Phase 2 - ICS Flashcards
1
Q
How do you differentiate between acute and chronic inflammation
A
Acute - typically involves neutrophils and is sudden onset - short-lived - usually resolves
Chronic - typically involves macrophages and lymphocytes; usually slow onset - longer-lived - may never resolve
Acute inflammation can become chronic inflammation but some inflammation can start as chronic e.g. TB
2
Q
What cells involved in inflammation?
A
Neutrophil polymorphs
Macrophages
Lymphocytes
Endothelial cells
Fibroblasts
3
Q
Characteristics of neutrophil polymorphs
A
- Short lived cells - 2 or 3 days
- polylobed nucleus
- First on the scene of acute inflammation
- Has cytoplasmic granules full of enzymes (lysosomes) that kill bacteria + are phagocytic
- Usually die at the scene of inflammation
- Release chemicals that attract other inflammatory cells such as macrophages
4
Q
Characteristics of macrophages
A
- Long lived cells (months to years)
- Phagocytic properties
- Ingest bacteria and debris
- May carry debris away
- May present antigen to lymphocytes
- can be found in biopsies even months after inciting incident
- can have different names in different tissues e.g. Kupfer cells, alveolar macrophages, microglial cells etc.
5
Q
Characteristics of lymphocytes
A
- Long lived cells (years)
- Produce chemicals which attract in other
inflammatory cells - Immunological memory for past infections
and antigens - plasma cells create antibodies
6
Q
Role of endothelial cells in inflammation
A
- Line capillary blood vessels in areas of inflammation
- Become sticky in areas of inflammation so
inflammatory cells adhere to them - Become porous to allow inflammatory cells
to pass into tissues (pulls apart to form holes) - Grow into areas of damage to form new
capillary vessels
7
Q
What causes characteristic appearance of inflammation
A
substances like histamine cause all capillaries in inflamed area to open and fill with blood - becomes red and swollen - much more fluid in the area than is normal
8
Q
What happens in septic shock
A
All capillaries in body open so BP drastically falls - there is not enough blood in the body to fill every capillary at once
9
Q
What is a granuloma?
A
particular type of chronic inflammation with collections of macrophages surrounded by lymphocytes
- only significant as it may be due to myobacterial infection like TB/leprosy etc.
- seen in Crohn’s and sarcoidosis
- could be seen around foreign material in tissues
10
Q
Sequence of acute inflammation
A
- injury or infection
- neutrophils arrive and phagocytose and release enzymes
- macrophages arrive and phagocytose
- either resolution with clearance of inflammation or por- gression to chronic inflammation
- examples of acute (neutrophil-mediated) inflammation -
acute appendicitis, frostbite, Streptococcal sore throat
11
Q
chronic inflammation
A
- either progression from acute inflammation or starts as
‘chronic’ inflammation such as infectious mononucleosis
(thus better term is macrophage/lymphocyte-mediated
inflammation) - no or very few neutrophils
- macrophages and lymphocytes, then usually fibroblasts
- can resolve if no tissue damage (e.g. viral infection like
glandular fever) but often ends up with repair and formation of scar tissue
12
Q
role of fibroblasts in inflammation
A
produce collagenous tissue in scarring following some types of inflammation
13
Q
how does ice reduce inflammation
A
it closes precapillary sphincters, closing some capillaries
14
Q
what do anti-inflmmatory medicines like aspirin and ibuprofen do to reduce inflammation?
A
inhibit prostaglandin synthetase
- prostaglandins are chemical mediators of inflammation so less prostaglandin release means less inflammation
15
Q
How do corticosteroids reduce inflammation?
A
they bind to DNA and down regulate mediators/genes of inflammation
16
Q
What is resolution and when does it occur?
A
It is when there is a complete recovery from inflammation/injury
Occurs when the initiating factor is removed AND the tissue is undamaged OR able to regenerate
17
Q
What is repair and when does it occur?
A
Repair is what happens when:
The initiating factor is still present OR tissue is damaged AND unable to regenerate
18
Q
Which cells can regenerate?
A
- hepatocytes
- pneumocytes
- all blood cells - helpful in chemotherapy
- gut epithelium
- skin epithelium
- osteocytes - via remodelling
19
Q
which cells can’t regenerate?
A
- myocardial cells
- neurones
(reason why strokes, MI and nerve damage is so problematic)
20
Q
What happens when cells can’t regenerate properly? In regards to tissue function what causes this?
A
Fibrous tissue forms
Commonly this is because the tissue can’t regenerate (e.g. heart muscle) or the damage is happening repeatedly/over a long period of time (e.g. repeated alcohol abuse - can cause cirrhosis of liver)
21
Q
What are the 2 types of skin wounds and their characteristics?
A
1st intention - edges of skin can be brought together to form a clean scar when healed - just a line of tough collagen in the dermis which causes typical scar tissue texture
2nd intention - edges of skin can’t be brought together - tissue has to grow into the gap (granulation tissue forms) - results in lots of collagen, bigger scar
22
Q
what is the alternative to fibrosis that occurs in the CNS?
