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Phase 2a - Conditions > Pathology > Flashcards

Pathology Flashcards

1
Q

What is acute inflammation?

A

Acute inflammation is the initial and often transient series of tissue reactions to
injury - may last from a few hours to a few days

  • Short duration

e.g. Appendicitis

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2
Q

What is the characteristic cell recruited to the tissue in acute inflammation?

A
  • Neutrophil polymorph (white blood cell) + Monocytes are the characteristic cells recruited to the tissue
  • Neutrophils phagocytose pathogens while monocytes migrate to tissue and become macrophages which secrete chemical mediators for chemotaxis
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3
Q

What are the steps for acute inflammation?

A
  • Initial reaction of tissue to injury:
    –> Vascular component: dilation of vessel
    –> Exudative component: vascular leakage of protein-rich fluid
  • Neutrophil polymorph (white blood cell) is the characteristic cell recruited to the tissue
  • The presence of the cellular component, the neutrophil polymorph, is essential
    for a histological diagnosis of acute inflammation
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4
Q

What are the outcomes of acute inflammation?

A

1) Resolution
- The complete restoration of tissues to normal

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

e.g. lobar pneumonia

2) Suppuration - pus formation e.g abscess

3) Progression to chronic inflammation when causative agent is not removed

4) Organisation:

  • Replacement by granulation tissue
  • New capillaries grow into the inflammatory exudate, macrophages migrate and fibrosis occurs
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5
Q

What are the causes of acute inflammation?

A

1) Microbial infections e.g pyogenic (pus causing) bacteria, viruses

2) Hypersensitivity reactions (immunologically mediated - e.g parasites, tubercle bacilli)

3) Physical agents e.g trauma, ionising radiation, heat, cold (frost-bite)

4) Chemicals e.g corrosives, acids, alkalis, reducing agents

5) Bacterial toxins

6) Tissue necrosis e.g. ischaemic infarction

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6
Q

What are the essential macroscopic appearances of acute inflammation?

A

1) Redness - rubor
2) Heat - calor
3) Swelling - tumor
4) Pain - dolor
5) Loss of function is also characteristic

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7
Q

What is Chronic inflammation?

A
  • Subsequent and prolonged response to tissue injury
  • Cells involved = lymphocytes, macrophages, plasma cells
  • Longer onset, long last effects
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8
Q

What are the causes of Chronic inflammation?

A
  • 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. Crohn’s, sarcoidosis

*Transplant rejection

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9
Q

What are the macroscopic appearances of chronic inflammation?

A
  • Chronic ulcer
  • Chronic abscess cavity
  • Granulomatous inflammation
  • Fibrosis
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10
Q

What are the microscopic appearances of chronic inflammation?

A
  • Characteristically lymphocytes, plasma cells and macrophages
  • Exudation is not a common feature
  • Evidence of continuing destruction
  • Possible tissue necrosis
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11
Q

Describe the cellular cooperation in chronic inflammation?

A
  • 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

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12
Q

Describe the role of Granulomas in chronic inflammation?

A
  • An 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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13
Q

Compare Acute inflammation vs Chronic inflammation

A

Acute inflammation:

  • Fast onset, short duration
  • Neutrophils + Monocytes
  • Neutrophil extravasation
  • Rubor, calor, tumor, dolor

Chronic inflammation:

  • Cellular infiltrate of lymphocytes, macrophages and plasma cells
  • Possible granulomas
  • Slow onset, long duration
  • Lymphocytes,
    macrophages+ Plasma cells
  • Fibrosis, scar tissue
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14
Q

Define thrombosis

A

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

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15
Q

Describe the role of platelets in thrombosis and embolism

A
  • 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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16
Q

Describe the formation of a thrombosis

A
  • 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 (Reduced blood flow, blood vessel injury, increased coagulability)
  • Typically thrombi are formed by 2 of these factors
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17
Q

Describe Virchow’s triad

A

1) Reduced blood flow - STASIS

Atrial fibrillation, long distance travel, varicose veins, venous obstruction (pregnancy), immobility, ventricular/venous insufficiency

