1
Q
What is the difference between a histopathologist and a cytopathologist?
A
- Histology is the study of tissue and histopathologists study diseases in tissue biopsies, usually using a light microscope
- Cytology is the study of cells and cytopathologists study cells from fine needle aspirates
2
Q
How do you distinguish a benign cell from a malignant cell?
A
- Malignant cells have high nuclear to cytoplasmic ratios, irregular nuclear membranes and an irregular distribution of chromatin within the nucleus
- Benign cells have low nuclear to cytoplasmic ratios, smooth nuclear membranes and evenly distributed chromatin
3
Q
Into what medium do you place a biopsy for histopathological assessment?
A
- Tissue biopsies are placed in formalin (a mixture of formaldehyde and saline)
4
Q
What happens to tissue if you do not do place it in formalin?
A
- The tissue will rot and will not be able to be examined
- Formalin crosslinks proteins within the tissue stopping its breakdown
5
Q
What is the stain used most commonly in histopathology?
A
- H+E (Haematoxylin and Eosin)
- Haematoxylin stains nuclei blue and eosin stains cytoplasm pink
6
Q
Which cell produces collagen which makes some tumours feel hard on palpation?
A
- Fibroblasts produce collagen around tumours
- Collagen is a protein which makes tumours and scar tissue hard to palpation.
7
Q
What is the difference between a transudate and an exudate?
A
- A transudate is a fluid (eg. within the pleural cavity) which is low in protein and an example of a transudate is a pleural effusion caused by heart failure
- An exudate is a fluid which is high in protein and an example of an exudate is an effusion caused by infection or malignancy.
8
Q
What is an adenocarcinoma?
A
- An adenocarcinoma is a malignant epithelial tumour showing gland formation (glandular differentiation)
9
Q
What is immunohistochemistry?
A
- Immunohistochemistry is the application of labelled antibodies to tissue slides in order to detect the presence of certain antigens of interest within the nucleus, cytoplasm or membranes of cells
- This technique is used to tell pathologists where a tumour has come from or the cell type which is present or what receptors a tumour is expressing.
10
Q
What is histology?
A
- Histology means the study of tissue and a tissue is a collection of structurally and functionally similar cells.
11
Q
What is gastrulation?
A
- This is the formation of 3 germ cell layers in the embryo - ectoderm, mesoderm and endoderm
12
Q
List some examples of mature tissues which derive from ectoderm
A
- Skin, nerves, eyes and ears
- adrenal, medulla and pituitary gland.
13
Q
List some examples of mature tissues which derive from mesoderm
A
- Muscle, bone + cartilage
- heart + blood vessels, the urogenital system, bone marrow, the lymphatic system and the adrenal cortex.
14
Q
List some examples of mature tissues which derive from endoderm
A
Lining of the gastrointestinal (GI) and respiratory tracts, GI organs (liver + pancreas), larynx, trachea
- lungs, thyroid gland, parathyroid glands and thymus.
15
Q
What epithelium covers the skin?
A
- Stratified squamous keratinising epithelium forms the epidermis of the skin.
16
Q
What happens to the surface keratin layer of the skin in psoriasis?
A
- In psoriasis there is an increased rate of epidermal turnover and this causes the keratin layer to get thickened
- Normal keratin has a basket-weave pattern with no nuclei visible but in psoriasis this basket weave is lost, the keratin layer is thickened and nuclei are retained in this layer because the keratinocytes do not have time to fully mature.
17
Q
Which structures provide strong adhesion between keratinocytes in the epidermis?
A
Desmosomes.
18
Q
What do you call a malignant tumour which derives from the epidermis of the skin (a malignant tumour of squamous epithelium) and how can you identify this?
A
- A malignant tumour of squamous epithelium is squamous cell carcinoma
- you can recognise a squamous cell carcinoma because it produces keratin and because you can identify desmosomes between the malignant cells.
19
Q
Which cell produces myelin and speeds up peripheral nerve conduction?
A
- Schwann cell. The schwann cell wraps its cytoplasm around the axon of a nerve insulating it and speeding up nerve conduction
- A schwann cell has a wavy spindle shaped nucleus.
20
Q
List 6 functions of epithelial cells.
A
- Protection.
- Absorption.
- Surface transport.
- Secretion.
- Excretion.
- Gas exchange.
21
Q
The most important stratified epithelial types are stratified squamous epithelium which may be keratinised or non-keratinised and transitional epithelium. Give one example of where you might find each of these in the body.
A
- Keratinised stratified squamous epithelium eg. epidermis of the skin.