A
Gliosis - replacement formed by glial cells not fibrous tissue - still not functioning brain tissue
23
Q
Types of autopsies and their distinctions and statistics
A
Hospital autopsy - cause of death known but clinician wants to know more - conducted with relatives’ consent - less than 10% of autopsies performed
- requires medical certificate of cause of death (mccd)
Medico-legal autopsies:
* Coronial autopsy - unknown cause of death but presumed to be due to natural causes - the deceased was not seen by a doctor within the last 14 days before death
* Forensic autopsy - suspected or known unnatural cause of death
- more than 90% of autopsies fall within the medico-legal section
24
Q
how many deaths are actually autopsied?
A
around 40% of deaths referred to coroner
only around 10% go on to autopsy
25
Which deaths referred to coroner?
* presumed natural but unkown cause of death
* presumed iatrogenic cause (even if it was a known risk the patient agreed to)
* presumed unnatural e.e. accidents, suicide, murder, neglect, deaths in custody/anybody who dies within a prison establishment, industrial death, death related to war/industrial pensions
26
Who makes referrals to coroners?
* Doctors - no statutory duty to refer but encouraged by common law duty and GMC
* registrar of births, deaths and marriages (BDM) - statutory duty to refer
* any properly intrested party e.g. relatives, police, anatomical pathology technicians
27
Who performs autopsies?
Histopathologists - hospital and coronial autopsies
Forensic pathologists - forensic autopsies (trained to deal with legal aspect as well)
28
What is the role of the coroner?
To answer 4 questions via a systematic scientific examination (the autopsy):
- who was the deceased
- when did they die
- where did they die
- how did they die (not why did they die) - to determine this last question is the main purpose of autopsy as the first three questions already usually have known answers
29
Name 2 key coronial legislations, their dates and key things mentioned within them
Coroners Rules - 1984
* autopsy as soon as possible
* by a pathologist of suitable qualification and experience (this wasn't clarified)
* report findings promptly and ONLY to coroner (it is a coroner's report only)
* autopsy must only be conducted in appropriate premises
Coroners Act - 1988
* allows coroner to order autopsy where death is likely natural to obviate need (SLIDES GLITCHED OUT NEED TO COME BACK AND FIX THIS)
30
What 2 amendments where made to coronial legislation and when?
In 2005:
- pathologist must tell coroner precisly what materials have been retained
- coroner authorities retention and sets disposal date
- coroner informs family of retention
- family has choice on what happens:
* return material to family
* retain for teaching/research
* respectful disposal
- coroner informs pathologist of family's decision
- pathologist has to keep record
- autopsy report must declare retention and disposal
Coroners and justice act - 2009:
- NOT fully enacted
- coroners can now defer opening the inquest and instead launch an investigation
- enshrines system of medical examiners
- little practical change to pathologists
- inquests now have conclusions NOT verdicts
- autopsies only on licensed premises
- by license holder
- any tissue retained needs consent from family EXCEPT when subject to coronial legislation or for criminal justice reasons
- public display requires consent from the deceased
- PENALTY: 3 years imprisonment and/or fine
31
stages of autopsy?
- get history/scene
- external exam
- digital autopsy - if needed:
* evisceration
* internal exam
- reconstruction
digital photography also taken at examinations and evisceration stages
32
What is examined in external examination (in autopsy)?
- Identification
* formal identifiers
* gender, age
* body habitus
* jewellery
* body modifications
* clothing
- disease and treatment
- injuries
33
What happens in evisceration during autopsy?
- y-shaped incision
- open all body cavities
- examin all organs in situ
- remove thoracic and abdominal organs
- remove brain
34
What is examined in internal examination during autopsy?
- heart + great vessels
- lungs, trachea, bronchi
- liver, gallbladder, pancreas
- spleen, thymus, lymph nodes
- Genitourinary tract
- Endocrine organs
- CNS
35
What prevents clots from forming within vessels?
1. Laminar flow - cells travel in the centre of arterial vessels and don't touch the sides
2. Endothelial cells are not 'sticky' when they are healthy
36
What is thrombosis?
The formation of a solid mass from blood constituents on an intact vessel in a living person
OR
solid mass of blood constituents
formed within intact vascular system
during life
37
Stages of thrombosis
(First injury)
Platelet aggregation
Clotting/coagulation cascade
Formation of fibrin mesh
38
What is fibrin
It is a large protein molecule which forms a mesh which can trap red blood cells and form the final clot
- platelets release chemicals when they aggregate which cause platelets to stick together and start the coagulation cascade
39
What kind of feedback is involved in thrombosis
Positive feedback loops
40
What causes thrombosis?
- Change in vessel wall
- change in blood flow
- change in blood constituents
Virchow's triad! stasis, vasc injury, hypercoagulability
usually a combination of 2 or 3 of these (e.g. endothelial cell injury from smoking causing endothelial cell injury - change in vessel wall and change in blood flow over injured/absent cells)
41
Common type of thrombosis and measures taken to prevent it
Deep vein thrombosis
early mobilisation after operation, low dose subcutaneous heparin
42
What is an embolism?
The process of a solid mass in the blood being carried through the circulation to a place where it gets stuck and blocks the vessel.
- solid mass is usually a thrombus
- can be caused by air bubbles too, cholesterol crystals (athreromatous plaque), tumour, amniotic fluid (rare in women with precipitate labour), fat (from severe trauma with multiple fractures??)
43
Where can an embolus go if it enters the venous system and why
It can travel through the vena cava, through the right side of the heart and into the lungs but will get stuck there as vessels will split into capillaries through which only single RBCs can fit. Lungs act as a filter for venous emboli
44
Where can an embolus in the arterial system can go?