2) Blood vessel injury - ENDOTHELIAL INJURY

Trauma (orthopaedic), Orthopaedic or major surgery, Hypertension, invasive procedures (cannulation)

3) Increased coaguability - HYPERCOAGULABILITY

Sepsis, smoking, coagulation disorders, malignancy (cancer)

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18
Q

Describe arterial thrombosis

A

Arterial Thrombosis:

  • An atheromatous plaque will result in a change in the vessel wall

1) Atheromatous plaque may have a fatty streak

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

3) This turbulence results in the loss of intimal cells

4) Fibrin deposition and platelet clumping occurs

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

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

7) The structure protrudes further into the lumen causing more turbulence and more platelet deposition

8) Thrombi grow in the direction of blood flow –> propagation

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19
Q

Describe Venous thrombosis

A
  • 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
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20
Q

What are the clinical features of arterial thrombi?

A
  • Loss of pulse distal to thrombus
  • Area becomes cold, pale and painful
  • Possible gangrene
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21
Q

What are the clinical features of venous thrombi?

A
  • Tender
  • Area becomes reddened and swollen
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22
Q

What are the outcomes of thrombosis?

A

1) Resolve:

  • Best case scenario
  • Body dissolves and clears it

2) Organised

  • Becomes a scar
  • Results in slight narrowing of the vessel lumen

3) Recanalisation

  • Intimal cells may proliferate
  • Capillaries may grow into the thrombus and fuse to form larger vessels

4) Embolus
- Fragments of the thrombus break off into the circulation

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23
Q

Compare arterial thrombosis and venous thrombosis

A

Arterial thrombus:

  • Commonly caused by atheroma
  • High pressure
  • Mainly made of platelets
  • Can lead to MI/Stroke

Treatment = Anti-platelets , e.g. Aspirin

Venous thrombus:

  • Commonly caused by stasis
  • Low pressure
  • Mainly made of RBC’s
  • Can lead to DVT/PE

Treatment = Anti-Coagulants , e.g. Warfarin

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24
Q

What is an Embolism

A

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

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25
Q

Describe Arterial embolism

A
  • 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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26
Q

What can a Venous embolism result in?

A
  • A venous embolism can result in a pulmonary embolism
  • In the venous system, emboli travel to the vena cava and lodge in the pulmonary arteries
  • This results in a PE
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27
Q

What can a Small emboli result in?

A
  • May occur unnoticed
  • Can cause idiopathic pulmonary hypertension
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28
Q

What can a Large emboli result in?

A
  • Acute respiratory or cardiac problems
  • Resolve slowly
  • Result in chest pain and shortness of breath
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29
Q

What can a Massive emboli result in?

A
  • Result 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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30
Q

Define Ischaemia

A

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 it

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31
Q

Define Infarction

A

Infarction is the necrosis of part of the whole of an organ that occurs when the artery supplying it becomes obstructed

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32
Q

What are the effects of ischaemia?

A
  • Effects can be reversible
  • Duration of an ischaemic attack is brief
  • Cardiomyocytes and cerebral neurons are most vulnerable
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33
Q

What are the effects of infarction?

A
  • 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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34
Q

Define Atherosclerosis

A
  • Disease characterized by the formation of atherosclerotic plaques in the intima of large and medium-sized arteries, e.g. coronary arteries
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35
Q

What does an atherosclerotic plaque involve?

A
  • 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
  • Is often asymptomatic
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36
Q

What can result if a thrombus forms on an atherosclerotic plaque?

A
  • Cerebral infraction
  • Carotid atheroma, leading to TIAs
  • MI
  • Aortic aneurysm (can cause sudden death)
  • Peripheral vascular disease
  • Gangrene
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37
Q

Describe the formation of an atherosclerotic plaque

A
  • 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 –> with T lymphocytes they will express cell adhesion molecules which recruit other cells into
    the area.
  • Smooth muscle proliferation (to intima) around the lipid core and formation of a fibrous cap (collagen)
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38
Q

What are the risk factors for atherosclerosis?

A
  • Hypercholesterolaemia –> most important risk factor
  • Smoking
  • Hypertension
  • Diabetes
  • Male sex
  • Increasing age
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39
Q

What are the preventative measures for atherosclerosis?

