Pathology Flashcards
Causes of fluctuating cognitive function
subdural haematoma cerebral abscess meningioma acute aortic regurgiation hypertensive encephalopathy alcohol intoxication
2 types of autopsy
hospital autopsy (less than 10%) medico-legal autopsy (over 90%)
autopsy requirements
consent needed
death certificate needed
Deaths referred to coroner
presumed natural (cause of death not known/not seen by doctor in last illness) presumed iatrogenic (clinical care - post-operative, anaesthetic, therapeutic complications) presumed unnatural (accident, suicide, industrial (asbestos), unlawful killing, custody death)
Who makes referrals?
Doctors
Registrar of BDM (Births, Deaths, Marriages)
Police
Relatives
Who performs autopsies?
Doctors
Histopathologist (hospital and coronial)
Forensic pathologists (coronial)
Role of coroner (questions that they need to answer)
Who was deceased?
when and where death occurred?
How did they come about their death?
What is an autopsy?
1) History/scene
2) External exam
3) Evisceration
4) Internal exam
5) Reconstruction
Samples taken during autopsy
Microbiology Toxicology XRAY Histology Genetics Photographs
External exam
Identification - Gender, age, jewellery, clothing, body mod
Injuries
Evisceration
Y-shaped incision Open all body cavities Examine all organs in situ Remove thoracic and abdo organs Remove brain
Internal exam
Internal organs, nodes, vessels, tracts and central NS
What is inflammation?
A reaction to injury or infection involving cells such as neutrophils and macrophages
When is inflammation bad?
Autoimmune
Inflammation classification
Acute (neutrophils) - sudden, short-duration, resolves usually
Chronic (lymphocytes and macrophages) - Slow onset, long-duration, may never resolve
Neutrophil polymorphs
Short lived cells, first line
First to act during acute inflammation
Use enzymes to kill bacteria, end up dying during the process resulting in puss
Macrophages
Long-lived cells Phagocytic Ingest bacteria Carry debris away Present antigen to lymphocytes
Lymphocytes
Longest lived cells
Produce chemicals which attract other inflammatory cells
Immunological memory
Endothelial cells
Become sticky in areas of inflammation so inflammatory cells adhere to them
Become porous to allow inflammatory cells into tissues
Fibroblasts
Long lived
Form collagen in areas of chronic inflammation and repair
Acute inflammation examples
Acute appendicitis
Acute inflammation outcomes
Resolution
Discharge of pus
Chronic inflammation
Chronic inflammation example
TB
Granulomas
Group of macrophages
Chronic inflammation
Treating inflammation
Inhibit prostaglandin synthetase (prostaglandins are chemical mediators of inflammation)
NSAIDs - Aspirin, Ibuprofen etc
Corticosteroids - bind to DNA and upregulate inhibitors of inflammation and downregulate chemical mediators of inflammation
LECTURE CATCHUP*
LC*
Carcinogenesis
Transformation of normal cells to neoplastic cells through permanent genetic mutations
Apples to malignant neoplasms only
Oncogenesis
Benign and malignant tumors
Crcinogens
Agents known or suspected to cause tumours
Carcinogenic
Cancer causing
Oncogenic
Tumour causing
Muatgenic
Act on DNA
Risk of cancer - Environmental
85%
Hepatocellular carcinoma
Uncommon in UK/USA
Common in areas with increased Hep B/C and mycotoxins
Oesophageal carcinoma
High incidence in Japan, China, Turkey and Iran
- Dietary factors (Linhsien chickens and hot tea respectively)
Behavioral risks
Lung cancer - smoking
Occupational risks
Bladder cancer - Dye and rubber industry
Scrotal cancer - Chimney sweeps
Classes of carcinogens
Chemical Viral Ionising and non-ionising radiation Hormones, parasites and mycotoxins Misc
Chemical carcinogens
Tend to require conversion from pro-carcinogen to ultimate carcinogen
Enzyme required may be confined to certain organs
Some act directly
Chemical carcinogens
Polycyclic aromatic hydrocarbons - Lung and skin cancer - Smoking
Aromatic amines - Bladder cancer - Rubber/dye industry
Nitrosamines - Gut cancer
Alkylating agents - Leukaemia
Radiant energy
UV light - Melanoma
Xeroderma pigmentosum condition has increased risk
Ionising radiation for long term increases skin cancer in radiographers
Lung cancer in uranium miners
Thyroid cancer in Ukranian children
Biological agents
Hormones - Oestrogen - Breast/endometrial cancer
Anabolic steroids - HCC
Mycotoxins - Aflatoxin B1 - HCC
Parasites - cHLOARCHIS SINESIS - Cholangiocarcinoma
Schistosomiasis - Bladder cancer
Misc
Asbestos
Metals
Host factors
Race - Increased Oral cancer in SE asia (reverse smoking, betal chewing), Decreased skin cancer in blacks (melanin)
Diet
Age - Increases
Gender - Breast cancer
Premalignant lesions - Colonic polyps, UC.