- Stratified squamous non-keratinising epithelium eg. cervix and oral mucosa.
- Transitional epithelium eg. bladder, ureters and renal pelvis.
22
Q
What is the main function of transitional epithelium?
A
Transitional epithelium allows the ureters and bladder to stretch.
23
Q
List the important connective tissues and muscle types.
A
- The connective tissues include adipose tissue, fibrous tissue (such as dermis, tendons, ligaments), cartilage, bone and haemopoietic tissue (blood, bone marrow).
- The muscles include cardiac, skeletal and smooth muscle.
24
Q
If you have a bacterial infection which white blood cell would be raised on a full blood count?
A
Neutrophils
25
If you have asthma which white blood cells would be found in the bronchial lining?
Eosinophils
26
Which cell is the bodies main producer of antibodies?
The plasma cell.
27
Define homeostasis and give an example of a negative feedback loop and a positive feedback loop.
- Homeostasis is the process by which internal variables are kept within a normal range of values
- An example of a negative feedback loop is the control of blood sugar by insulin
- An example of a positive feedback loop is the coagulation (clotting) cascade.
28
What is the function of the Golgi apparatus?
The Golgi apparatus is responsible for protein modifications and for glycosylation of proteins and lipids.
29
What is the function of the Rough Endoplasmic Reticulum (RER)?
- Production of proteins and lipids and production of all of the cell organelles.
- Ribosomes translate mRNA into proteins and these proteins fold in the endoplasmic reticulum.
- Sugars can also be added to proteins in the RER
- If proteins misfold they are degraded or if this is excessive a stress response is triggered which can then initiate apoptosis.
30
What is the function of the Smooth Endoplasmic Reticulum?
- Smooth endoplasmic reticulum is the site of steroid and lipoprotein synthesis
- It can also make drugs less hydrophobic allowing their export
- Smooth endoplasmic reticulum (or sarcoplasmic reticulum) is also responsible for the release and storage of calcium ions that regulate muscle contraction.
31
Which ion channel is damaged in the disease cystic fibrosis?
- The cystic fibrosis transmembrane regulator or CFTR, which is responsible for chloride transport across cell membranes
- This leads to the secretion of sticky thick mucus.
32
List four mechanisms by which cells communicate.
1. Autocrine signalling.
2. Paracrine signalling.
3. Endocrine signalling.
4. Synaptic signalling.
33
List 4 possible outcomes following a ligand binding to a cell surface receptor and give one example of a ligand associated with each outcome.
1. An ion channel opens eg. neurotransmitter at neuromuscular junction.
2. A G-protein is activated eg. hormones.
3. A tyrosine kinase is activated eg. epidermal growth factor.
4. A latent transcription factor is activated eg. interferon.
34
Describe the function of a transcription factor and give one example of a transcription factor which facilitates cell division and one which stops cell division.
- A transcription factor (TF) is a protein which controls the rate of transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence
- MYC is an example of a TF that facilitates cell division
- p53 is an example of one which stops division.
35
What structural feature of collagen gives it strength and which vitamin is needed for collagen production? Give an example of one disease caused by a genetic collagen defect.
- Collagen has a triple helical structure which gives it significant strength
- This strength is enhanced by the presence of lateral cross links of the triple helices by covalent bonds which require vitamin C to form
- Genetic defects in collagen result in diseases such as osteogenesis imperfecta and Ehlers-Danlos syndrome.
36
Which disease is caused by a mutation in a component of elastin and what are the clinical consequences of abnormal elastin in this disease?
- Marfan's syndrome is caused by a mutation in the fibrillin-1 gene which is a component of elastin and elastin is important in the structure of heart valves, blood vessels, skin and ligaments
- Heart defects and lens dislocations are seen in Marfan's syndrome.
37
What are integrins and give two examples of where integrins are important in biology?
- Integrins are transmembrane glycoproteins which attach cells to the extracellular matrix and mediate cell-cell interaction
- Integrins mediate the interaction between white blood cells and the lining of blood vessels in the setting of inflammation
- They are also important in platelet aggregation in clotting and in tumour invasion.
38
What drives cell cycle progression?
Cell cycle progression is driven by proteins called cyclins and cyclin-associated enzymes called cyclin-dependent kinases (CDKs).
39
Where are the checkpoints in the cell cycle and what happens at each checkpoint?
1. Start (G1/S) checkpoint - to check if nutrition, the environment and cell size are favourable for replication and that all DNA is intact.
2. G2/M checkpoint - to check that DNA has been completely replicated.
3. Metaphase/anaphase checkpoint - to check that all DNA is intact and if all chromosomes are attached to the mitotic spindle.
