general pathology Flashcards
hospital autopsies
<10% of autopsies in the UK
Requires Medical Certificate cause of Death (MCCD)
Audit, teaching, governance, research
medico-legal autopsies
> 90% of autopsies in the UK
Coronial
forensic
presumed natural death
Cause of death not known
not seen by doctor within days of death
presumed iatrogenic deaths
peri/post operative deaths
anaesthetic deaths
abortion
complications of therapy
presumed unnatural deaths
accidents
custody deaths
war/industrial pensions
doctor referral for autopsy
No statutory duty to refer
common law duty
GMC guidance
registrar of BDM referral for autopsy
statutory duty to refer
other referrals for autopsy
Relatives
the police
anatomical pathology technicians
histopathologists
Hospital autopsies
coronial autopsies (Natural deaths, drowning, suicide, accidents, road traffic deaths, fire deaths, industrial deaths, peri/post operative deaths)
forensic pathologists
Coronial autopsies (homicide, death in custody, neglect and any done by histopathologists due to the action of a third party)
inflammation
local and physiological response to tissue injury
not a disease but a manifestation of disease
outcomes and harmful effects of inflammation
Benefits=
resolution
suppuration
organisation
Diseases= Digestion of normal tissue Swelling Compressing brain tissue Fibrosis from chronic inflammation Autoimmunity Over reaction to stimulus
acute inflammation
initial and often transient series of tissue reactions to injury
sudden onset
short duration
usually resolves
cell type= neutrophil polymorphs
chronic inflammation
Subsequent of often prolonged tissue reactions following the initial response
slow onset or sequel to acute
long duration
may never resolve
cell type= macrophages
cells involved in inflammation
neutrophil polymorphs macrophages lymphocytes endothelial cells fibroblasts
neutrophil polymorphs (inflammation)
short lived
first on the scene of acute
cytoplasmic granules full of enzymes that kill bacteria
usually die at the scene of inflammation
release chemicals that attract other inflammatory cells such as macrophages
macrophages (inflammation)
long lived cells- weeks to months
phagocytic properties
ingest bacteria and debris
carry debris away
present antigens to lymphocytes
lymphocytes (inflammation)
long lived cells- years
produce chemicals that attract other inflammatory cells
immunological memory
endothelial cells (inflammation)
line capillaries
become sticky in areas of inflammation so inflammatory cells adhere to them
become porous to allow inflammatory cells to pass into tissues
fibroblasts (inflammation)
long lived cells
form collagen in areas of chronic inflammation
causes of acute inflammation
microbial infections (bacterial, viruses)
hypersensitivity (parasites, allergic reactions)
physical agents (trauma, ionising radiation, heat)
chemicals (corrosives, acids, alkalis)
bacterial toxins
tissue necrosis
microbial infections (inflammation)
most common cause of acute inflammation
viruses lead to death of cells by intracellular multiplication
bacteria release exotoxins
parasitic infections and TB inflammation are examples of where hypersensitivity is important
hypersensitivity inflammation
altered state of immunological responsiveness causes inappropriate or excessive immune reaction
damages tissues
has cellular or chemical mediators
physical agents in inflammation
tissue damage leading to inflammation may occur through physical trauma, UV or other ionising radiation, burns or frostbite
chemicals in inflammation
corrosive chemicals provoke inflammation through gross tissue damage
infecting agents may release specific chemical irritants that lead directly to inflammation
tissue necrosis (inflammation)
death of tissues to due lack of oxygen or nutrients
usually from inadequate blood flow
acute inflammatory response due to peptides released from dead tissue
macroscopic appearance of inflammation
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Tumor, Calor, Rubor, Dolor, Loss of function
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Swelling, Heat, Red, Pain, Loss of function
Rubor
Redness
acutely inflamed tissue appears red
caused by dilation of small blood vessels in damaged area
Calor
Heat
only in peripheral parts of the body- skin
caused by increased blood flow- hyperaemia
vascular dilation to deliver blood to area
systemic fever from chemical mediators, contributes
tumor
Swelling
oedema- accumulation of fluid in extravascular space as part of fluid exudate
physical mass of inflammatory cells migrating into the area
formation of connective tissue
dolor
Pain
partly stretching of tissues due to oedema and pus under pressure in abscess cavity
chemical mediators- bradykinin and prostaglandins and serotonin- induce pain
loss of function
movement of inflamed area is consciously and reflexly inhibited by pain
severe swelling may immobilise tissues
Acute inflammation response has 3 processes
changes in vessel diameter and flow
increased vascular permeability and formation of the fluid exudate