Transplacental exposure - Diethylstiboestrol - Increased vaginal cancer
Cancer
Latent interval between exposure and cancer development
Tumour
Any abnormal swelling - Neoplasm (tends to be), inflamamtion, hypertrophy, hyperplasia
Neoplasia
A lesion which is autonomous, abnormal, persistent and is a new growth. It persists after the initiating stimulus has been removed
Neoplasia
25% of pop
20% of all deaths
Deaths from cancer
Prostate cancer is most common in men, but lung cancer is most common killer
Breast cancer is most common in women though
Structure of neplasms
Neoplasm, neoplastic cells, derived from nucleated cells usually monoclonal, growth pattern and synthetic activity related to the parent cell,
Neoplasm, stroma, connective tissue framework, mechanical support, nutrition.
Tumour angiogenesis
1) Avascular tumour nodule
2) Vascularised tumour
3) Vascularised tumour with central necrosis
Neoplasm structure
Tumour cells + stroma
Classifying neoplasms
Behavioral: Benign/borderline/malignant
Histogenetic: Cell of origin
Benign neoplasms
Localised Non-invasive Slow growth rate Low mitotic activity Close resemblance to normal tissue Circumscribed or encapsulated Necrosis rare Ulceration rare Growth on mucosal surfaces often exophytic
Benign neoplasms concerns
Pressure on adjacent structures Obstruct flow Produce hormones Transform to malignant neoplasm Anxiety
Malignant neoplasms
Invasive Metastases Rapid growth rate Variable resemblance to normal tissue Poorly defined/irregular border Hyperchromatic nuclei Increased mitotic activity Necrosis and ulceration common Growth on mucosal surfaces and skin often endophytic
Malignant neoplasms concerns
Destruction of adjacent tissue Mets Blood loss from ulcers Obstruction of flow Hormone production Paraneoplastic effects Anxiety and pain
Histogenetic classifiation
Histogenesis - specific cell of origin of a tumour
histopathlogyical examination
nomenclature of neoplasia
neoplasms may arise from epithelial cells, connective tissue, lymphoid tissue
nomenclature of neoplasms
all neoplasms have suffix -oma
prefeix depending on behavioural classificaiton and cell type
Benign epithelial noeplasms
Papilloma - benign tumour of non-glandular, non-secretory epithelium
prefix with cell type of origin e.g. squamous cell papiloma
benign epithelial neoplasms
adenoma - benign tumour of glandular or secretory epithelium
malignant epithlial neoplasms
carcinoma - malignant tumour of epithelial cells
prefixed by name of epithelial cell type e.g. trnaslational cell carcinoma
Carcinomas of glandular epithelium - adenocarcinomas
Benign connective tissue neoplasms
Lipoma - adipocytes Chondroma - cartilage Osteoma - bone Angioma - vascular Angiolipoma - blood and fat cells neoplastic Rhabdomyoma - sriated muscle Leiomyoma - smooth muscle
Maligantn connective tissue neoplasms
Liposarcoma - adipose tissue
Rhabdomyosarcoma - striated muscle
Osteosarcoma - bone
etc
Carcinomas and sarcomas classified further
Degree of differentiation
Anaplastic
Where cell type of origin is unknown
Some exceptions
Not all -omas are neoplasms: granuloma, tuberculoma, mycetoma
Not all malignant tumours are carcinoma or saroma: melanoma, mesothelioma, lymphoma
cancer summary
Behaviour: benign or malignant
histogenesis: cell of origin
suffix: -oma denotes neoplasm
prefix: benign or malignant, and cell type
Carcinoma in situ
Not invaded anywhere
Invasive carcinoma
Invaded basement membrane
Can be micro-invasive
Cancer growth
Invasion of basement membrane - proteases (matrix metalloproteinases in liver cancer)
Invade bm - cancer cells moving through bm
Invasion of extracellular matrix using proteases, then cell motility again to invade through again.