40
What enforces cell cycle checkpoints and give an example of one of these? What is the consequence of a defective cell cycle enforcer?
- Cyclin-dependent kinase inhibitors (CDKIs) stop the cell cycle and enforce the checkpoints
- An example of a CDKI is p16
- Defective CDKI checkpoint proteins allow cells with DNA damage to replicate increasing the risk of malignancy.
41
What is the difference between embryonic stem cells and adult stem cells?
- Embryonic stem cells are totipotent stem cells which can give rise to all types of differentiated tissues
- Adult stem cells (also known as tissue stem cells) can only replace cells in the tissue in which they reside and these cells are found in stem cell niches in many organs.
42
What are the two properties which define a stem cell?
1. Self-renewal - the capacity of stem cells to retain their numbers.
2. Asymmetric division - the capacity of stem cells to generate two daughter cells, one of which can differentiate into mature cells and one of which remains undifferentiated and retains its self-renewal capacity.
43
Define the 5 reversible cell adaptations which occur in response to a change in environment and give an example of each adaptation
1. Hypertrophy.: an increase in cell size eg. myocardial hypertrophy in response to sustained high blood pressure.
2. Hyperplasia: an increase in cell number eg. endometrial hyperplasia due to prolonged stimulation of the endometrium by the hormone oestrogen.
3. Metaplasia: a change from one differentiated (mature) cell type to another mature cell type which is better able to withstand the adverse environment eg. intestinal metaplasia of the oesophagus (Barretts oesophagus).
4. Dysplasia: disordered cell growth caused by a carcinogen eg. cervical dysplasia caused by human papilloma virus infection.
5. Atrophy: a reduction in cell size eg. if a muscle loses its nerve supply it will undergo denervation atrophy.
44
What are the 3 possible outcomes for a cell which is irreversibly damaged?
1. Necrosis.
2. Apoptosis.
3. Necroptosis.
45
What is necrosis?
- Necrosis is an accidental/unregulated form of cell death where cell membranes are damaged causing lysosomal enzymes to be released and the cell contents to leak resulting in an inflammatory reaction
- Necrosis is always pathological.
46
What molecular features characterise necrosis?
- In necrosis, mitochondria are damaged, depleting ATP and causing failure of energy-dependent functions
- Influx of calcium activates enzymes eg. proteases
- Free radicals accumulate and damage proteins, lipids and nucleic acids.
- Increased membrane permeability affects plasma membranes, lysosomal membranes and mitochondrial membranes
- Intracellular proteins which leak out of necrotic cells can also appear in the serum eg. Troponin is released into the blood stream in the context of myocardial necrosis and can be measured to confirm a myocardial infarction (heart attack).
47
What is apoptosis?
- Apoptosis is programmed cell death and can be either physiological or pathological
- It can be caused by protein or DNA damage
- There is no loss of membrane integrity and no inflammatory reaction.
48
Explain how the intrinsic apoptosis pathway works.
- The intrinsic pathway is triggered by cell injury, DNA damage or decreased hormone stimulation
- There is inactivation of a molecule called BCL-2 which is an anti-apoptotic molecule normally
- This inactivation allows cytochrome C to leak from the inner mitochondrial matrix into the cytoplasm of the cell to activate caspases
- Caspases are proteases which can breakdown cell proteins.
49
Explain how the extrinsic apoptosis pathway works.
- The extrinsic pathway can be activated by FAS ligand binding to the FAS death receptor on a target cell, activating caspases
- This is the mechanism by which lymphocytes which respond to self can be eliminated
- This pathway can also be triggered by Tumour Necrosis Factor (TNF) binding to the tumour necrosis factor receptor on a target cell
- Some viruses and normal cells can produce a molecule called FLIP which can block apoptosis.
50
Once a cell dies by apoptosis, what happens then?
- Phosphatidylserine flips from the inner to the outer aspect of the cell membrane and this is recognised by macrophage receptors
- Macrophages phagocytose the apoptotic bodies and the dead cells disappear within minutes
- This is a very efficient process.
51
Describe the anatomical regions of a normal tubular bone
- A normal tubular bone has an epiphysis, physis (growth plate), metaphysis and diaphysis
- The epiphysis extends from the base of the articular surface to the region of the growth plate
- The metaphysis extends from the growth plate to where the diameter of the bone becomes narrow
- the diaphysis or shaft extends from the base of one metaphysis to the base of the opposing one
- In immature or growing bones the metaphysis is separated from the epiphysis by a cartilaginous growth plate or physis.
52
What are the differences between woven bone and lamellar bone?