Anywhere downstream of its entry point
45
What is ischaemia?
A reduction of blood flow to a tissue (without any other implications)
46
What is an infarcation?
The reduction in blood flow to a tissue that is so reduced that it cannot support the maintenance of cells resulting in cell death
- usually a macroscopic event caused by arterial thrombosis
- most organs have a single artery supplying them so are very susceptible to infarction
47
Which organs are less susceptible to complete infarction and why?
These organs have more than one source of arterial supply (acts as backup even if one artery blocked)
Liver - supplied by portal venous and hepatic artery
Lung - supplied by pulmonary venous and bronchial artery
Brain - multiple arteries connect to circle of Willis
48
What is atherosclerosis?
The accumulation of fibrolipid plaques in systemic arteries (in the walls)
49
Why is atherosclerosis an issue?
It reduces the blood flow in important areas e.g. the heart which can cause infarcts and necrosis. It would also increase the pressure of blood when it is being forced through the narrower lumen which increases risk of thrombosis and further atherosclerosis.
50
At what ages does atherosclerosis typically present and in what forms?
- fatty streaks in aorta can be seen in late teens/early 20s. These don't necessarily lead to atherosclerotic plaques.
- 30s/40s/50s - established atherosclerotic plaques form
- 40s-80s - complication from atherosclerosis (thrombosis, intraplaque haemorrhage (plaques have blood vessels in them) etc.)
51
Risk factors for atherosclerosis
- hypertension
- hyperlipidaemia
- cigarette smoking (vaping can also contribute as it contains nicotine)
- poorly controlled diabetes mellitus (typically type 1 tends to be better controlled than type 2 so type 2 diabetic are more affected typically)
- deprivation (atherosclerosis is more common in the north of the UK and research has correlated it with deprivation, especially in males)
(- age)
52
What do atherosclerotic plaques consist of?
- fibrous tissue
- lipids (cholesterol) - shows up as often needle shaped clear spaces in histology sections (lipids dissolve during processing)
- inflammatory lymphocytes are also found in plaques, however it is not an inflammatory condition
53
Explain disease process of atherosclerosis
- plaque forms under endothelium, often from thrombus formation
- plaque can cause irregularity in blood flow increasing chance of endothelial damage in the area
- thrombosis over plaque causes bigger plaques to form
- plaques can hemorrhage causing more atherosclerosis
- when the vessel is significantly occluded, it can cause angina
- when the vessel is mostly/fully occluded, can cause myocardial infarction/other infarcts/necrosis
People don't typically get symptoms and seek help till the later stages by which point it could be too late
54
Where is atherosclerosis found in the human body?
In high pressure, arterial systems (aorta + systemic circulation)
It is NOT found in low pressure circulation (pulmonary circulation)
55
What theories are there on the pathogenesis of atherosclerosis?
* Lipid insulation theory (DISCREDITED)
- idea that cholesterol from the lumen got under endothelium and formed plaques
- radio labeling cholesterol showed that plaque cholesterol is made by the body and doesn't come from diet
* Endothelial damage theory
- endothelial cells are delicate and metabolically active
- they are easily damaged by cigarette smoke, nicotine, CO, shearing forces at arterial divisions (worsened by hypertension), hyperlipidaemia, the products of glycosylation
- causes endothelial ulceration, leads to thrombosis and microthrombi
- platelets contain lots of cholesterol so this generates atherosclerotic plaques
56
Complications of atherosclerosis
- infarction due to occlusion
- parts of plaques can break off causing embolism (can cause smaller infarcts downstream which could add up to cause significant damage later)
- atherosclerosis in the aorta weakens the wall. This can cause the wall to rupture causing an aortic aneurysm which often leads to death(there is now screening in place for everyone over a certain age to reduce the incidence of this happening)
57
What is apoptosis and when does it occur?
Programmed cell death
- occurs when the cell senses a certain amount of DNA damage
58
What is necrosis and when does it occur?
The destruction of cells (usually a large amount together) by an external factor
- occurs from
* infarcts,
* contact with toxic venom from reptiles and insects,
* frostbite,
* pancreatitis (pancreas is autodigested by the enzymes it produces - the debris gets trapped retroperitoneally causing bruising)
59
Why is apoptosis important?
In normal cell turnover, it prevents resting cells with accumulated genetic damage from dividing. If cells with genetic damage divide they may produce cells which eventually develop into cancer cells.
- it also removes older fully differentiated cells so they can be replaced by newer cells
In development - removes unneeded cells (e.g. webbing between fingers)
60
What triggers apoptose? Give one mechanism.
P53 is a protein in cells which can detect DNA damage and then trigger apoptosis
- high levels of P53 suggests a lot of DNA damage
61
What happens with apoptosis in cancer?
Cancer cells have very low rates of apoptosis and are typically longer lived than normal cells. There is mutation of the P53 gene causing increase in tumour size and an accumulation og genetic mutations.
62
How does a cell apoptose?
The cell triggers a series of proteins which lead to the cascade release of digestive enzymes (MANY of which are caspases) within the cell which autodigest the cell.
63
What happens with apoptosis in HIV?
The HIV virus can induce apoptosis, typically in CD4 helper cells (t helper cells) which reduces their number and results in an immunodeficient state (AIDS).