A
  • Smoking cessation
  • Blood pressure control
  • Weight reduction
  • Low dose aspirin –> inhibits aggregation of platelets
  • Statins –> cholesterol reducing drug
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40
Q

Define Apoptosis

A

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

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41
Q

What factors inhibit Apoptosis?

A
  • Growth factors
  • Extracellular cell matrix
  • Sex steroids
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42
Q

What factors induce Apoptosis?

A
  • Glucocorticoids
  • Free radicals
  • Ionising radiation
  • DNA damage
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43
Q

What are the two pathways for Apoptosis?

A

The intrinsic pathway and the extrinsic pathway

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44
Q

What does the intrinsic apoptosis pathway involve?

A
  • The intrinsic pathway responds to growth factors and biochemical stress
  • p53 gene induces cell cycle arrest and initiates DNA damage repair
  • If damage is difficult to repair, p53 can induce apoptosis
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45
Q

What does the extrinsic apoptosis pathway involve?

A
  • The extrinsic pathway is used by the immune system to eliminate lymphocytes
  • It involves ligand-binding at death receptors on the cell surface
  • Ligand-binding results in the clustering of receptor molecules (such as TNFR1 + CD95) on the cell surface and the initiation of signal transduction cascade
  • Caspases are activated, triggering apoptosis
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46
Q

Define Necrosis

A

Necrosis is traumatic cell death which indices inflammation and repair - It is characterised by bioenergetic failure and loss of plasma membrane integrity

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47
Q

What are the different types of necrosis?

A
  • Coagulative necrosis - can occur in most organs
  • Liquefactive necrosis
  • Caseous necrosis
  • Gangrene
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48
Q

What is the most common type of necrosis

A
  • Coagulative necrosis - can occur in most organs
  • Caused by ischaemia
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49
Q

Where does liquefactive necrosis occur?

A

It occurs in the brain due to its lack of substantial supporting stroma

50
Q

Describe Caseous necrosis

A
  • It causes a ‘cheese’ pattern
  • TB is characterised by this form of necrosis
  • Caseous necrosis in biopsy = TB
51
Q

Describe Gangrene

A
  • Gangrene is necrosis with rotting of the tissue
  • The affected tissue appears black due to deposition of iron sulphide
52
Q

Define Hypertrophy

A
  • Increase in cell size without cell division
  • Muscle hypertrophy can be seen in athletes due to increased muscle activity
  • Hypertrophy of uterine smooth muscle at puberty and pregnancy - stimulated by oestrogens
53
Q

Define Hyperplasia

A
  • Increase in cell number by mitosis
  • This can only happen in cells that divide –> cannot happen in myocardial cells or nerve cells
  • Hyperplasia of bone marrow cells can be seen in those living at high altitudes
54
Q

Define Atrophy

A
  • 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
55
Q

Define Metaplasia

A
  • The change in differentiation of a cell from one fully-differentiated cell type to another
  • Occurs 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

56
Q

Define Dysplasia

A
  • Morphological changes seen in cells in the progression to becoming cancer
  • Imprecise term –> not cancer, but could become cancer
  • Also refers to a lack of development i.e. dysplasia in bones whereby the
    bones simply haven’t developed properly
57
Q

Define Carcinogenesis

A
  • The transformation of normal cells to neoplastic cells through permanent
    genetic alterations or mutations
  • This term only applies to malignant (invade surrounding tissues) neoplasms
  • Its a multistep process
58
Q

Define Neoplasm

A
  • A lesion resulting from the autonomous or relatively autonomous abnormal
    growth of cells - a new growth
  • A neoplasm can’t arise in erythrocytes as they don’t have a nuclei
59
Q

Define Tumour

A
  • Any abnormal swelling
  • It includes neoplasm, inflammation, hypertrophy and hyperplasia
60
Q

Define Carcinogen

A

An environmental agent participating in the causation of tumours

61
Q

What are the different types of carcinogens?