- Woven bone is bone which is made rapidly such as in the unborn child, a healing fracture or in some diseases
- Type I collagen fibres are laid down and then mineralised as criss-cross woven bone which is able to withstand stress equally well in all directions.
- In lamellar bone, the collagen fibres are nearly parallel and this takes longer to make but is much stronger
- The collagen fibres run in opposite directions in alternating layers of lamellar bone, helping the bone to resist torsion forces.
- Normally the entire mature skeleton is composed solely of lamellar bone.
53
What is osteoid?
- Osteoid is unmineralized bone matrix and is composed of type I collagen and glycosaminoglycans (GAGs)
- Calcium hydroxyapatite, a calcium salt crystal is then deposited which gives bone its strength and rigidity.
54
What are the two ossification methods by which bone normally forms?
Intramembranous ossification and endochondral ossification.
55
Describe intramembranous ossification and give an example of bones which form by this method.
- During intramembranous ossification bone develops directly from sheets of mesenchymal (undifferentiated) connective tissue
- The flat bones of the face, most of the cranial bones and the clavicles (collarbones) are formed via intramembranous ossification.
56
Describe endochondral ossification and give some examples of bones which form by this method.
- In endochondral ossification, bone develops by replacing hyaline cartilage.
- Cartilage serves as a template to be completely replaced by new bone and this takes much longer than intramembranous ossification
- Bones at the base of the skull and long bones form via endochondral ossification.
57
Describe the layers of a long bone beginning at the external surface and moving towards the centre of the bone.
The layers of a long bone, beginning at the external surface are:
1. Periosteum.
2. Outer circumferential lamellae.
3. Compact bone (Haversian systems).
4. Inner circumferential lamellae.
5. Endosteal surface of compact bone.
6. Trabecular bone.
58
Describe the structure of an osteon/Haversian system.
- Compact bone is organized as parallel columns known as Haversian systems or osteons which run lengthwise down the axis of long bones
- These columns are composed of lamellae - concentric rings of bone surrounding a central channel or Haversian canal that contains nerves blood vessels and the lymphatic system of bone
- The parallel Haversian canals are connected to one another by the perpendicular Volkmann's canals.
59
Describe the process of bone remodelling.
- Bone remodelling begins when mononuclear osteoclast-precursors (derived from haematopoietic stem cells) arrive at a bone surface and differentiate into functional osteoclasts. Remodelling is regulated by cell-to-cell interactions and cytokines
- Mature osteoclasts secrete acid and proteases (matrix metalloproteinases) onto the bone surface, excavating a pit known as Howship’s lacuna.
- The resorption phase ends with osteoclast apoptosis and a reversal phase follows characterised by activation of osteoblasts (of mesenchymal origin) to replace the excavated bone.
- The activity of osteoclasts and osteoblasts is normally tightly coupled, and the amount of bone synthesized matches the amount resorbed.
- The newly secreted matrix called osteoid becomes mineralised to form mature bone.
- The remodelling cycle ends where new bone formation is complete and the osteoblasts are either incorporated into the new bone matrix as osteocytes or become quiescent surface bone lining cells.
- The net result of each cycle is a formation of a new osteon - a packet of bone in which the collagen fibres are aligned.
60
Describe the regulation of osteoclast activity by the Receptor Activator of Nuclear Factor Kappa Beta (RANK) and Osteoprotegrin (OPG).
- Osteoclasts are derived from the same mononuclear cells that differentiate into macrophages.
- Osteoblast/stromal cell membrane-associated RANK ligand (Receptor Activator of Nuclear Factor Kappa Beta ligand) binds to its receptor RANK located on the cell surface of osteoclast precursors.
- This interaction, in the background of macrophage colony-stimulating factor (M-CSF), causes the precursor cells to produce functional osteoclasts.
- Stromal cells also secrete osteoprotegrin (OPG) which acts as a decoy for RANKL, preventing it from binding the RANK receptor on osteoclast precursors. - - Consequently OPG prevents bone resorption by inhibiting osteoclast differentiation.
- Bone resorption or bone formation can be favoured by altering the RANK:OPG ratio.
- Parathyroid hormone and steroids promote osteoclast differentiation and bone turnover.
- In contrast, bone morphogenetic proteins and sex hormones block osteoclast differentiation or activity by favouring OPG expression.
61
List five factors which can impair fracture healing.
1. Displaced/comminuted fractures - can lead to deformity.
2. Inadequate immobilisation - prevents normal callus maturation causing delayed or non-union.
3. Open fractures - can become infected.
4. Malnutrition.
5. Skeletal dysplasia (congenital abnormalities).
62
Describe the features of osteonecrosis.