Move into and travel through lymphatic or blood vessel
Stick to side of vessel wall
Out into extracelllular matrix
Regrowth and create own blood supply (angiogenesis) at metastatic site
Inhibitors of angiogenesis
Avastin (standard treatment for macular degeneration)
Routes for mets
Blood vessels
Common organ for mets to occur
Any common cancers, sarcomas, often mets to lung
Colorectal/colon cancer tends to spread to
Liver
Also anything which drains to portal venous system mets to liver
tumours that mets to bone
prostate breast lung kidney thyroid
lung cancers
non-smoker - adenocarcinoma
smoker - squamous cells carcinoma
Chemotherapy
Vinblastine (antimicrotubule agent)
Etoposide
Ifosamide (binds to dna directly and cross links it to prevent replication)
cisplatin does same as ifosamide
Chemotherpay
Uusally hits normal cells which are dividing - myelosuppression, hair loss, diarrhoea
Good for fast dividing tumours (lymphomas, acute leukaemias), not for slower dividing ones
Increase in tumour size
Cell division
Lack of apoptosis
Targeted chemo
more effective
less se
How to find differences between normal and cancerous tissue
gene arrays
proteomics
tissue microarrays
How to exploit differences
make a monoclonal ab against growth factor receptors to prevent growth factors binding so no activation signals and no proliferation
Small molecular inhibitor of growth factor receptor, same effects but harder to make
Cetuximab
mab on end means monoclonal ab
Chimeric so that body does not identify as foreign
EGFR blocker
Herceptin
Chimeric mab against EGFR 2 (Her-2)
Her-2 has a TKI switch
2 Her-2 molecules binding together activates signals for proliferations
Hereceptin mab causes Her-2 protein to be endocytosed and destroyed, this reduces her-2 numbers and so reduces its activity
Lymphocytes then are triggered and join
Her-2 gene is amplified in breast cancer, so Herceptin is used for adjuvant chemo in her2-positive breast cancer
How to detect her-2 amplification
FISH - Fluorescent in situ hybridisation
Immunohistochemistry
Anti-PD1
PD1 overexpression in tumours causes immunosuppression
Small molecular inhibitors
Gleevec - Inhibits c-kit receptor
Gefitinib - EGFR TKI inhibitor
Transfusion consists of
RBCs
Platelets
Volume (saline)
MI treatment (atherosclerosis)
PCI
Stent
Anticoag
How to avoid DVT in post surgery
gENERAL PROPHYLAXIS - ted STOCKINGS, HEPARINS
lONG TERM - IVC cage and anti coag
Coroner
Interested in non-natural deaths
Several chest infections may indicate
Lung cancer (asbestos, car fumes, soot, smoking)
Tissue for diag (lung)
Sputum
bronchoscopy
Pleural biopsy
Histology and cytology of lung cancer
Small cell cancer is worse than large cell
TNM staging is applied to all tumours
T - Tumour size (larger the grade, larger tumour size)
N - Lymph nodes (Larger grade, further LN spread)
M - Mets (Distant is worse)
Resolution vs repair
Resolution - Initiating factor removed, tissue undamaged or able to regenerate
Repair - Initiating factor still present. tissue damaged and unable to regenerate
Cells that can regenerate
Hepatocytes Pneumocytes All blood cells Gut epithelium Skin epithelium Osteocytes
Skin wounds - Healing by 1st intention
1) Incision
2) Exudation of fibrinogen
3) Weak fibrin join
4) Epidermal regrowth and collagen synthesis
5) Strong collagen join
Skin wounds - Healing by 2nd intention
1) Tissue loss
2) Granulation tissue
3) Organisation
4) Eary fibrous scar
5) Scar contraction
Repair
Replacement of damaged tissue by fibrous tissue
Collagen is produced by
Fibroblasts
Cells that can’t regenerate
Myocardial cells
Neurones
Upper abdo pain
Refer for OGD (Oesophagogastroduodenoscopy)
Suspect gastritis
Check for any inflammation via biopsy
Infection by helicobacter indicated by raised urease levels
Gastrin overproduction - excess acid from body gland gastric cells
Gastritis increases risk of gastric/duodenal ulceration
Treat with antibiotics
Types of inflammatory cells
Macrophage Plasma cell Neutrophil Lymphocyte Giant cell
The inflammatory process also stimulates
Kinin system
Fibrinolytic system
Coagulation system
Complement cascade
Scarring
Healing response which seals up the tissues
But contractures/adhesions alter anatomy and can get worse with time
Lymphoma
