

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Thank you for coming!

ostevens2@sheffield.ac.uk

jlscott2@sheffield.ac.uk