64
How does the body respond to necrosis?
The only thing the body can do is try and clear up the debris by macrophages phagocyting dead cells (or microglial cell in the brain). Necrotic tissue is usually replaced by fibrous scar tissue though fibrosis doesn't happen in the brain.
65
What is a congenital defect?
A defect present at birth
66
What can cause congenital defects?
Issues with apoptosis and/or cell migration
Can be caused by inherited genetic abnormalities or an acquired (non-genetic, caused by environmental factors) abnormality, genetic or physical
67
What controls cell migration during development?
Homeobox genes - code for particular regions and control migration. Issue with this can be caused by genetic abnormalities or environmental problems (e.g. if the environment prevents the right chemicals from diffusing at the right time)
68
Examples of congenital abnormalities caused by migration issues during fetal development
Spina bifida - three main types:
- spina bifida occulta - small gap in spine but no opening on back so often not noticed till late childhood or adulthood
- meningocele - meninges protrude out as a sac through an opening in the back - could cause nerve damage
- myelomeningocele - meninges AND spinal cord protrude out as a sac through an opening in the back - likely nerve damage
Cleft palate
Ventricular septal defect - can cause heart murmur (fairly common in babies) - most cases of this close up within 1st year of life
69
Types of genetic abnormalities, examples and complications where known
Chromosomal abnormalities
- mostly not viable with life
- main viable one is Down's syndrome (trisomy 21)
- people with Down's tend to get cataracts and dementia earlier - lens and beta amyloid genes are found on chromosome 21
Mendilian inheritance - abnormality caused by a sngle gene
Autosomal inheritance
- e.g. Familial adenomatous polyposis (FAP) - characterized by cancer of the large intestine (colon ) and rectum
- recessive e.g. - cystic fibrosis
Polygenic inheritance - more common (difficult to identifiy exactly what is causing what result)
- can be late presenting e.g. Huntington's (caused by accumulation of Huntingtin protein)
70
Examples of acquired congenital abnormalities
- Growth hormone irregularities (gigantism if increase occurs in childhood, acromegaly if increase occurs after puberty - a decrease causes dwarfism)
- Achondrplasia - causes abnormality of fibroblast growth factor receptor protein - slows bone growth in growth plate - leads to dwarfism
71
Define hypertrophy
The increase in size of a tissue caused by an increase in the SIZE of constituent cells
72
Define hyperplasia
Increase in size of a tissue caused by an increase in the NUMBER of constituent cells
73
Example of hypertrophy
Increasing the size of skeletal muscle
- skeletal muscle can't divide but each muscle fibre can increase in size - caused by either an increase in sarcoplasm (sarcoplasmic hypertrophied muscle) or an increase in myofibrils as well as sarcoplasm (myofibril hypertrophied muscle). Muscle with increased myofibrils is stronger than sarcoplasmic hypertrophied muscle
74
What can cause hypertrophy?
- mutation in myostatin gene (e.g. certain cattle)
- training (e.g. body builder)
75
Examples of hyperplasia
Increasing the number of smooth muscle
- Benign prostatic hyperplasia - can block urethra
- endometrial hyperplasia - caused by an increased level of oestrogen compared to progesterone - causes excess bleeding/post-menopausal bleeding
76
Example of both hypertrophy and hyperplasia occuring at once
In smooth muscle cells of the uterus during pregnancy
77
Define atrophy
A decrease in the size of tissue caused by a decrease
in number of the constituent cells or a decrease in their size
78
Examples of atrophy
Cerebral atrophy in dementia
Muscle atrophies when not used - could be due to not enough exercise of because of impaired nerves
Optic atrophy - atrophied optic nerve (death of retinal ganglion cell axons)
79
Define metaplasia
The change in differentiation of a cell from one fully-differentiated type to a different fully-differentiated type
80
Examples of metaplasia
- metaplasia of ciliated columnar cells in bronchi to squamous cells in smokers due to damage - leads to smoker's cough as they have no cilia to waft up foreign material so they have to cough it up
- Barrett's oesophagus
81
Define dysplasia
An imprecise term for the morphological changes that may be seen in cells (often epithelium) in the progression on to development of cancer (neoplasia)
- visble on h&e stain
- can be a spectrum from mild, moderate, severe, carcinoma present and evetually invasive cancer
82
What causes cells to age?
- IN DIVIDING CELLS (e.g. skin, gut epithelium):
telomere shortening - telomeres are structures found at the end of chromosomes that get shorter each time the cell devides - this limits the number of times the cells can divide thus limiting regenerative ability and causing aging
* telomere length is inherited paternally and correlates to paternal age at death
- IN NON-DIVIDING CELLS (e.g. neurones):
after a certain amount of accumulation of damage, the cells will eventually die
83
why is identifying dysplasia useful?
treatment can be given to eradicate the dysplastic epithelium and so prevent the development of invasive cancer (as shown by the NHS cervical screening programme)
84
Which factors may cause damage to cells (in relation to aging)
- loss of calcium influx control
- damage to mitochondrial DNA
- loss of DNA repair mechanism
- peroxidation of membranes
- free radical generation
time-dependant activation of aging and death genes
- telomere shortening
- accumulation of toxic by-products of metabolism
- cross-linking or mutations of DNA
- cross-linking of proteins
85
What is the current upper limit of human age
ages around 120s
86
What is progeria?