formation of the cellular exudate- emigration of neutrophil polymorphs into extravascular space
stages in neutrophil polymorph emigration (inflammation)
margination of neutrophils
pavementing of neutrophils
pass between endothelial cells
pass through basal lamina and migrate into adventitia
endogenous chemical mediators cause:
inflammation
vasodilation
emigration of neutrophils
chemotaxis
increased vascular permeability
itching and pain
chemical mediators released from cells
inflammation
histamine
lysosomal compounds
chemokines
plasma factors
inflammation
enzymatic cascade systems, which are unrelated and produce various inflammatory mediators
systemic effects of inflammation
pyrexia
constitutional symptoms
weight loss
amyloidosis
causes of chronic inflammation
transplant rejection
progression from acute
primary chronic
recurrent episodes of acute
macroscopic appearance of chronic inflammation
chronic ulcer
chronic abscess cavity
thickening of the wall of a hollow viscus
granulomatous inflammation
fibrosis
microscopic features of chronic inflammation
The cellular infiltrate consists characteristically of lymphocytes plasma cells and
macrophages
A few eosinophil polymorphs may be present, but neutrophil polymorphs are scarce
Some of the macrophages may form multinucleate giant cells
There may be evidence of continuing destruction of tissue at the same time as tissue
regeneration and repair
Tissue necrosis may be a prominent feature, especially in granulomatous conditions such as tuberculosis
granulomas
aggregate of epitheliod histiocytes (activated macrophages)
may contain other cells such as lymphocytes and histiocytic giant cells
granulomatous inflammation is a specific type- such as tuberculosis and leprosy
epitheliod histiocytes
resemble epithelial cells
activated macrophages
arranged in clusters
little phagocytic activity but adapted to secretory function
appearance of granulomas
may be augmented by presence of caseous necrosis or by conversion of some of the histiocytes into multinucleate giant cells
histiocytic giant cells
form where particulate matter, that is indigestible by macrophages, accumulates
form when foreign particles are too large to be ingested by just one macrophage
multinucleate giant cells w/ 100+ nuclei
little phagocytic activity
types of histiocytic multinucleate cells
langhans giant cells- horse shoe arrangement of peripheral nuclei at one pole
foreign body giant cells- large with nuclei randomly scattered throughout
touton giant cells- central ring of nuclei, peripheral to which there is lipid material
treating inflammation
aspirin
ibuprofen- inhibit prostaglandin synthase
steroids- bind to DNA up regulate inhibitors of inflammation and down regulate chemical mediators of inflammation
regeneration/resolution
initiating factor is removed
tissue is undamaged or able to regenerate
examples of regeneration
liver after surgery to remove a lobe
lobar pneumonia- pneumocytes can regenerate
skin abrasions
skin wounds- healing by first intention
repair
initiating factor is still present
tissue is damaged and unable to regenerate
replacement of damaged tissue by fibrous tissue
collagen produced by fibroblasts
brain fibrosis= gliosis
examples of repair
heart after myocardial infarction
brain after cerebral infarction
liver cirrhosis
skin wounds- healing by second intention
cells that regenerate
hepatocytes pneumocytes blood cells gut epithelium skin epithelium osteocytes
cells that dont regenerate
myocardial cells
neurones
regeneration example
healing by first intention-
sutured edge to edge two edges fill gap with blood and fibrin epidermis regrows fibroblasts form collagen scar forms, stronger than normal skin
repair example
healing by seconds intention
large amount of tissue loss- normally trauma
can’t be sutured together
gap present so no epithelial cells to regenerate
gap filled by capillaries and collaged until two edges can grow
large scar formed
Ways our healthy body prevents thrombosis occurring spontaneously
Laminar flow- cells travel in the centre of arterial vessels and don’t touch the side
endothelial are not sticky when they are healthy
thrombosis definition
the formation of a solid mass from blood constituents in an intact vessel of a living person
formation of a thrombus
platelet aggregation
platelets release chemicals when they aggregate causing them to start the cascade of clotting proteins in the blood
both of these reactions involve positive feedback loops; therefore difficult to stop
once clotting cascade has started there is a formation of insoluble fibrin
causes of thrombosis
change in vessel wall
change in blood flow
change in blood constituents
usually a combination of two or three
drugs preventing thrombosis
aspirin
heparin
warfarin
embolus definition
mass of material in the vascular system able to become lodged within a vessel and block it
formed when a solid mass in the blood is carried through the circulatory system to a place where it gets stuck and blocks it
