ICS - Pathology Flashcards
Give 2 benefits and 2 limitations of inflammation in the body
Benefit - Destruction of invading microorganisms and walling off of an abscess, preventing spread of infection.
Limitations - Acts as a space occupying lesion, compressing surrounding structures. Fibrosis after chronic inflammation may distort tissues and permanently alter function.
Characteristic inflammation cell
Neutrophil polymorph
4 outcomes of inflammation
Resolution - goes away
Suppuration - abscess or pus formation
Organisation - Healing by fibrosis (scarring)
Progression to chronic inflammation
Describe organisation (inflammation outcome)
Substantial tissue damage means tissue cant regenerate specialised cells. Dead tissues and inflammatory exudate removed from damaged areas by macrophages. Defect becomes filled by specialised granulation tissue, which contains fibroblasts that produce collagen.
What are the 3 stages of inflammation?
Increased vessel calibre (inflammatory cytokines mediate vasodilation)
Fluid exudate
Cellular exudate
5 causes of acute inflammation
Microbial infection
Hypersensitivity reactions
Physical agents (trauma, ionising radiation, heat/cold)
Tissue necrosis
Bacterial toxins
5 macroscopic features of acute inflammation
Redness (Rubor)
Heat (Calor)
Swelling (Tumour)
Pain (Dolor)
Loss of function
Explain why macroscopic features of acute inflammation occur
Redness - Dilation of small blood vessels in damaged area
Heat - Vascular dilation and increased blood flow. Systemic fever due to chemical mediators of inflammation.
Swelling - swelling due to oedema from fluid exudate
Pain - Stretching and distortion of tissues due to inflammatory oedema.
Loss of function - fibrosis distorts tissue.
What is fluid exudate?
Exudate is fluid that leaks out of blood vessels into surrounding tissues. Fluid made up of cells, proteins and solid materials.
Is also known as pus.
Stages in neutrophil polymorph emigration
Margination - Vascular dilation = slowing of blood flow and oedema = increase in plasma viscosity.
Adhesion - Pavementing occurs at site of inflammation, Adhesion molecules expressed on endothelial surface and neutrophils adhere and roll along endothelium.
Neutrophil emigration - Neutrophils, eosinophil polymorphs and macrophages all insert pseudopodia between endothelial cells and migrate through gap.
Diapedesis - RBC also escape from vessels - passive process depending on hydrostatic pressure.
Role of histamine and TNF-a in inflammation
Histamine and TNF-a released mast cells cause expression of adhesion molecules on surface of endothelial cells. = very firm neutrophil adhesion to endothelial surface.
4 effects of endogenous chemical mediators of inflammation
Vasodilation
Chemotaxis
Increased vascular permeability
Itching and pain
Diagnostic criteria for acute inflammation
Presence of neutrophil polymorphs
3 endogenous chemical mediators of acute inflammation
Bradykinin
Histamine
Nitric oxide
5 systemic effects of acute inflammation
- Fever
- Weight loss
- Fatigue
- Reactive hyperplasia
- Tachycardia
(There are loads - tachypnoea, hypotension, depression, athralgia etc etc)
Benefits and drawbacks of fluid exudate in inflammation
Benefits
- Dilution of toxins
- Entry of antibodies
- Fibrin formation
Drawbacks
- Digestion of normal tissues
- Swelling
- Inappropriate inflammatory response (hypersensitivity)
Define chronic inflammation, and what cells is it characterised by?
Subsequent and prolonged tissue reactions to injury following initial response.
Characterised by lymphocytes, plasma cells and macrophages. Some macrophages form multinucleated giant cells. Not many neutrophils.
4 causes of chronic inflammation
Primary chronic inflammation
Transplant rejection
Recurrent acute inflammation (e.g. cholecystitis due to gallstones)
Progression from acute (suppurative most common)
4 causes of primary chronic inflammation
Resistance of infective agent to phagocytosis (TB)
Granulomatous disease (e.g. sarcoidosis, crohns)
Autoimmune disease
Exogenous material (silica, asbestos)
5 Macroscopic features of chronic inflammation
Chronic ulcers
Chronic abscess cavity
Thickening of hollow organ wall
Granulomatous inflammation
Fibrosis
Define granuloma
An aggregate of epithelioid histocytes. (horseshoe shape)
(where immune system walls off substance but is unable to eliminate it)
Why do you get exudate in inflammation?
Capillary hydrostatic pressure increases and plasma proteins are pushed into extravascular space, increasing osmotic pressure there. Results in much more fluid leaving vessels than is returning.