A

1) CHEMICAL
- B-naphthylamine (dyes and rubber industry) can cause bladder cancer

  • Polycyclic aromatic hydrocarbons (soot exposure) can cause scrotal carcinoma

2) VIRUSES
- EBV is linked to Burkitt’s lymphoma

  • HPV is linked to cervical cancer

3) RADIATION
- U-V light - UVB more than UVA
- Ionising radiation - skin cancer in radiographers

4) HORMONES

  • Oestrogen has been shown to increase the incidence of mammary &
    endometrial cancer
  • Anabolic steroids have been shown to increase the incidence of
    hepatocellular carcinoma
  • Hormones, parasites & mycotoxins
  • Miscellaneous
  • Aflatoxins (Mycotoxin) linked to hepatocellular carcinoma
  • Asbestos has been linked to mesothelioma
62
Q

What host factors influence carcinogenesis?

A
  • Race
  • Diet
  • Constitutional factors - age, gender etc.
  • Premalignant lesions
  • Transplacental exposure
63
Q

Describe the differences between a benign and malignant tumour?

A

BENIGN
- Does not invade the basement membrane

  • Exophytic (grows outwards)
  • Low mitotic activity
  • Circumscribed
  • Necrosis and ulceration is rare

MALIGNANT
- Invades the basement membrane

  • Endophytic (grows inwards)
  • High mitotic activity
  • Poorly circumscribed
  • Necrosis and ulceration is common
64
Q

Describe the structure of a tumour?

A

Solid tumours consist of neoplastic cells and stroma

65
Q

Describe the role of stroma and neoplastic cells in the progression of a tumour?

A
  • The neoplastic cells synthesise or secrete cell products such as
    collagen, mucin or keratin; these often accumulate within the
    tumour
  • The stroma = mattress
  • It contains fibroblasts, collagen and blood vessels which perfuse the tumour
66
Q

What stimulates angiogenesis in a tumour?

A
  • Angiogenesis in tours is induced by factors secreted by the tumour cells
    such as vascular endothelial
    growth factor (VEGF)
  • This action is
    opposed by factors such as
    angiostatin and endostatin which have potential in cancer therapy
67
Q

How can benign tumours still cause morbidity and mortality if they are confined to their site of origin?

A
  • Pressure on adjacent structures (e.g. benign meningeal tumour
    causing epilepsy)
  • Obstruction to the flow of fluid (e.g. benign epithelial tumour
    blocking duct)
  • Production of a hormone (e.g. benign thyroid tumour causing
    thyrotoxicosis (excessive thyroid hormone)
  • Transformation into a malignant neoplasm
  • Anxiety & stress since patient thinks the lesions may be
    something more sinister
68
Q

Describe metastasis

A
  • Malignant neoplasms are invasive - they invade and destroy surrounding tissue
  • Invasion enables the neoplastic cells to penetrate the walls of blood
    vessels and lymphatic channels and thereby spread to other sites -
    this process is called metastasis (the spread of a malignant tumour
    from its site of origin)
  • All malignant tumours are invasive but not all metastasize - e.g. basal cell carcinoma
69
Q

What are the major histogenetic categories of origin?

A
  • Epithelial cells (forming carcinomas)
  • Connective tissues (forming sarcomas)
  • Lymphoid (ONLY GIVE RISE TO MALIGNANT NEOPLASMS) and/or
    haemopoietic organs (forming lymphomas or leukaemias)
70
Q

How do you name epithelial tumours?

A
  • All have suffix –oma

BENIGN

  • Papilloma (non-glandular tissue/non-secretory) - e.g. squamous cell papilloma/transitional cell papilloma
  • Adenoma (glandular/secretory tissue)

MALIGNANT

  • Carcinoma – malignant tumour of epithelial cells
    e.g. transitional cell carcinoma
  • Adenocarcinoma - malignant tumour of glandular epithelium
    e.g. adenocarcinoma of the stomach/breast
71
Q

How do you name BENIGN connective tumours?

A
  • Benign = oma
  • Malignant = sarcoma
  • Lipoma – benign tumour of adipocytes
  • Rhabdomyoma – benign tumour of striated muscle
  • Leiomyoma – benign tumour of smooth muscle cells
  • Chondroma – benign tumour of cartilage
  • Osteoma – benign tumour of bone
72
Q

How do you name MALIGNANT connective tissue tumours?