It is a condition where people have oddly shaped cells that limit division sooner and such these people age more quickly
87
What is the only known way to slow aging
Caloric restriction - fewer calories means the body has less resources and metobolises less and thus produces fewer toxic metabolites (DOUBLE CHECK the single page info sheet)
88
Give common complications of aging
Dermal elastosis - wrinkly - uv hits cells - cross-linking of proteins
Osteoporosis - wedge shaped vertebral fractures - more common in post-menopausal women due to increased bone resorption and decreased bone formation due to lack of oestrogen (delayed by hrt)
Cataract - uv light cross-linking proteins in lens
Dementia - nuronal loss in alzhimers - plaques of beta amyloids - nerofibrillary tangles -Around 20% of people over 80 have dementia
Sarcopemia - lack of muscle - Caused by atrophy - muscles can’t divide - age and die - Can be improved by weight carrying exercises
Deafness - hair cells in cochleae can’t divide or regenerate - damaged by high volumes (particularly in mid ranges of sound wave length)
89
How can cancers metastesize?
- They can spread to local lymph nodes as lymph vessels have thin walls
- They can spread through the blood to bone
90
Which cancers commonly spread to bone?
Breast, prostate, lung, thyroid and kidney
91
Characteristics of basal cell carcinoma metastasis (and squamous cells carcinoma and melanoma comparitively)
- only invades locally - it never spreads to other parts of the body (can still erode through important structures and cause death in some cases)
- (more common in older men)
- Can be cured via complete excision
- squamous cell carcinomas sometimes metastasize
- melanomas commonly metastasize
92
Characteristics of leukemia metastasis
cancer of white blood cells so circulates around body and affects all parts
- requires systemic chemotherapy
lymphoma also affects systemically
93
Characteristics of breast cancer
- may not metastasize
- most commonly metastasizes to axillary lymphnodes
- can also spread through blood to metastasize to bone
- can be oestrogen-positive or HER2-positive (a protein)
* both promote the growth of cancer cells
94
Treatment of breast cancer
- first check if it is cancer (could be something benign or something else altogether)
- if it has not metastasized then it can be fully excised (however micro tumours may still be present and cancer could recur)
- If it has spread to axillary lymph nodes (checked via ultrasound and potentially a biopsy) then all axillary lymph nodes should be cleared along with the excision
- if it is a small tumour and it hasn't spread to the axillary lymph nodes then it probably hasn't spread to the rest of the body. If it is a big tumour and it has spread to the axillary lymph nodes then it has probably metastasized to the rest of the body.
- if there is a lot of metastasis then it would be more beneficial to start systemic chemo instead of doing a major excision surgery.
- to reduce risk of recurrence adjuvant therapy is done; traditionally for breast cancer radiotherapy is used
- the patient is oestrogen receptor positive (test with stained biopsy to check), they may be put on adjuvant anti-oestrogen therapy to decrease recurrence (recommended to be given for 10 years). However, this causes early menopause for younger women.
95
Definition of carcinogenesis
The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations
- applies only to malignant neoplasms
- it is a multi-step process that often occurs sequentially
96
What is oncogenesis
Relates to the formation of any type of tumour - benign and malignant
(tumour is more just a swelling, malignant neoplasms are cancer)
97
What are carcinogens
Agents known or suspected to cause tumours by causing mutation of DNA
98
Difference between carcinogenic and oncogenic
Carcinogenic = cancer causing
Oncogenic = tumour causing
99
What percentage of cancer risk is environmental
85%
100
What are some issues faced when trying to identify carcinogens?
- Latent interval may last decades (the time required for cancer to actually develop after exposure)
- Complexity of environment (lots of different things could have affected/had cancer risk)
- Ethical constraints (limits to what you can test on people)
101
Give examples of epidemiological evidence of environmental cancer risk
- Hepatocellular carcinoma is uncommon in UK/USA but common in areas with high Hep B/C infections and mycotoxins (toxics produced by certain fungi - also causes gallbladder cancer)
- Oesophagall carcinomas have higher incidence in Japan, China, Turkey and Iran; linked to dietary factors in japan and china (Linhsien chickens story), and drinking very hot coffee (turkey, iran)
102
Examples of occupational/behavioral risks for cancer
- Lung cancer (35 000 deaths per year) has a strong association with smoking
* Kent micronite filter had asbestos as well
- Bladder cancer has higher incidence in aniline dye and rubber industries due to presence of β-naphthylamine
- Scrotal cancer (noted in 1777 by Sir Percival Pott) has a higher incidence in chimney sweeps due to presence of polycyclic aromatic hydrocarbons from soot
103
What are the classes of carcinogens
Chemical
Viral
Ionising and non-ionising radiation
Hormones, parasites and mycotoxins
Miscellaneious
104
Characteristics of chemical carciogens
- No common structural features (makes them difficult to identify)
- Some act directly, Most require metabolic conversion from pro-carcinogens to ultimate carcinogens
- Enzyme required may be ubiquitous or confined to certain organs
* Depends where they are encountered and where they are metabolised
105
Examples of common chemical carcinogens
- Polycyclic aromatic hydrocarbons
- Aromatic amines
- Nitrosamines
- Alkylating agents
106
What can you find polycyclic aromatic hydrocarbons in and what cancers can they cause?