4 changes to local blood vessels in inflammation
- Vascular Dilation (causing redness and warmth)
- Increased permeability (causing oedema and pain)
- Endothelial cells activate (express cell-adhesion molecules, allowing binding of circulating leukocytes)
- Clotting in small blood vessels (prevents circulation of pathogens)
What cell is the most important source of histamine?
Mast cells
What stimulates histamine release in inflammation?
C5a causes histamine and TNF-a release from mast cells.
7 microscopic features of chronic inflammation
Lymphocytes
Plasma cells
Macrophages
Multinucleate giant cells
New fibrous tissue
Tissue necrosis may be present
Eosinophil polymorphs
What enzyme acts as a marker of granulomatous disease?
Angiotensin converting enzyme (secreted by granulomas)
What cells regenerate? (5)
Hepatocytes
Pneumocytes
All blood cells
Gut and skin epithelium
Osteocytes
What cells don’t regenerate? (2)
Myocardial cells
Neurones
Define abscess
Acute inflammation with a fibrotic wall
What is the difference between repair and resolution?
In resolution, initiating factor removed and tissue can regenerate.
In repair, initiating factor still present and tissue can’t regenerate
What 2 properties of blood flow mean thrombosis formation is uncommon?
- Laminar flow (cells travel in centre of vessels)
- Non sticky endothelial cells
Describe Virchows triad
3 factors that could contribute to thrombosis
1. Endothelial injury (cellulitis, trauma, HTN, smoking)
2. Venous stasis (Immobility, pregnancy, AF)
3. Hypercoagulability (Major surgery, malignancy, pregnancy, sepsis)
Treatment of arterial and venous thrombosis
Arterial - Antiplatelets
Venous - DOAC/Warfarin
What are alpha and dense granules in platelets?
Alpha granules contain substances that aid adhesion to damaged vessel
Dense granules contain substances that cause platelets to aggregate
Fates of thrombi
Resolution
Organisation
Decreased blood flow
Define cytokine and chemokine
Cytokines are secreted by cells of the immune system and affect other cells
Chemokines induce directed movement of cells
Define thrombosis
Solid mass of blood constituents formed within intact vascular system during life
6 constituents of an atherosclerotic plaque
- Lipids (e.g. cholesterol)
- Smooth muscle
- Macrophages
- Foam cells (macrophages that phagocytose LDL)
- Platelets
- Fibroblasts
6 risk factors for atherosclerosis
- Cigarette smoking
- Hypertension
- Hyperlipidaemia
- Uncontrolled diabetes mellitus
- Lower socioeconomic status
- Old age
5 stages of atherosclerosis
- Fatty streak (10 years precursor)
- lipid accumulation
- Platelet aggregation
- Fibrin mesh and RBC trapping
- Fibrous cap formation
What is granulation tissue composed of?
Fibroblasts/myofibroblasts
New thin walled capillaries
Endothelial cells
Keratinocytes
Healing by first intention vs second
First - wound edges approximated (e.g. by glue, staples, plasters, sutures) so healing begins top down. Reduces tissue loss, allowing body to heal smaller area than initial wound.
Second - wound edges cant be approximated. Larger tissue loss occurs and wound heals from bottom up. Higher risk of infection. Relies on body’s own mechanisms. Needed in cases of large burns or ulcers, where approximation would reduce mobility or function.
Pathogenesis of atherosclerosis
- High LDL causes them to deposit and oxidise in tunica intima, activating endothelial cells which present leukocyte adhesion molecules.
- Leukocytes move into intima and attract monocytes (macrophages/T helper cells)
- Macrophages take up oxidised LDL and form foam cells, which release IGF-1 causing smooth muscle to migrate to intima from media.
- Smooth muscle proliferation forms fibrous cap.
- As foam cells die they release lipid content, growth factors and cytokines, growing plaque.
- Plaque either occludes vessel or ruptures, triggering platelet aggregation and clotting.
Causes of outcomes of inflammation
Resolution - normal
Suppuration - excessive exudate
Repair and organisation - excessive necrosis
Chronic - persistent causal agent
Define Atrophy with example
Decrease in tissue size due to reduction in number of constituent cells or cell size.
Example: Loss of innervation, or under usage = muscle atrophy
OR
Thyroid gland atrophy in Hashimotos thyroiditis.
Define hyperplasia with example
Increase in tissue size due to increase in number of constituent cells (by mitosis)
Physiological: Ductal hyperplasia in pregnancy
Pathological: BPH/ Endometrial hyperplasia
CANT OCCUR IN MYOCARDIAL OR NERVE CELLS (dont divide)
Define hypertrophy with physiological and pathological examples
Increase in cell size without division
Physiological: Skeletal muscle hypertrophy in athletes. Uterine smooth muscle in puberty and pregnancy.