- Osteonecrosis is ischaemic necrosis of bone and bone marrow.
- The vascular insufficiency can occur through injury to blood vessels, thromboembolism, external pressure on vessels or through venous occlusion.
- In the setting of ‘the bends’, nitrogen which has previously been in solution within fatty bone marrow forms a gas as the pressure is reduced when a diver ascends.
- This gas can put pressure on blood vessels causing obstruction and infarction.
63
List the conditions which are known to be associated with osteonecrosis.
- Alcohol abuse
- Bisphosphonate therapy (jaw bones)
- connective tissue disorders
- steroid treatment
- chronic pancreatitis
- The ‘bends’
- Gaucher disease
- infection
- pregnancy
- radiotherapy
- sickle cell disease
- trauma and tumours.
64
Which bacteria commonly cause osteomyelitis?
- Staphylococcus aureus is present in over half of patients and other common bacteria include streptococci, gram negative enteric organisms and anaerobic bacteria.
- Contiguous spread from adjacent infected tissue or opened bones causes about 80% of osteomyelitis and this is often polymicrobial.
- Haematogenously spread osteomyelitis usually results from a single organism.
65
Which bones are more commonly affected in children compared to adults?
- In children gram positive infections are most common and these usually affect the metaphyses of the tibia, femur or humerus.
- In adults haematogenously spread osteomyelitis usually affects the vertebrae.
66
What are the 5 features of acute inflammation?
1. Calor (Heat).
2. Rubor (Redness).
3. Tumor (Swelling).
4. Dolor (Pain).
5. Functio Laesa (Loss of Function).
67
List 4 causes of acute inflammation
1. Infection.
2. Tissue necrosis.
3. Foreign bodies.
4. Immune reactions.
68
What is the difference between a cytokine and a chemokine?
- Cytokines are proteins produced by many cell types that can mediate and regulate inflammatory reactions.
- Cyto means cell and kine refers to kinesis or movement.
- Chemokines are chemotactic cytokines.
- These are produced as a chemical cloud which spreads out from the source of inflammation and can attract specific white blood cells.
69
What is the Hageman Factor?
- This is a factor produced by the liver as an inactive protein.
- It circulates in the blood stream until it is activated by exposure to collagen.
70
How do steroids reduce inflammation?
- Corticosteroids are broad-spectrum anti-inflammatory agents that reduce the transcription of genes encoding phospholipase A2, COX-2, proinflammatory cytokines (interleukin-1 and tumour necrosis factor) and iNOS.
71
What causes fever in the context of acute inflammation?
- Pyrogens (eg. lipopolysaccharide) cause macrophages to release interleukin 1 (IL-1) and tumour necrosis factor (TNF) which increase COX activity in perivascular cells of the hypothalamus.
- This causes production of PGE2 which raises the temperature set point.
72
What causes the swelling seen in acute inflammation?
- Histamine (from mast cells) causes endothelial cells to contract and endothelial cells can also be disrupted.
- This results in leakage of fluid from post-capillary venules into the interstitial space.
73
What is oedema?
- An excess of fluid in the interstitial tissue or serous cavities.
- Can be an exudate (a fluid high in protein containing cell debris) or a transudate (a fluid low in protein).
74
What is pus?
An inflammatory exudate rich in leucocytes (mostly neutrophils), the debris of dead cells and in many cases microbes.
75
What causes pain in the context of acute inflammation?
Bradykinin and PGE2 sensitise sensory nerve endings.
76
Which cell dominates 3 days after acute inflammation begins?
Macrophage.
77
List 3 organs which mediate the systemic protective effects seen in acute inflammation and the cytokines which mediate these effects.
1. Brain. Fever (mediated by TNF IL-1 and IL-6).
2. Liver. Production of acute phase proteins (mediated by IL-1 and IL-6).
3. Bone marrow. Leukocyte production (mediated by TNF, IL-1 and IL-6).
78
What is repair and when does it happen?
- Repair is replacement of damaged tissue with a collagen rich or fibrous scar.
- This occurs when regenerative stem cells are lost or when the tissue which is injured lacks regenerative capacity
79
What is granulation tissue?
- Granulation tissue formation is seen in the initial phase of repair
- granulation tissue consists of proliferated capillaries (which provide nutrients) fibroblasts (which deposit type 3 collagen) and myofibroblasts (which mediate wound contraction).