A
  • Liposarcoma – malignant tumour of adipocytes
  • Rhabdomyosarcoma – malignant tumour of striated muscle
  • Leiomyosarcoma – malignant tumour of smooth muscle cells
  • Chondrosarcoma – malignant tumour of cartilage
  • Osteosarcoma – malignant tumour of bone
  • Angiosacroma - malignant vascular tumour
  • Neurosarcoma - malignant tumour of the nerve
73
Q

What some exceptions to the rules of nomenclature in naming tumours?

A
  • Not all -omas are neoplasms e.g. granuloma –> chronic inflammation
  • Not all malignant tumours are carcinoma or sarcoma
  • Melanoma - malignant neoplasm of melanocytes
  • Mesothelioma - malignant tumour of mesothelial cells (line body
    cavities and outer surface of internal organs, secrete lubricating
    fluid)
  • Lymphoma - malignant neoplasm of lymphoid cells, all are malignant
74
Q

What are other exceptions to naming tumours?

A

Tumours named after the person who first discovered/described them:

  • Burkitt’s lymphoma - B-cell lymphoma caused by Epstein Barr virus
  • Ewing’s sarcoma - malignant tumour of bone
  • Hodgkin’s lymphoma - malignant lymphoma characterised by the
    presence of Reed-Sternberg cells
  • Kaposi’s sarcoma - malignant neoplasm derived from vascular
    endothelium, commonly associated with AIDs

• Teratoma - neoplasm of germ cell origin that forms cells representing all
three germ cell layers of the embryo; ectoderm, mesoderm & endoderm

• Carcinosarcomas - mixed malignant tumours showing characteristics of
epithelium & connective tissue

75
Q

Why do neoplastic cells proliferate so much and why are they immortal?

A
  • Neoplastic cells show uncontrolled proliferation with a prolonged or
    indefinite lifespan
  • This is enabled by autocrine growth stimulation due to abnormal expression of oncogenes
  • Inactivation of genes (tumour suppressor genes) that normally
    inhibit growth pathways
  • Reduced apoptosis due to the abnormal expression of apoptosis
    inhibiting genes (e.g. bcl-2)
76
Q

Define Metastasis

A
  • The process whereby malignant tumours spread from their site of origin
    (the primary tumour) to form other tumours (secondary tumours) at distant
    sites
  • Exception: Basal cell carcinoma is a malignant cancer that never metastasises
77
Q

Describe the process of metastasis

A

1) DETACHMENT of tumour cells from their neighbours

2) INVASION of the surrounding connective tissue to reach conduits of metastasis

3) INTRAVASATION into the lumen of vessels

4) EVASION of host defence mechanisms, such as NK cells

5) ADHERENCE to endothelium at a remote location

6) EXTRAVASATION of the cells from the vessel lumen into the surrounding tissue

7) Tumour cells proliferate in the new environment

  • Liposarcoma normally metastases to lung
78
Q

Which cancers metastasize to bone?

A
  • Bone is a site favoured by haematogenous metastases
    from five carcinomas:
    • Lung
    • Breast
    • Kidney
    • Thyroid
    • Prostate

Type of Tumours Promptly Leaping To Bone

  • Metastases are frequently multiple whereas primary
    tumours are usually solitary
  • Interestingly, solid tumours rarely metastasis to skeletal
    muscle or spleen despite their rich blood supply
79
Q

What are the types of ways tumours metastasize?

A

Haematogenous, lymphatic and transcoelemic spread

80
Q

What is transcoelomic spread?

A
  • In pleural, pericardial & peritoneal cavities where this results in a neoplastic effusion (an abnormal amount of
    fluid collecting between pleura, caused by tumour)
  • The fluid is rich in protein (it is an exudate) and may
    contain fibrin
  • The fluid also contains the neoplastic cells causing the
    effusion
  • Peritoneal effusions (ascites) may be due to involvement by any abdominal tumour
  • Pleural and pericardial effusions are common
    consequences of carcinomas of the breast and the lung
81
Q

What is the most common type of metastases?