Found in:
Smoke from smoking, soot, mineral oils
Can cause:
Lung cancer, Skin cancer
107
What can you find aromatic amines in and what cancers can they cause?
Found in rubber and (aniline) dye industries (beta-naphthylamine)
Causes bladder cancer
108
What can you find nitrosamines in and what cancers can they cause?
They are proven in animals and can be found in processed meat.
Can cause gut cancer
109
What can you find alkylating agents in and what cancers can they cause?
They are used in chemotherapy.
They have a small risk of causing leukaemia in humans
110
Characteristics of viral carcinogens
Most oncogenic viral infections don't result in cancer. The ones that do cause approximately 10-15% of all cancers.
111
Examples of DNA virus carcinogens
- Human herpes virus B (HHVB)
- Epstein Barr Virus (EBV)
- Hep B Virus (HBV)
- Human papillomavirus (HPV)
- Merkle cell polyomavirus (MCV)
112
What cancers are associated with HHVB?
Kaposi sarcoma (more common in immunosuppressed people and can lead to AIDS diagnosis)
113
What cancers are associated with EBV?
- Burkitt lymphoma
- Nasopharyngeal carcinoma
114
What cancers are associated with HBV?
- Hepatocellular carcinoma
115
What cancers are associated with HPV?
Squamous cell carcinomas of:
- cervix
- penis
- anus
- head and neck
116
What cancers are associated with MCV?
Merkle cell carcinoma (rare but quite aggressive)
117
Examples of ionising and non-ionising radiation that can cause cancer
- UV light (UVA or UVB - increases risk of BCC, melanoma and SCC) - increased risk from this carcinogen is experienced if people have xeroderma pigmentosum
- Skin cancer in radiographers
- Lung cancer in uranium miners
- Certain parts of country has granite bedrock so increased risk of radon exposure as uranium decays into radon
- Thyroid cancer in Ukrainian children (from Chernobyl explosion)
118
Does ionising radiation have long or short term effects?
Long term effects
119
Examples of hormones with carcinogenic properties and what they cause
- Increased oestrogen - increased risk of breast and endometrial cancer (women without children are at more risk as having children lowers oestrogen levels)
- Anabolic steroids (mimics testosterone, stimulates muscle tissue growth) - increased risk of hepatocellular carcinoma
120
Which mycotoxin is carcinogenic
Aflatoxin B1 → hepatocellular carcinoma (and adenocarcenoma of the gall bladder)
121
Examples of carcinogenic parasites and what they cause
- Chlonorchis sinensis (chinese liver flu) - causes cholangiocarcinoma (blie duct cancer)
- Shistosoma - causes squamous cell metaplasia of the bladder causing a carcinoma in the bladder (most bladder cancers are urothelial). The parasite spends some time in the liver but doesn't cause liver cancer.
122
Examples of miscellaneous carcinogens
- Asbestos - causes mesotheliomas (cancer of mesothelium - e.g. pleura and pericardium)
- Metals (e.g. arsenic)
123
Host factors that can affect cancer risk (i.e. things the individual is/does that affect their risk of getting cancer)
- Ethnicity/Culture
- Diet
- Lifestyle
- Constitutional factors (age, gender etc.)
- Having premalignant lesions
- Transplacental exposure to carcinogens
124
Give evidence of culture/ethinicity playing a factor in cancer risk.
- there is increased oral cancer risk in Indiad and SE Asia due to reverse smoking (lit end is put in mouth causing thermal damage) and betal chewing
- there is decreased skin cancer in those with darker skin
125
Give examples of how diet plays a role in determining cancer risk
- Excess alcohol use increases risk of cancers of the mouth, oesophagus, liver, colon and breast (sort of like uppermost GI, liver, colon and breast)
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Give examples of how lifestyle plays a role in determining cancer risk
- Obesity increases risk of breast, oesophagus, colon and kidney cancer
- Exercise reduces risk of colon and breast cancer (has a positive effect on risk for most cancers)
- Increased smoking increases risk of lung cancer
- Unprotected sex increases risk of HPV-related cancer (cervix, penis, oropharyngeal - all the sites typically associated with sex)
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Give examples of how constitutional factors play a role in determining cancer risk
- Inherited predisposition
* familial polyposis coli (chr 5)
* retinoblastoma (chr 13) - more common in children(?)
- Age
* incidence increases with age (accumulate more mutations over time)
- Gender
* breast cancer is around 100x more common in women than men
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What is a premalignant lesion
Identifiable local abnormality associated with increased risk of malignancy at that site
129
Examples of premalignant lesions
- Colonic polyps (uncertain if they start off carcinogenic or not)
- Cervical dysplasia (CIN) (if untreated ⅓ will get better, ⅓ nothing will happen, ⅓ get cervical cancer)
- Ulcerative colitis
- Undescended testis
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Example of transplacental carcinogenesis
Diethylstilboestrol (used to be given for morning sickness) → increased risk of vaginal cancer in unborn female children
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Stages of cancer growth
1. the mutated cells have a growth advantage over normal cells (if mutated cells don't have growth advantage they will be apoptosed)
2. They will rapidly divide and replace the normal cells and fill that area forming a *carcinoma in situ*. They can't go anywhere as they have no interaction with lymphatics or blood.