80
List 5 important growth factors which are necessary for repair and their actions
1. Transforming growth factor (TGF) alpha. Epithelial cell and fibroblast proliferation.
2. TGF-beta. Fibroblast proliferation and inhibition of inflammation.
3. Platelet-derived growth factor (PDGF). Growth of endothelium, smooth muscle and fibroblasts.
4. Fibroblast growth factor (FGF). Angiogenesis.
5. Vascular endothelial growth factor (VEGF). Angiogenesis.
81
What are the four phases of normal wound healing?
1. Coagulation or clotting phase.
2. Inflammatory phase.
3. Proliferative phase or granulation tissue formation phase.
4. Remodelling phase.
82
What happens in the coagulation and inflammatory phases of wound healing?
- Blood-borne cells, that is neutrophils, macrophages and platelets play critical roles.
- These cells provide growth factors which are needed for recruitment of epithelial cells and connective tissue cells into the wound bed.
83
What happens in the proliferative phase of wound healing?
- The proliferative phase starts approximately 3 days after injury and is characterized by increased levels of epithelial and fibroblast proliferation and migration.
- There is also extracellular matrix synthesis in response to autocrine and paracrine growth factors and angiogenesis or new blood vessel growth.
- Because of the presence of blood vessels, the tissue has a granular appearance termed granulation tissue.
84
What happens in the remodelling phase of wound healing?
- Approximately 1 to 2 weeks after injury, myofibroblasts that are present within the granulation tissue begin to remodel the extracellular matrix which is followed by apoptosis of resident cells which leads to the formation of an acellular scar.
85
What is the difference between wound healing by primary and secondary intention?
- In primary intention, wound edges are brought together with sutures which leads to minimal scarring.
- In secondary intention, the edges are not brought together and granulation tissue will fill the gap and then myofibroblasts contract the wound in which case scar tissue will form.
86
What is the difference between a keloid scar and a hypertrophic scar?
- A hypertrophic scar is defined as excess production of scar tissue that is localised to the area of the wound.
- A keloid scar is exuberant production of scar tissue that is out of proportion to the wound size.
- Keloids are associated with excess type 3 collagen deposition and are more common in black people.
- They often affect the ear lobes, face and upper extremities.
87
Name one vitamin and two minerals which are important for wound healing and how these contribute to the wound healing process.
- Vitamin C, copper and zinc.
- Deficiencies of vitamin C and copper will delay healing as these two elements are involved in the formation of collagen crosslinks.
- Zinc deficiency is also associated with poor wound healing as zinc is a co-factor for collagenase which is required to replace type 3 collagen with type 1 collagen.
88
List 5 reasons other than mineral/vitamin deficiency for impaired wound healing.
1. Presence of foreign bodies.
2. Infection.
3. Poor blood supply.
4. Diabetes.
5. Malnutrition.
89
What is an oncogene?
- Proto-oncogenes are essential for cell growth and differentiation.
- Mutations of proto-oncogenes form oncogenes that lead to unregulated cell growth.
90
Which component of the mitogen activated protein pathway activates BRAF?
RAS
91
What is Knudsons two-hit hypothesis?
Knudsons two hit hypothesis applies to tumour suppressor genes and states that both copies of the gene must be affected to cause disease.
92
What is the role of telomerase in carcinogenesis?
- Telomerase normally shorten with serial cell divisions eventually causing cell senescence.
- Cancers often show upregulation of telomerase.
93
How do cancers create a new blood supply to support their growth?
Cancers commonly produce fibroblast growth factor and vascular endothelial growth factor which are both angiogenic factors responsible for blood vessel creation.
94
What is dysplasia?
- Dysplasia is disordered cell growth, which most often refers to a proliferation of pre-cancerous cells.
95
What is a neoplasm?
- Neoplasm means new growth.
- This growth is unregulated, clonal and irreversible.
- Neoplastic tumours can be benign or malignant.
96
What is the term used to describe a malignant tumour of epithelial origin?
Carcinoma
97
What is the term used to describe a malignant tumour of soft tissue?
Sarcoma
98
What is the term used to describe a malignant tumour of lymphocytes?
- Lymphoma.
- If malignant lymphocytes or malignant myeloid cells involve the bone marrow and appear in the peripheral blood, this is leukaemia.
99
What is the term used to describe a malignant melanocytic tumour?
Malignant melanoma
100
What is the term used to describe a benign tumour of blood vessels?
Haemangioma
101
What is the term used to describe a malignant tumour of blood vessels?
Angiosarcoma
102
What is the term used to describe a benign tumour of fat?
Lipoma
103
What is the term used to describe a malignant tumour of fat?
Liposarcoma
104
What is a benign skeletal muscle tumour called?