cause of embolism
thrombus
air
other- cholesterol crystals, tumours, amniotic fluid, fat
embolism location
in venous system then- vena cava -> right side of heart -> lodge in pulmonary arteries (location depends on size) -> can lodge as lungs split into capillaries (lungs act as a filter for venous emboli
in arterial system it can travel anywhere downstream
ischaemia
reduction in blood blow to a tissue without any other implications
inadequate blood supply
infarction
reduction in blood flow to a tissue with subsequent local cell death
macroscopic event usually caused by thrombus blockage
atheroma
aka atherosclerosis
pathology of arteries when there is deposition of lipids in the arterial wall with surrounding fibrosis and chronic inflammation
the plaques can enlarge to occlude the lumen of vessels
endothelium overlying a plaque may rupture and initiate thrombosis within the vessel
plaques are predominant cause of myocardial or cerebral infarction
plaques contain:
fibrous tissue
lipids- cholesterol
lymphocytes
atherosclerosis distribution in arteries
never low pressure systems- pulmonary arteries
high pressure systems=common e.g. aorta
epidemiology of atherosclerosis
increases with age
more common in lower socioeconomic populations due to risk factors
risk factors of atherosclerosis
raised serum lipids- hyper lipidaemia
hypertension
diabetes mellitus
cigarette smoking
endothelial damage theory
Any factor that causes endothelial damage in arteries will lead eventually, by repeated small
amounts of damage, to the formation of atherosclerotic plaques
The major process after endothelial damage is chronic inflammation with macrophages and
fibroblasts
The lipids within plaques probably derive from the breakdown of inflammatory cells in the
plaque
Understanding pathogenesis of atheroma enables prevention or to stop progression
atherosclerosis formation
endothelial cells dysfunction- cholesterol damages wall
high levels of LDL begins to accumulate in arterial wall
macrophages attracted to site of damage and take up lipid to form foam cells- inflammatory response
formation of a fatty streak= earliest stage of a plaque
activated macrophages release their own products- cytokines and growth factors
smooth muscle proliferation around lipid core and formation of a fibrous cap of collagen
complications of atherosclerosis
cerebral infarction
carotid atheroma- emboli causing transient ischemic attacks
myocardial infarction
aortic aneurysms
peripheral vascular disease
gangrene
prevention of atherosclerosis
reduce lipids- reduces epithelial damage
reduce BP- reduces epithelial damage
stop smoking- reduces epithelia damage
low dose aspirin reduces platelet aggregation at site of damage
apoptosis definition
programmed cell death of a single cell
necrosis definition
unprogrammed death of a large number of cells due to an adverse event
apoptosis uses
turnover of cells- stem cells divide to produce new cells which mature and differentiate and eventually die by the process of apoptosis
embryogenesis- apoptosis removes cells no longer needed as organs develop
DNA damage- cells can detect DNA damage (p53 protein)
initiation and control of apoptosis
apoptosis is implemented by caspases and Bcl2 protein
decision as to whether a cell should activate this process or not is less well understood
alternatives to apoptosis can be used
cells with a lot of DNA damage prefer apoptosis
abnormal apoptosis can occur in a variety of situations including drugs, graft versus host disease and neurodegeneration
p53 is involved in detection of DNA damage
breakdown in control of apoptosis can cause Cancer (lack of) or HIV (too much)
necrosis
catastrophic event that physically causes death of a large number of cells and resolved or is repaired by basic inflammatory processes
examples of necrosis
infarction burn frostbite toxic spider venom avascular necrosis of bone pancreatitis
types of necrosis
coagulative necrosis- sticks together
liquefactive necrosis- liquid
caseous necrosis- resembles soft cheese e.g. TB
genetic disease
one that occurs primarily from a genetic abnormality
some diseases that are pure genetic diseases
inherited diseases
caused by inherited genetic abnormality
may not manifest until later in life
types of inherited disease
chromosome abnormalities e.g. Down syndrome
Mendelian inheritance e.g. single gene disorders
single gene disorder
abnormality of a single gene causes the disease
dominant or recessive
dominant definition
will be present where there is only one copy of the abnormal gene
e.g. Huntington’s
Recessive definition
only expressed if both copies of the gene are abnormal
e.g. cystic fibrosis
co-dominant definition
both alleles are expressed
e.g. AB blood group
autosomal definition
occurring on the non-sex chromosomes
sex-linked definition
occurs on the sex chromosomes
regions which dont have a corresponding region on the opposing chromosome
mostly x-linked as men only have one Y and women have none
more common in males as they only have one X
polygenic inheritance