3. The carcinoma invades through the basement membrane - initially forming a micro-invasive carcinoma (which can be locally excised) and then becoming an invasive carcinoma which has access to lymphatics and blood and can metastasize
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Why would a local excision be preferable to radiation therapy? Give specific example.
It would be better to locally excise a tumour in the cervix than using radiation therapy in order to preserve fertility in younger women.
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What is required for the cancer to invade through the basement membrane?
Needs to breakdown collagen of basement membrane and then extracellular matrix.
Need matrix metalloproteinases:
- collagenase
- cathepsin D
- urokinase-type plasminogen activator
And cells need motility:
- tumour cell derived motility factors
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Stages of metastasis
- Growth
- Invasion of basement membrane
- Invasion of extracellular matrix
- Intravasation (going into blood vessels)/going into lymphatics which also requires collagenases and cell motility
- Avoid immunological response from body
- Exit blood/lymph
- Angiogenesis to grow more than 1mm (up to 1mm things can just diffuse in)
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How do cancer cells evade host immune defense in blood?
- aggregation with platelets
- shedding of surface antigens
- adhesion to other tumour cells (central cells in lump will be protected from immune cells)
136
What is required for extravasation?
- Adhesion receptors (sense environment to coordinate cell action)
- collagenases
- cell motility
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What substances stimulate cancer growth and angiogenesis?
- vascular endothelial growth factor
- basic fibroblast growth factor
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Inhibitors of angiogenesis?
Statins
- angiostatin
- endostatin
- vasculostatin
(- avastatin doesn't work for cancer inhibition but does work as macular degenration treatment)
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Why is it important to check the lungs if any common or developed cancers are present in the patient
- Lungs act as a filter for anything coming from venous circulation so tumours can get stuck and grow in the lungs
- cancer can then metastasize from the lung as well
- e.g. sarcomas and any common cancers
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What is the term for having cancers everywhere in the body and what often causes this
Carcinomatosis
- often from lung cancer
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Which cancers commonly metastasize through blood to the liver
- Colorectal, stomach and pancreatic cancers
- carcinoid tumours of intestine
These all go through the portal venous system so end up in liver
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What are the two types of bone metastasis? Give examples of cancers that cause these effects
Sclerotic metastasis - more bone grows: looks whiter in x-rays
- e.g. prostatic cancer metastasis
Lystic metastasis - bone eaten away by tumour
- e.g. from breast cancer metastesis
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How does conventional cemo work
Vinblastin stops division by stopping spindle fibres
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Pros of conventional chemo
good for fast dividing tumours
e.g.:
– germ cell tumours of testis
– acute leukaemias
– lymphomas
– embryonal paediatric tumours
– choriocarcinoma
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Cons of conventional chemo
- not selective for tumour cells
- most common tumours are slower dividing so not always very effective
- affects normal cells that are dividing causing:
* myelosuppression (decreased bone marrow activity - fewer blood consitiuents)
* hair loss
* diarrhoea
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What does targeted chemo do and why can it be better than conventional chemo
Expolits some differences between cancer cells and normal cells to target drugs to cancer cells specifically
- more effective
- fewer side effects
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How can differences between cancer cells and normal cells be identified
- Gene arrays
- Proteomics (looking at their proteomes)
- Tissue microarrays
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What are the two methods of blocking increased signelling in cancer cells? What are their pros and cons.
Monoclonal antibodies
- fairly easy to identify and make
- more difficult and expensive to make monoclonal antibodies that can be used by humans as they need to be engineered to have a human tail
- they don't work on receptors that are permanently turned on regardless of if substances are attaching to them or not NOR do they work on things like the HER-2 receptors which don't actually have anything that binds to them and are activated in a different way
Small molecular inhibitors
- time consuming and difficult to identify and make
- it will work on all overactive receptors (that they are complementary to) as they bind to the bottom of the recptor and prevent them from signelling to the DNA
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How does HER-2 receptors function
They float around in the plasma membrane and promotes proliferation when they bump into other HER-2 receptors
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What is a common growth receptor targeted by cancer treatments
Growth factor A receptors
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What is the intermediate signelling protein for growth factor A receptors
Tyrosine kinase
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What is the cancer treatment specific to HER-2 receptors. What else is it used for and why.
Herceptin
- it is also used as an adjuvant therapy, for 1 year after the cancer is gone/stabilised, as it is cost effective to do this.
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Why doesn't cancer treatment work sometimes
Tumours like melanomas have lots of mutations and can be resistant to treatment
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What is an effective but uncommon cancer therapy?
CAR-T therapy - involves using the patient's own cells to formulate a treatment in the labs - very time consuming and expensive so not commonly used
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Definition of tumour
Any abnormal swelling.
Can be:
- neoplasm
- inflammation
- hypertrophy
- hyperplasia
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Definition of neoplasm
A lesion resulting from the autonomous or relatively autonomous abnormal growth of cells which persists after the initiating stimulus has been removed.
(new growth that is
- autonomous
- abnormal
- persistant
- not subject to normal homeostatic control)
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What proportion of the population will develop cancer during lifetime?
1 in 2 people (or 1/4??) - diff stats in diff places
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Does cancer risk increase or decrease with age? Why?
It increases as more mutations accumulate over time
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What % of all deaths is caused by cancer?
20%
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What are the 3 most common cancers in men and women respectively?