Rhabdomyoma
105
What is a malignant skeletal muscle tumour called?
Rhabdomyosarcoma
106
What is a benign tumour of smooth muscle called?
Leiomyoma
107
What is a malignant smooth muscle tumour called?
Leiomyosarcoma
108
What is a benign peripheral nerve sheath tumour called?
Schwannoma
109
What is a malignant peripheral nerve sheath tumour called?
A malignant peripheral nerve sheath tumour!
110
What is a benign tumour of fibroblasts called?
Fibroma
111
What is a malignant tumour of fibroblasts called?
Fibrosarcoma
112
What is tumour grade?
Low grade tumours grow slowly while high grade tumours grow rapidly and metastasize quickly.
113
List 3 factors which allow tumours to invade.
1. Decreased cell adhesion - reduced expression of e-cadherin and expression of integrin receptors.
2. Secretion of proteolytic enzymes – collagenases, gelatinases and stromeolysins.
3. Increased cell motility - loss of contact inhibition.
114
Describe the steps which are involved in tumour metastasis.
1. Detachment of tumour cells.
2. Invasion of connective tissue to reach lymphatics and blood vessels.
3. Intravasation into the lumen of the vessels.
4. Evasion of host defence by natural killer cells and T-cells.
5. Adherence to endothelium at the remote location eg. liver, lung, bone.
6. Extravasation of cells from the vessel into the tissue at the new location.
7. Survival and growth at the new location.
115
List the two possible routes of metastasis
1. Lymphatic - to draining lymph nodes. Usually the first site of metastasis for carcinomas.
2. Haematogenous - to liver, lung, bone and brain. Favoured by sarcomas, which do not tend to use the lymphatic route of metastasis.
116
List the 5 carcinoma primary sites which most commonly metastasise to bone.
1. Lung.
2. Breast.
3. Kidney.
4. Thyroid.
5. Prostate.
117
Which virus causes patients who are immunosuppressed to develop multiple squamous cell carcinomas of the skin? Think here of any virus you know of which can infect squamous epithelium.
Human papilloma virus (HPV)
118
List 3 mechanisms by which tumour cells can evade immune surveillance.
1. Selection of antigen-negative clones.
2. Loss of MHC molecules.
4. Expression of PD1 ligand which can switch of T-cells.
119
What is the tumour stage and what system is currently used for staging tumours?
- The stage of a tumour refers to how large it is and how far it has spread.
- We currently use the TNM system for staging cancers.
- T refers to the tumour size or extent of local invasion.
- N refers to lymph node metastases
- M refers to distant metastases.
120
Why do tumours cause profound weight loss (cachexia)?
- The catabolic state of a cancer patient with severe weight loss and debility is called cachexia and is thought to be mediated by tumour-derived humoral factors that interfere with protein metabolism causing muscle loss (sarcopenia).
- Weight loss can also be associated with nutrition interference eg. due to oesophageal obstruction severe pain or depressive illness.
121
What is the Warburg effect?
- Most cancers produce energy by a high rate of glycolysis with formation of lactic acid whereas normal cells have a low rate of glycolysis with oxidation of pyruvate in mitochondria.
- This effect is called the Warburg effect and is the reason why positron emission tomography (PET) scans work.
122
What is the term used to describe a benign tumour of osteoblasts?
Osteoma
123
Which familial syndrome is characterised by osteomas and large bowel polyps and is associated with an increased risk of colorectal carcinoma development?
Gardner syndrome
124
What is the term used to describe a benign tumour of cartilage and what does this look like on an x-ray?
- Chondroma or enchondroma (if it arises within the medullary cavity).
- On x-ray, there is a circumscribed lucency with central irregular calcifications or a sclerotic rim and an intact cortex.
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A pathologist issues the following report on a pedunculated bone tumour taken from the lower femoral metaphysis of a 20-year-old male patient. The tumour was pointing away from the knee joint. "There is a cap of hyaline cartilage which is undergoing endochondral ossification and which merges with the underlying trabecular bone. There are no atypical features". What tumour is being described here?
An osteochondroma (exostosis).
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A 25-year-old male presents with severe pain at night in his upper right thigh, which is relieved by aspirin. An x-ray shows a 1.1 cm lucency in the cortex of his right femur with a surrounding rim of reactive bone formation. Under the microscope, this shows a central nidus consisting of osteoid trabeculae separated by a vascular fibrous stroma. The nidus has a sharp margin which interfaces with a surrounding rim of mature bone. Which tumour is being described here?
- This is an osteoid osteoma.