Malignant neoplasm of lymphoid cells
Chemo treatment
Damages fast dividing neoplastic cells but also hits - Hair, marrow and GI tract
Thrombosis
1) Normal laminar flow
2) Endothelial cell injury
3) Platelet aggregation
4) Thrombus formation
5) Fibrin deposition
Thrombosis
Solid mass of blood constituents formed within intact vascular system during life
Thrombosis triad
Change in vessel wall - endo cell injury due to smoking which changes wall and also blood flow
Change in blood flow
Change in blood constituents
Aspirin
Inhibits platelet aggregation
Embolus
Solid mass in blood being carried through circulation to a place where it gets stuck and blocks the vessel
This solid mass tends to be a thrombus such as a DVT of the leg veins which breaks off and embolises through the large veins and right side of the heart to the lungs
Ischaemia
Reduction in blood flow
Infarction
Reduction in blood flow with subsequent death of cells
Why blood clots don’t form all the time
Laminar flow - Cells travel in the centre of arterial vessels and don’t touch the sides
Endothelial cells which line vessels are not sticky when healthy
Most common type of thrombosis
DVT - Deep Vein Thrombosis (hosital inpatients)
Prevention of DVT for inpatients
Mobilisation
Low dose SC heparin
Venous stockings
Less common causes of embolus
Air - pressurised systems of IV fluids/bloods
Cholesterol crystals from atheromatous plaques
Tumour
Amniotic fluid in pregnant women
Embolism venous route
Embolus which enetrs the venous system will travel to the vena cava, through the right side of the heart and will lodge into the pulmonary arteries
From here it cannot get into the arterial circulation of the heart because the blood vessels in the lung split down to capillary size, so the lung acts as a filter for any venous emboli
Ischaemia
Simply a reduction in blood flow to a tissue without any other implications
Infarction
Reduction in blood flow to a tissue that is so reduced that it cannot even support mere maintenance of the cells in that tissue so they die
Infarction is usually macroscopic caaused by thrombosis of an artery - such as thrombus in the LAD coronary artery causing infarction of the anterior wall of the left ventricle
Organs with dual arterial supply
Less suspectible to infarction
Liver - Portal venous and hepatic artery
Lung - Pulmonary venous and bronchial artery
Brain - COW
Coronary artery infarctions
Right CA - Inferior infarct, can also include posterior septum
LAD - Anterior infarct (sudden death)
Circumflex artery - Lateral infarct
Regional transmural myocardial infarction
Infarction that is transmural through all cardium layers (endocardium to epicardium layers)
Subendocardial myocardial infarction
Infarct of the myocardium that is subendocardial
Initial reaction of tissue to injury
Vascular - Dilation of vessels
Exudative - Vascular leakage of protein-rich fluid
Neutrophil polymorphs are charcteristic of cells recruited to the tissue
Materials that resist digestion
Keratin
Necrotic bone
Cholesterol crystals
Sodium urate
Stroke
Cerebral infarction
Heart attack
Myocardial infarction
Infarction and ischaemia
Infarction is always due to ischaemia but ischaemia does not always cause infarction
Angina
Ischaemia may cause chest pain but no infarction
Atheroma
AKA Atherosclerosis
Pathology of arteries involving deposition of lipids in the arterial wall with surrounding fibrosis and chronic inflammation
These plaques can enlarge to occlude the lumen of vessels
Predominant cause of MI and CI
Atheroma - Risk factors
Raised serum lipids (LDL/triglycerides cause direct damage to endothelial cells) Hypertension (Shearing force on endothelial cells which are delicate in nature) Diabetes mellitus (Superoxide anions Smoking (CO, nicotine)
Atheroma formation - 2 Processes
Endothelial damage (due to lipids, raised BP, smoking) Chronic inflammation (Macrophages and fibroblasts)
Prevention/slowing progression of atheromas
Reducing lipids
Reducing BP
Smoking cessation
Low dose aspirin will reduce amount of platelet aggregation at site of endothelial damage
Atherosclerosis
Common in high pressure systems such as aorta rather than low pressure systems such as pulmonary arteries
Plaque composition
Fibrous tissue