Pathological: RV Hypertrophy in pulmonary hypertension
Define metaplasia with example
The change in differentiation from one fully differentiated cell type to another.
Example: Squamous to columnar in Barrett’s oesophagus
OR
Ciliated respiratory epithelium to squamous in smokers
Define dysplasia with example
Imprecise term for morphological (cell shape, structure, form) differences in cell on way to becoming cancerous.
E.g. Barrett’s oesophagus, Gastritis (chronic inflammation = epithelial metaplasia)
Define Carcinogenesis
Transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations (only applies to malignant (invasive) neoplasms)
6 steps of metastasis
- Detachment of tumour cells from neighbours
- Invasion of surrounding tissues to reach metastasis conduits (blood/lymphatics)
- Intravasation into lumen of vessels
- Evasion of host defence mechanisms
- Adherence to endothelium at remote location
- Extravasation of cells from lumen to surrounding tissue
Which cancers metastasise to bone and how do they spread
Lung
Breast
Kidney
Thyroid
Prostate
Haematogenous spread
Invasion vs metastasis
Invasion is ability of cancer cells to directly extend and penetrate into surrounding cells, whilst metastasis uses lymphatic or blood vessels to form a secondary tumour elsewhere
How is basal cell carcinoma treated?
Complete local excision is curative (basal cell carcinoma is locally invasive but doesn’t metastasise)
Name a drug that inhibits platelet aggregation
Aspirin, can be prescribed low dose to prevent thrombosis
3 disease causing processes of atherosclerosis
- Vessel stenosis - more than 50-70% occlusion = critical reduction of blood flow. Tissue ischaemia reversible at first with pain only at exertion. Severe stenosis = pain at rest
- Plaque rupture = Activation of coagulation cascade, leading to thrombosis which can occlude vessels
- Ruptured atherosclerotic aneurysm
Define infarction
Local cell and tissue death due to obstruction of blood supply
5 preventative measures against atherosclerosis
- Smoking cessation
- Blood pressure control
- Weight reduction
- Low dose aspirin (inhibits platelet aggregation)
- Statins
5 possible complications of atherosclerosis
Cerebral infarction
Myocardial infarction
Aortic aneurysm
PVD
Gangrene
How does smoking damage arteries?
Free radicals oxidise LDL
Nicotine and CO damage endothelial cells
What protein detects DNA damage in cells, leading to apoptosis?
P53 protein
Where is apoptosis found physiologically?
In tissues with high cell turnover (Skin. gut)
Give an example of apoptosis in disease?
HIV
Define necrosis and give a pathological example
Traumatic cell death, which induces inflammation and repair, for example frostbite, cerebral infarction.
apoptosis vs necrosis
Apoptosis is non inflammatory and controlled. Organelles retailed and chromatin unaltered. Apoptosis affects single cells. Cells shrink and fragment into apoptotic bodies.
Necrosis is inflammatory and traumatic. Cells burst, organelles spread, chromatin altered. Necrosis affects groups of cells. Cells swell and lysis.
Inducers and inhibitors of apoptosis (3 each)
Inducers - DNA damage, glucocorticoids, loss of matrix attachment
Inhibitors - Growth factors, Extracellular cell matrix, Sex steroids
Intrinsic apoptosis pathway
Intrinsic - Responds to biochemical stress or growth factors. P53 gene responds and activates either: Bcl-2 which responds to apoptosis inhibitors or Bax which enhances apoptotic stimuli. More Bax or less Bcl-2 stimulates Caspases, leading to apoptosis.
Extrinsic apoptosis pathway
Extrinsic - Apoptosis activated by ligand binding at death receptors on cell surface, e.g. TNFR1 (tumour necrosis factor receptor) or Fas. Initiates signal transduction cascade and activates caspases.
What do caspases do?
Caspases are proteases that cause apoptosis through degradation of cytoskeletal framework and nuclear proteins.
Why is apoptosis non inflammatory?
Dead cells are arranged into apoptotic bodies, which are eventually phagocytosed.
Why is necrosis inflammatory?
Spillage of cell contents provoke inflammatory response
Give the 4 types of necrosis
Coagulative - Caused by ischaemia, causes proteins to coagulate and tissue is digested by macrophages, making firm tissue soft. Necrotic tissue = inflammation.