A
  • Lymphatic metastasis is common (secondary tumours in lymph nodes)
  • Carcinomas prefer lymphatic spread
  • Sarcomas prefer haematogenous spread
82
Q

What is tumour staging?

A
  • Staging is the extent of a tumours spread
  • Determined by histopathological examination and clinical examination
83
Q

What is the TMN staging system?

A

TNM Staging:

T - Refers to the primary tumour size
N – Refers to lymph node status - degree of lymph node involvement
M – Refers to extent of metastatic status

84
Q

What are the 6 signs of ishchaemia?

A

1) Pain
2) Pallor
3) Perishingly cold
4) Pulseless
5) Paraesthesia
6) Paralysis

85
Q

Why is there a long interval between a normal cell transforming into a growing neoplasm?

A
  • This process entails multiple genetic events
  • Initiation, promotion, and progression
86
Q

Describe the cellular events in carcinogenesis

A

• Initiation:
- When carcinogen induces a genetic alteration(s) that give the
transformed cell its neoplastic potential

• Promotion:
- The stimulation of clonal proliferation of the initiated transformed
cell

• Progression:
- The process culminating in malignant behaviour characterised by
invasion and its consequences

87
Q

Describe genetic mechanisms in carcinogenesis

A
  • Genetic alterations are the root cause of neoplastic cellular behaviour

1) Telomerase expression =
immortalisation on the cells - cells lacking
telomerase (most cells in the body, except for
stem cells and germ cell) have only a limited
replicative ability

2) Tumour suppressor gene inactivation

3) Activation or abnormal expression of
oncogenes to self stimulate cell
proliferation

• Tumour suppressor gene inactivation and
abnormal oncogene expression work in
together to drive cells from their normal state of
regulated growth to the deregulated and
uncontrolled growth that characterises neoplastic

88
Q

What is genomic instability

A
  • Maintenance of genomic integrity involves genes and their
    products (e.g p53) that sense and repair DNA damage
  • Failure of these processes causes genomic instability enabling the
    specific genetic alterations that result in neoplastic transformation
  • Genomic instability increases naturally with age
89
Q

What are the two types of tumour suppressor genes

A
  • Tumour suppressor genes (TSGs) are categorised according to their
    mechanism of action
  • Caretaker - These genes maintain the integrity of the genome by repairing
    DNA damage
  • Gatekeeper - These genes inhibit the proliferation or promote the death of
    cells with damaged DNA
90
Q

Give examples of CARETAKER tumour suppressor genes

A
  • BRCA 1:
    • Involved in DNA repair
    • If it mutates then breast & ovarian cancer
  • BRCA 2:
    • Involved in DNA repair
    • If it mutates then breast, prostate & pancreatic cancer
91
Q

Give examples of GATEKEEPER tumour suppressor genes

A

P53:

• The p53 levels rise in cells that have sustained DNA
damage until either the damage is repaired or the cell undergoes apoptosis - this prevents the propagation of possibly mutated genes

RB1:

• Transcriptional regulator; controls cell cycle G1/S
checkpoint

• Associated with retinoblastomas

• Retinoblastomas are malignant tumours derived
from the retina; they occur almost exclusively in
children

92
Q

What are oncogenes?

A
  • These are genes driving the neoplastic behaviour of cells
  • They do this by using the enzyme reverse transcriptase that enables viral DNA to be transcribed into complementary DNA = infected cell genome
  • In normal cells these cellular oncogenes are ESSENTIAL for normal cell
    and tissue growth & differentiation particularly during embryogenesis
    and healing
  • But when these genes are activated or inappropriately expressed they
    contribute to the growth of a tumour
93
Q

How are oncogenes activated in tumours?

A

1) Mutation = oncogene = excessively active

2) Gene amplification/ enhanced transcription = Excessive production of a normal oncoprotein

94
Q

What are oncogene products?

A

Growth factors + intracellular signalling

95
Q

Describe the mechanism of action of oncogenes

A
  • Translocation - Transcribed
  • Point mutation - eg. single base substitution in
    oncoprotein= hyperactive oncoprotein
  • Amplification - cellular proliferation stimulated by excessive quantities of the oncoprotein
96
Q

What factors influence tumour invasion?