Lipids - cholesterol
Lymphocytes
Atherosclerosis - Complications
MI
Cerebral infarct (CI) due to carotid atheroma embolising and causing TIA or CI
Aortic aneurysms - Rupture causes sudden death
Gangrene
Apoptosis
Programmed cell death of a single cell
Necrosis
Unprogrammed death of a large number of cells due to an adverse event such as infarction, burns, frostbite, etc
Apoptosis
Important in normal body function
In the gut, there is a steady turnover of cells with stem cells dividing to produce new cells which mature and differentiate and eventually die by apoptosis
Apoptosis
Implemented by Caspases and Bcl2 protein
Alternatives to apoptosis for cells
Autophagy
Closing down protein synthesis
Cell cycle arrest
Apoptosis
If a cell has a lot of DNA damage then apoptosis will be preferred over the other options
Apoptosis process
1) Bcl2 protein and activated Fas receptor signal Caspases
2) Caspases cause apoptosis
Necrosis example
Toxic spider venom Frostbite Cerebral infarction Avascular necrosis of bone Pancreatitis
Necrosis types
Coagulative
Liquifactive
Caseous
Sickle cell anaemia - Genetic cause
1) Point mutation in the beta-globin chain of haemaglobin
2) Causes the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the 6th position
3) This is a very specific genetic abnormaility
4) This always produces an abnormal haemaglobin which causes RBCs to sickle (deform) when oxygen sats are low
Sickle cell anaemia
Single gene disorder - abnormality of a single gene causes disease
Polygenic diseases
Genetic diseases resulted from the interaction of several different genes usually on different chromosomes
Breast cancer
Polygenic disorder
BRCA1 and BRCA2 along with many other genes
Congenital disease
Born with it (genetic)
Rhesus haemolytic disease
In newborns where maternal antibodies attack RBCs of baby in utero
Fetal alcohol syndrome
Baby with facial characteristics - Small eye openings, smooth philtrum, thin upper lip
Pituitary adenoma
Growth hormone excess
Hypertrophy
Increased tissue size due to increased cell size
Hyperplasia
Increased tissue size due to increased number of cells
Hypertrophy examples
Physiological - Skeletal muscle cells
Pathological - Myocardium undergoes hypertrophy in patients with raised BP
Hyperplasia examples
Physiological - During pregnancy and lactation, the breast epithelial cells respond to increased physiological demands by undergoing hyperplasia
Pathological - Prostate undergoes hyperplasia with age in response to a relative excess of oestrogen stimulation
Atrophy
Decrease in size of an organ or tissue
Atrophy examples
Physiological - Thymus in early adult life. Genitals, mandible, cerebrum and lymphoid tissue atrophy in later life
Pathological - Occurs as a result of a loss of blood supply, loss of innervation, pressure, lack of nutrition, lack of hormonal stimulation, or as a result of hormonal stimulation
Metaplasia
Reversible transformation of a mature differentiated cell type into another fully differentiated cell type
It is an adaptive response to injurous stimuli
Metaplasia examples
Transformation of the normal pseudostratified columnar ciliated epithelium ciliated epithelium of the bronchi into squamous epithelium following repeating smoking
Dysplasia
Premalignant condition characterised by increased growth, cellular atypia and decreased differentiation
Caused by long exposure to chronic inflammation and carcinogenic substances
Dysplasia examples
HPV infection in squamous epithelium of uterine cervix
Ageing manifestations
Cancer development Neurodegeneration - Alzheimer's dementia and Parkinson's disease Osteoarthritis Hearling loss Vision loss Reduced immunity
Ageing manifestations - Cellular causes
Damage to mitohondrial DNA
Accumulation of toxic by-products of metabolism
Free-radical generation
Time-dependent activation of ageing and death genes
Oestrogen and bone relationship
Lack of oestrogen = decreased bone formation and increased bone resorption
Neurodegeneration during ageing - mechanisms
Cortical atrophy
Shrinkage of hippocampus
Enlarged ventricles
Muscle degeneration
Decreased growth hormone
Decreased testosterone
Increased catabolic cytokines
Deaffness - mechanism
Loss of hair cells in cochlear which are unable to regenerate