interaction of several genes usually on different chromosomes
e.g. breast cancer
many diseases have strong genetic component still need the appropriate environment to be expressed as disease
congenital diseases
present at birth
mostly genetic but can be acquired- rhesus haemolytic disease or foetal alcohol syndrome
acquired diseases
disease or condition developed after birth
caused by non-genetic environmental factors but may have strong genetic background
disorders of development
neural tube defect
cleft palate
spina bifida
ventricular septal defect
disorders of growth
GH deficiency
GH excess
mutation in the COL2A1- type II collagen
mutation in fibroblast growth factor receptor 3 gene
hypertrophy
increase in size of tissue caused by an INCREASE IN SIZE of cells without an increase in number
physiological uses of hypertrophy
skeletal muscle cells exposed to an increased workload cannot divide and respond by hypertrophing
pathological hypertrophy
myocardium undergoes hypertrophy with high BP
hyperplasia
increased growth caused by an INCREASE IN NUMBER of cells
can be accompanies by increase of cell size
physiological use of hyperplasia
during pregnancy and lactation, breast epithelial cells respond to increase in demands by increasing in number
pathological hyperplasia
prostate undergoes hyperplasia with age in response to excess of oestrogen stimulation
atrophy
decrease in size of tissue caused by DECREASE IN NUMBER of constituent cells or by DECREASE IN THEIR SIZE
physiological use of atrophy
various embryological structures undergo atrophy during foetal life
thymus atrophies in early adult life
pathological atrophy
occurs as a result of loss of blood supply, loss of innervation, loss of pressure, lack of nutrition, lack of or result of hormonal stimulation
metaplasia
reversible transformation of one mature cell type into another fully differentiated cell type
adaptive response to injurious stimuli
e.g. transformation of normal pseudostratified columnar epithelium of bronchi intro squamous epithelium following repeated exposure to cigarette smoke
dysplasia
premalignant condition characterised by increased growth, cellular atypia and decreased differentiation
imprecise term for morphological changes seen in cells in progression into cancer
ageing
progressive loss of various functions and accumulation of diseases
mechanisms of ageing
many organs do not have cells that regenerate so if they die there will be a loss of function in that organ
acquired cancers may occur because of accumulated DNA damage over a lifetime of cell divisions
manifestations of ageing
development of acquired cancers
neurodegeneration- dementia, parkinsons
dermal elastosis
osteoporosis
osteoarthritis
vision loss
deafness- loss of hair cells
reduced immunity
cancer
generic term for malignant tumour
metastasis
the development of secondary malignant growths at a distance from a primary site of cancer
metastatic tumours
arise from cells that naturally move around the body- lymphocytes
tumours from these cells will never stay in one site so the treatment for these must always be for the whole body
non- metastatic tumour
only spread locally and do not metastasise to other regions
tumours can be treated by local excision
mixture of non-metastatic and metastatic
most common tumours e.g. breast cancer
tumour staging is important
if it hasnt spread it can be excised
but if it has spread then it requires excision and systemic treatment
useful cancer treating facts
basal cell carcinoma of the skin invades locally- so can be locally excised
carcinomas spread to lymph nodes that drain the primary site and so can spread through the blood to bone
most common carcinomas to do so are breast, prostate, lung, thyroid and kidney
carcinogenesis
the transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations
applies only to malignant tumours
carcinogens
agents known or suspected to cause cancer
oncogens
cause tumours
environmental agents and cancer
account for 85% of cancer risk factors
chemical viruses radiation biological agents (hormones, parasites, mycotoxins) miscellaneous
host factors and cancer
race diet age gender premalignant lesions transplacental exposure
chemicals and cancer
no common structural features
some act directly
most require metabolic conversion from pro-carcinogens to ultimate carcinogens
radiant energy and cancer
ionising radiation
long term effect
skin cancer and sunlight
lung cancer in uranium miners
biological agents and cancer
hormones- oestrogen increases risk of mammary cancer
mycotoxins- aflatoxin B2= hepatocellular carcinoma
parasites- shistosoma= bladder cancer
miscellaneous carcinogens
asbestos
conventional chemotherapy mechanism of action
vinblastine= antimicrotubule agent- prevents anaphase
etoposide= prevents topoisomerase II- prevents DNA replication
cisplatin and ifosamide= bind directly to DNA- inhibits DNA synthesis by cross linking
Conventional chemotherapy issues
not selective for tumour cells
usually affects normal cells that also divide fast- myelosuppression, hair loss, diarrhoea