A
  • Decreased cellular adhesion
  • Secretion of proteolytic enzymes (matrix proteinases)
  • Abnormal or increased cellular motility
  • Invasion is the most important sole criterion for malignancy
97
Q

How can you recognise invasion in epithelial tumours?

A

The basement membrane serves as a clear line of demarcation between the
tissue boundaries

98
Q

How can you recognise invasion in connective tissue tumours?

A
  • Invasion is less easy to recognise unless there is
    clear evidence of vascular or lymphatic permeation;
  • Histological features, such as mitotic activity are usually assessed for prognosis
99
Q

Define carcinomatosis?

A

Extensive metastatic disease

100
Q

What are the 4 categories of cells that renew?

A

1) LABILE CELLS:
- Have a good capacity to regenerate
- E.G. Surface epithelial cells

2) STABLE CELL POPULATIONS:
- Divide at a very slow rate normally

  • Still retain their capacity to divide when necessary
  • E.G. Hepatocytes and renal tubular cells

3) PERMANENT CELLS:
- Have no effective regeneration

  • E.G. Nerve cells and striated muscle cells

4) STEM CELLS
- Cells lost through injury or normal ageing are replaced from the stem cell
pool present in many labile & stable cell populations

101
Q

Define complete restitution

A
  • Loss of part of a labile cell population can be completely restored
  • e.g. in a minor skin abrasion:
  • The epidermis is lost over a limited area, but at the margins of the lesion
    there remain cells that can multiply to cover the defect

• At first, cells proliferate and spread out as a thin sheet until the defect is
covered

• When a confluent layer has been formed, the stimulus to proliferate is
switched off; this is known as contact inhibition, and controls both
growth and movement

• Once in place, the epidermis is rebuilt from the base up until it is
indistinguishable from normal - this whole process is called healing

102
Q

Define organisation

A
  • The repair of specialised tissues by the formation of a fibrous scar
  • Granulation tissue is formed in the early stages, often on a scaffold of fibrin,
    and any dead tissue is removed by phagocytes such as neutrophil
    polymorphs and macrophages
  • The granulation tissue contracts and gradually accumulates collagen to form the scar, which then undergoes remodelling
  • Organisation is a common consequence of pneumonia
  • In all instances, the organised area is firmer than normal, and often shrunken
    or puckered
103
Q

Define granulation tissue

A
  • The combination of capillary loops and myofibroblasts is known as
    GRANULATION TISSUE
104
Q

How is granulation tissue involved in repair?

A
  • When specialised or complex tissue is destroyed, it cannot be
    reconstructed - in these situations repair occurs

• Capillary endothelial cells proliferate and grow into the area to be repaired

• At the same time, fibroblasts are stimulated to divide and to secrete
collagen and other matrix components.

  • They also acquire bundles of muscle filaments and attachments to adjacent cells - these modified cells
    are called myofibroblasts and display features and functions of both
    fibroblasts and smooth muscle cells.
  • As well as secreting a collagen
    framework, they play a fundamental role in wound contraction
105
Q

Describe wound contraction and healing

A

• Wound contraction is important for reducing the volume of tissue for
repair; the tissue defect may be reduced by 80%

• It results from the contraction of myofibroblasts in the granulation tissue -
these are attached to each other and to the adjacent matrix components,
so that granulation tissue as a whole contracts and indrawn the
surrounding tissues

• Collagen is secreted and forms a scar, replacing the lost specialised
tissues - infection & associated inflammation are liable to increase
scarring

106
Q

What is healing by second intention?

A
  • When there is tissue loss or some other reason as to why the wound margins are not apposed, then another mechanism is necessary for
    repair
  • For example if there is haemorrhage locally this will keep the sides apart
    and prevent healing by first intention, infection similarly compromises
    healing
  • Phagocytosis to remove any debris
  • Granulation tissue to fill in defects and repair specialised tissue lost
  • Epithelial regeneration to cover the surface
107
Q

Give examples of cells that regenerate

A
  • Hepatocytes
  • Pneumocytes
  • All blood cells
  • Gut epithelium
  • Skin epithelium
  • Osteocytes
108
Q

Give examples of cells that don’t regenerate

A
  • Myocardial cells
  • Neurones
109
Q

Define congenital disease

A
  • A disease that is present at birth
  • Including chromosomal disorders + spontaneous genetic diseases
110
Q

Give an example of a genetic inherited disease?