- Osteoblastoma is like an osteoid osteoma but is larger than 2 cm and involves the posterior components of the vertebrae and the pain does not respond to aspirin.
- In addition these tumours do not induce a marked bony reaction.
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Which bone tumour has a soap bubble appearance on x-ray and involves the epiphysis of long bones in young adults?
- Giant cell tumour of bone.
- This is a locally aggressive tumour of osteoclast precursors which may recur after currettage treatment.
- There is also a small risk (4%) of lung metastasis but these may regress and are seldom fatal.
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What is the name given to a malignant tumour of osteoblasts?
Osteosarcoma.
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What is the name given to a malignant tumour of chondrocytes?
Chondrosarcoma.
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What is Ewing sarcoma?
- A lucent tumour which involves the diaphysis of long bones in male children under the age of 15.
- It is a malignant proliferation of small round blue cells of neuroectodermal origin and often presents with metastatic disease but responds to chemotherapy.
- 5 yr survival is 65-80% for localized disease and 25-40% for metastatic disease.
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What is the typical x-ray appearance of Ewing sarcoma?
- They usually present as moth-eaten, permeative, destructive lucent lesions in the diaphysis of long bones, with a large soft tissue component, without osteoid matrix and they show a typical onion skin periosteal reaction.
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What are the risk factors for osteosarcoma?
1. Familial retinoblastoma: In familial retinoblastoma there is an inheritable mutation in the retinoblastoma tumour suppressor gene which predisposes the patient to develop eye tumours called retinoblastomas as well as other tumours, including osteosarcoma.
2. Paget’s disease is a disease causing an increased rate of bone turnover.
3. Damage to the bone caused by infarction and radiation also increase the risk of osteosarcoma. These are referred to as secondary osteosarcomas.
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How does the pathologist make the diagnosis of osteosarcoma?
Under the microscope, osteosarcomas show a proliferation of malignant osteoblasts producing osteoid.
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What does an osteosarcoma look like on X-ray?
- Osteosarcomas involve the metaphysis of long bones, in the region of the growth plate, often involving the knee region.
- Radiographs show a large destructive mixed lytic and sclerotic mass with infiltrative margins and a sunburst appearance.
- The tumour frequently breaks through the cortex and lifts the periosteum resulting in reactive sub-periosteal new bone formation.
- The triangular shadow between the cortex and raised ends of the periosteum (known radiologically as the Codman triangle) is indicative of an aggressive tumour but is not pathognomonic of osteosarcoma.
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What bone lesions can show a Codman triangle?
- The Codman triangle may be seen with osteosarcoma, Ewing sarcoma, osteomyelitis, aneurysmal bone cyst, giant cell tumour, metastasis, chondrosarcoma and malignant fibrous histiocytoma.
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What causes the sunburst pattern seen with osteosarcoma on imaging?
This occurs when the tumour grows quickly and the periosteum does not have enough time to lay down a new layer and instead the Sharpey's fibres stretch out perpendicular to the bone.
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Which tumour shows a progressively enlarging, destructive mass involving the axial skeleton with a characteristic rings and arcs pattern of calcification?
Chondrosarcoma
138
Describe the four changes that take place to facilitate the movement of cells of the immune system from the blood stream to the tissues, mentioning one important mediator for each
- Vasodilation: causes a change in laminar flow, mediated by histamine
- Margination: partly due to change in laminar flow, but also mediated by adhesion molecules (eg. Integrins) which allow cells to adhere to endothelium
- Emigration: the change in vascular permeability, mediated by histamine, bradykinins, and leukotrienes allows movement of fluid and cells from the vessel into tissues
- Chemotaxis: attracts cells to site where needed, mediated by complement components leukotrienes and cytokines
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A 12 year old boy falls on outstretched hand causing a fracture of the distal end of his right radius, if the fractured bone goes through the normal healing sequence, describe the typical histological features that a pathologist will see in the tissue at the following time points (less than 24 hours after fracture, one week after fracture, three weeks after the fracture)
- Less than 24 hours after fracture: rupture of blood vessels causes the formation of a haematoma (blood clot) which fills the fracture gap
- (the blood clot provides a fibrin (protein involved in clotting blood) mesh which seals the fracture site and provides a scaffold for the influx of inflammatory cells, fibroblasts and support for new capillary growth (granulation tissue))
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- One week after fracture: soft callus forms (osteoclast and osteoblast activity stimulated)
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- Three weeks after fracture: bony callus (new bone formation, woven bone formation)
- (remodelling occurs, reduces size of the callus until the shape and outline of the fractured bone are re-established as lamellar bone, the healing process is complete with the restoration of the medullary cavity)