Liquefactive - Brain liquifies due to lack of supporting stroma (blood, lymph, connective tissue, nerves)
Caseous - e.g. TB. Tissue structureless
Gangrene - Tissue rots, appears black due to iron sulphide deposition from degraded haemoglobin. Usually due to bacteria.
Acquired vs inherited
Acquired - No DNA involvement, result from environmental factors
Inherited - Caused by changes in DNA, passed genetically
What syndromes are trisomy 21, 18 and 13
Trisomy 21 - Down’s
Trisomy 18 - Edwards
Trisomy 13 - Patau’s
All are spontaneous mutations
Define neoplasm
New, autonomous, abnormal, persistent growth. Only occurs from nucleated cells
Define tumour
Any abnormal growth (neoplasm + inflammation + hypertrophy + hyperplasia)
Arterial vs venous thrombosis: Clinical effects
Arterial:
Pale, pulseless, paralysis, paraesthesia, perishingly cold, painful
Venous:
Area becomes tender, warm, red, swollen. (95% in legs (DVT)). Superficial veins distended. Oedematous.
How might you differentiate an arterial ulcer from a venous ulcer?
Arterial: Distal extremities. hairless, pale/ necrotic wound tissue, skin shiny pale taut, minimally exudative
Venous: Gaiter area, lower calf to medial malleolus. Irregular shape, granular appearance, more exudative, firm odoema, thick skin.
Arterial vs venous thromobosis: causes
Arterial: atherosclerosis (See card on process)
Venous: grow by successive deposition via propagation. When BP low, blood flow is less laminar, thrombi can grow near valves.
Why dont you get atheroma in veins
They have a lower blood pressure
Pharmacological ways to prevent thrombosis
Aspirin - inhibits platelet aggregation
Warfarin (severe) - inhibits vitamin K (clotting factor)
What clotting factors are Vit K dependant
K-10,9,7,2
Possible complications of arterial embolism passing through heart
Cerebral infarct (stroke)
Renal infarct
Bowel ischaemia
Foot ischaemia (dry gangrene)
5 host factors that influence carcinogenesis
Race
Diet
Constitutional factors - age, gender etc.
Premalignant lesions
Transplacental exposure
Naming conventions of cancers of cancers of connective tissue
- Adipocytes
- Striated muscle
- Smooth muscle
- Cartilage
- Bone
- Vascular
-oma and -sarcoma
- Adipocytes: lipo-
- Striated muscle: Rhabdomyo-
- Smooth muscle: leiomyo-
- Cartilage: Chondro-
- Bone: Osteo-
- Vascular: Angio-
What 2 ways are cancers classified
- Behaviour (benign or malignant)
- Histogenesis (origin cells)
What are the 2 major subdivisions of histogenic cancer classification
Epithelial cells: Non glandular : Papilloma/ Carcinomas
Glandular: Adenoma/adenocarcinoma
Connective tissues: -Oma/ -Sarcomas
3 ways benign cancers can be pathological
- Can secrete hormones (e.g. prolactinoma)
- Can cause obstruction to flow of fluid (e.g. BPH - urinary issues)
- Pressure on adjacent structures (e.g. pituitary adenoma pressing on optic chiasm)
Benign vs malignant tumour behaviours
Benign
- localised (no BM invasion)
- Slow growing
- Closely resemble normal tissue
- Necrosis and ulceration is rare
- Exophytic (grow outward)
Malignant
- invasive (but not always metastatic - Basal cell carcinoma is malignant but doesnt metastasise)
- Grow fast
- Irregular border and dont resemble parent cell as much
- Hyperchromatic nuclei that stain dark
- Necrosis common
- Endophytic (grow inward)
Organs with a dual artery supply
Liver - portal venous and hepatic artery supplies
Lung - pulmonary venous and bronchial artery supplies
Brain - circle of willis and multiple arterial supplies
Less susceptible to infarction
How are malignant tumours pathological
- Pressure on and destruction of adjacent tissue
- Formation of metastases
- Blood loss (ulcerated surfaces)
- Obstruction of flow (malignant tumor of colon = intestinal obstruction)
- Paraneoplastic effects (SIADH/ Cushings)
Why is cell differentiation important in malignant cancers?
A tumour with poorly differentiated cells is more aggressive than well differentiated tumours.
Grade 1- Well differentiated (75% cells resemble parent)
Grade 2 - Moderately differentiated (10-75%)
Grade 3 - Poorly differentiated (<10%)
What is an anaplastic cancer?
A cancer whose cells are so poorly differentiated they lack recognisable histogenic features. These are extremely aggressive
What is carcinoma in situ?