Prostate, lung, bowel
Breast, lung, bowel
161
Which cancer is most common cause of death in men and women?
Lung
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What does a neoplasm consist of?
Neoplastic cells and stroma
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What are characteristics of neoplastic cells?
- derived from nucleated cells
- usually monoclonal
- growth pattern related to parent cell
- synthetic activity related to parent cell (collagen, mucin, hormones etc.)
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Characteristics of stroma connected to neoplasm
Gr. = mattress
connective tissue framework (fibroblasts, collagen, maybe myofibroblasts)
mechanical support
nutrition
(not usually neoplastic itself however it will grow while neoplastic cells continue to live)
looks paler in histological slides
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Why do malignant neoplasms often have some necrosis?
They tend to grow faster than angiogenesis can occur so some cells necrose (often centrally)
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Methods of classification of neoplasms
Behavioural: benign/malignant
Histogenetic: the specific cell of origin of a
tumour
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Behavioural classification of neoplasms
benign
Borderline (e.g some ovarian lesions - typically uncommon - defy precise classification - treat as if malignant)
malignant
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Characteristics of benign neoplasms
- Localised, non-invasive
- Slow growth rate (compared to malignant)
* Low mitotic activity
- Close resemblance to normal tissue
- Circumscribed or encapsulated (compressed rim of tissue around them) - discrete well-defined
- Nuclear morphometry often normal
- Necrosis rare
* Ulceration rare
- Growth on mucosal surfaces often exophytic (upwards and outwards growth)
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How can benign neoplasms cause morbidity and mortality?
- Pressure on adjacent structures
- Obstruct flow
- Production of hormones (not regulated by normal feedback loops)
- Transformation to malignant neoplasm
- Anxiety
170
Characteristics of malignant neoplasms
Invasive
* Poorly defined or irregular border (have a 'crab-like' cut surface)
Potential for metastases
Rapid growth rate
* Increased mitotic activity
Variable resemblance to normal tissue
Hyperchromatic nuclei (darker than normal)
Pleomorphic nuclei (vary in size)
Necrosis common
* Ulceration common
Growth on mucosal surfaces and skin often endophytic (down and in)
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How do malignant neoplasms cause morbidity and mortality?
Destruction of adjacent tissue
Metastases
Blood loss from ulcers
Obstruction of flow
Hormone production
Paraneoplastic effects (hormone/antibody mediated - effects in other parts of body)
Anxiety and pain
172
Which cells can neoplasms arise from?
Epithelial cells
Connective tissues
Lymphoid/haematopoietic organs
173
Nomenclature of neoplasia
Most neoplasms have the suffix -oma
Prefix depends on behavioural classification and cell type
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What is a benign tumour of non-glandular, non-secretory epithelium called
Papilloma
Prefix with cell type of origin e.g. squamous cell papilloma (squamous is most common - commonly reffered to as viral warts)
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What is a benign tumour of glandular or secretory epithelium called?
Adenoma
Prefix with cell type of origin e.g. colonic adenoma, thyroid adenoma
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What is a malignant tumour of epithelial cells called?
Carcinoma
Prefixed by name of epithelial cell type e.g. urothelial Ca
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What is a malignant tumour of glandular epithelium called?
Adenocarcinomas
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Give the names of benign connective tissue neoplasms
Lipoma: adipocytes
Chondroma: cartilage
Osteoma: bone
Angioma: vascular
Rhabdomyoma: striated muscle (rhabdo - striated, myo - muscle)
Leiomyoma: smooth muscle (leio - smooth)
Neuroma: nerves
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Name malignant connective tissue neoplasms
Sarcoma is general term for malignant connective tissue
Liposarcoma - adipose tissue
Rhabdomyosarcoma - striated muscle
Leiomyosarcoma - smooth muscle
Chondrosarcoma - cartilage
Osteosarcoma - bone
Angiosarcoma - blood vessels
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What is the term for a cancer where the cell of origin is unknown
Anaplastic
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Examples of neoplasms that don't follow nomenclature rules
melanoma: malignant neoplasm of melanocytes
Mesothelioma: malignant neoplasm of mesothelial cells
lymphoma: malignant neoplasm of lymphoid cells
Burkitt’s lymphoma
Ewing’s sarcoma (bone)
Grawitz tumour (renal carcinoma)
Kaposi’s sarcoma (type of angiosarcoma)
Teratoma (contain cells from all layers of germ cells - typically in ovarian cancers)
Embryonal tumours (blastomas)
Mixed tumours (tumours having collided together)
APUDomas (amine content &/or precursor uptake and decarboxylation)
Carcinosarcomas (uterine or endometrial - stroma is also malignant, very poor prognosis)
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How can cancers be further classified
By different degree of differentiation
183
Stages of inflammation
- Icreased vessel permeability
- Fluid exudate
- Cellular exudate
(research + flesh out)
184
Stages of Neutrophil action
- Margination
- Adhesion
- Emigration
- Diapedesis
(research + flesh out)
185
Outcomes of inflammation
- Resolution
- Supporation
- Organisation
- Progression
(research + flesh out)
186
DDx of clubbing
- Hereditary
- Cyanotic heart disease
- Infective endocarditis
- Cystic fibrosis
- Bronchiectasis (releases growth factors)
- Tuberculosis
- Inflammatory bowel disease
- Liver cirrhosis