A

• Caused by an inherited genetic abnormality

• Cystic fibrosis - autosomal recessive

• Sickle cell anaemia - autosomal recessive

• Familial adenomatous polyposis - autosomal dominant

• Colour blindness - X-linked, men more susceptible

• Huntington’s - present at birth but only manifests later in life

111
Q

Give an example of a genetic spontaneous disease?

A
  • Caused by a spontaneous mutation

• Down’s syndrome - Trisomy 21; mental retardation, flattened
facial profile & short hands

• Edwards’ syndrome - Trisomy 18; ear, jaw, cardiac & renal
abnormalities

• Patau’s syndrome - Trisomy 13; microcephaly, cleft palate & abnormal ears

112
Q

Give an example of a non-genetic environmental disease?

A
  • Acquired by environmental factors

• Good example is fetal alcohol syndrome since its not genetic but still present at birth

113
Q

Give an example of an acquired disease?

A
  • Disease caused by non-genetic environmental factors

• Tuberculosis
• Lung cancer
• Bone fracture
• AIDS

114
Q

Give an example of a multifactorial disease?

A

Diseases due to many different factors

• Neural tube defects:

  • Spina bifida - failure for neural tube to close properly resulting in exposed spinal cord
  • Anencephaly - absence of major portion of brain
  • Hydrocephalus - Build up of fluid on the brain
  • Likely to have a multifactorial pathogenesis although a dietary
    deficiency of folate (vitamin B9) is an established factor

• Cleft palate:

  • A congenital split in the roof of the mouth
  • The pathogenesis is particularly sensitive to both genetic &
    environmental disturbances
115
Q

Why do elderly adult cells not divide as well as fetal cells?

A
  • A cell’s ability to divide decreases the older we get

• Our fetal cells have the greatest potential for division

• Ageing is influenced by genetic and environmental
factors

116
Q

Why does a cell’s ability to divide decrease the older we get?

A
  • It happens due to telomeric shortening
  • At the tip of each chromosome, there is a non-coding randomly repetitive DNA sequence - the telomere
  • There telomeric sequences are not fully copied during DNA synthesis prior to
    mitosis - as a result a single-stranded tail of DNA is left at the tip of each
    chromosome; this is excised and, with each cell division, the telomeres are
    SHORTENED
  • Eventually the telomeres are so short that DNA polymerase is unable to
    engage with it and thus the cell is incapable of further replication
  • Only in germ cells and in embryos are telomeres replicated by the enzyme
    telomerase
  • Telomere length is inherited from your FATHE
117
Q

Describe the pathology of elderly

A
  • Sarcopaenia:

• Muscle loss due to ageing, begins from 40 onwards but accelerates
significantly from 80 onwards
• Caused by decreased growth hormone, decreased testosterone and
increased catabolic cytokines

  • Deafness - due to loss of hair cells in the ear
  • Senile dementia - due to brain atrophy since NERVE CELLS CANNOT
    REPLICATE
  • Cataracts - caused by UV light damage resulting in cross-linking proteins in
    the eye
  • Osteoporosis - due to lack of oestrogen as well as vitamin D & calcium in
    earlier life
  • Dermal elastosis - essentially wrinkling caused by UV light damage resulting
    in less collagen and less elastin in the skin - becomes more fragile
  • Impaired immunity - due to immunological changes resulting in less
    production of immune cells such as T cells
118
Q

What cells produce collagen in fibrous scarring?

A

Fibroblasts

119
Q

What is a carcinoma in situ?

A

A malignant epithelial neoplasm that has not yet invaded through the original basement membrane

120
Q

What is an invasive carcinoma?

A

A carcinoma that has breached the basement membrane – it can now spread elsewhere

121
Q

What is a Micro-invasive carcinoma?

A

A carcinoma that has breached the basement membrane but hasn’t invaded very far away from the original carcinoma

Phase 2a - Conditions (8 decks)

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