A tumour presenting all the features of a malignant cancer but has not yet penetrated the basement membrane. In these cases, excision is a cure.
Tumours which commonly metastasise to liver
Colon
Stomach
Pancreas
Intestine
3 ways neoplastic cells are adapted to differentiate so much
- Growth stimulation due to oncogene overexpression and tumour suppressor gene inactivation
- Reduced apoptosis due to abnormal expression of apoptosis inhibiting genes (bcl-2)
- Telomerase - Prevents telomeric shortening, so cell cycles are not restricted - can divide forever.
What 6 cancers are caused by alcohol?
Oropharynx
Larynx
Oesophagus
Liver
Breast
Colorectal
3 ways alcohol causes cancer
- Ethanol makes it easier for cells in oropharynx to absorb other carcinogens
- Ethanol increases oestrogen levels
- Alcohol’s metabolite, acetaldehyde, is a mutagen
What cancers can be caused by these chemicals:
1- polycyclic aromatic hydrocarbons?
2- aromatic amines?
3- nitrosamines?
4- alkylating agents?
1- lung or skin cancer
2- Bladder
3- Gut
4- Leukaemia
What cancers are caused by Epstein Barr virus
Burkitt’s Lymphoma
Hodgkin’s lymphoma
Nasopharyngeal carcinoma
What cancers are caused by Human papillomavirus (HPV)
Squamous cell carcinomas of cervix, penis, anus, head, neck
What cancers are caused by human herpes virus 8
Kaposi sarcoma
Primary effusion lymphoma
3 lifestyle risk factors for cancer
Excess alcohol causes cancer
Obesity increases risk of some cancers
Unprotected sex increases risk of HPV related cancer
Define oncogenesis
Development of benign or malignant tumour
What 2 types of cells do tumours consist of?
Neoplastic cells
Stroma
Function of stroma
Mechanical support
Intercellular signalling
Nutrition to neoplastic cells
What does stroma consist of
Fibroblasts
Collagen
Blood vessels
Major categories of origin for cancers
- Epithelial cells (carcinomas)
- Connective tissues (sarcomas)
- Lymphoid (lymphoma/leukaemia - ALWAYS MALIGNANT)
3 genetic alterations that transform a normal cell to neoplastic
- expression of telomerase - avoids shortening of telomeres, meaning cell can divide perpetually
- Loss or inactivation of both copies of a tumour suppressor gene, remove inhibitory control
- Activation or abnormal expression of oncogenes to stimulate cell proliferation
3 mutations that can cause abnormal oncogene activation
- Translocation
- Point mutation
- Amplification
Why should a wide margin be removed when excising tumours
To ensure tumour cells that could cause a local recurrence arent left behind
Factors influencing tumour invasion
- Decreased cellular adhesion
- Secretion of proteolytic enzymes
- Abnormal/increased cellular motility
Tumour grading vs staging
Grading is an assessment of malignancy/aggressiveness
Staging is an extent of spread
3 main features when assessing grading
- Mitotic activity
- Nuclear size, hyperchromasia (dark staining), pleomorphism
- Resemblance to normal tissue
Explain the staging system for tumours
TNM
T - Tumour size
N - Degree of lymph Node involvement
M - Extent of distant Metastases
4 characteristics of a neoplastic cell
- Autocrine growth stimulation (overexpression of GF, mutations of tumour suppressor genes)
- Evasion of apoptosis
- Telomerase
- Sustained angiogenesis and ability to invade BM
- Invasive growth
Explain the disease/ mutation involved in colorectal cancer.
Oncogenes implicated.
Inheritance pattern.
FAP (familial adenomatous polyposis) - caused by mutation in APC gene (adenomatous polyposis coli).
Causes multiple adenomas at early age in large intestine. KRAS and c-MYC oncogenes.
Autosomal dominant inheritance.
Define germline mutation
A mutation in sex or germ cells (egg or sperm). Can be passed onto child and mutation will present in all cells of childs body.
Define somatic mutation
Spontaneously arise in any cell except germ cells in life. Limited to that cell and its descendants. No inheritance.
What cancers are screened for in the UK
Breast
Bowel
Cervical
What cancers are caused by BRCA1 and BRCA2 mutations
BRCA1 - Breast and ovarian
BRCA2 - Breast, prostate, pancreatic
How are the 3 screened cancers screened for
Cervical - Cervical swab
Breast - Mammogram
Colorectal - Faecal occult blood
What does the heel prick test screen for
Sickle cell
Cystic fibrosis
Hypothyroidism