not good treatment for slow dividing tumours
conventional chemotherapy tumours
fast dividing tumours
germ cell tumours of testis
acute leukaemias
lymphomas
embryonal paediatric tumours
targeted chemotherapy
more effective with fewer side effects
recognises differences between normal cells and cancer cells
detecting differences between normal and cancer cells
gene arrays- different expression of genes (overexpression of growth factor receptor due to mutation in this gene)
proteomics- different proteins
tissue microarrays
Cetuximab (Erbitux)
monoclonal antibody against epidermal growth factor receptor
chimeric IgG humanised monoclonal antibody,
binds competitively to extracellular domain of EGFR,
antitumour activity in xenograft models,
blocks production of VEGF, interleukin 8 and bFGF
programmed cell death protein I
immune checkpoint
inhibits t cell response
prevents auto-immunity in normal physiology
treating breast cancer using oestrogen receptors
epithelial cells respond to oestrogen as a growth factor, giving a drug that blocks oestrogen receptors on the cancer cells should inhibit their growth
only effective if the breast cancer has oestrogen receptors on the surface of its cells
treating breast cancer using HER2 protein
some tumours overexpress a growth factor on the cell surface (HER2 protein) (coded for by (HER2 gene)
20% of breast cancer have amplified number of copies of this gene
use herceptin and lapatinib
neoplasm
a lesion resulting from the autonomous or relatively autonomous abnormal growth of cells which persists after the initiating stimulus has been removed
Neoplasia is: o Autonomous o Abnormal o Persistent o New growth
neoplasm and tumour difference
tumour is any abnormal swelling, including:
neoplasm,
inflammation,
hypertrophy,
hyperplasia
neoplastic cells
derive from nucleated cells
usually monoclonal
growth pattern related to parent cell
synthetic activity related to parent cell (collagen, keratin, hormones etc. )
tumour angiogenesis
benign neoplasms are slow growing therefore dont outgrow blood supply
malignant neoplasms are fast growing so outgrow blood supply- forms central necrosis
classification of neoplasms
classification occurs to determine treatment and prognosis
methods of classification= behavioural (benign/malignant)
histogenetic (cell of origin)
behavioural classification
classified as benign, borderline, malignant
Borderline tumours defy precise classification
benign neoplasms
- localised, non-invasive
- slow growth rate
- low mitotic activity
- close resemblance to normal tissue
- circumscribed or encapsulate
- nuclear morphometry often normal
- necrosis and ulceration are rare
morbidity and mortality of benign neoplasm
pressure on adjacent structures obstruct flow produce hormone transform into malignant anxiety
malignant neoplasm
- invasive
- metastasise
- rapid growth
- variable resemblance to normal tissue
- poorly defined or irregular border
- hyperchromatic and pleomorphic nuclei
- increased mitotic activity
- necrosis and ulceration= common
- encroach upon and dectroy surrounding tissue
- have ‘crab like’ cut surface (cancer= latin for crab)
morbidity and mortality of malignant neoplasms
destruction of adjacent tissue metastases blood loss from ulcers obstruction of flow hormone production anxiety and pain
histogenetic classification
histogenesis= specific cell of origin of tumour
nomenclature of neoplasia
have suffix -oma
prefix defends on behavioural and histogenesis
benign epithelial neoplasms
papillomas:
- benign tumour of non-glandular, non secretory epithelium
- prefix with cell type of origin, e.g. squamous cell papilloma
adenomas:
- benign tumour of glandular or secretory epithelium
- prefix with cell type of origin e.g. colonic adenoma
malignant epithelial neoplasms
carcinomas:
- malignant tumour of epithelial cells
- prefixed with cell type e.g. transitional cell carcinoma
adenocarcinomas:
- carcinomas of glandular epithelium
e. g. adenocarinoma of colon
benign connective tissue neoplasms
prefix of cell of origin
- lipoma=adipocytes
- chondroma=cartilage
- osteoma=bone
- angioma=vascular
- rhabdomyoma=striated muscle
- leimyoma=smooth muscle
malignant connective tissue neoplasms
- liposarcoma=adipose tissue
- chondrosarcoma=cartilage
- osteosarcoma=bone
- angiosarcoma=blood vessels
- rhabdomyosarcoma=striated muscle
- leiomyosarcoma=smooth muscle
further malignant classification
anaplastic= cell type of origin is unknown
carcinomas and sarcomas are further classified according to degree of differentiation (low grade is more differentiated)
exceptions to neoplasm classification
- not all omas are neoplasms (granuloma= inflammation)
- not all malignant tumours are carcinoma or sarcoma (melanoma= malignant melanocytes, lymphoma=malignant lymphoid cells)
- some tumours are named after people (burkitt’s lymphoma, kaposi’s sarcoma, grawitz tumour)
in situ neoplasia
applies only to epithelia neoplasms
the lesion has the cytological features of a malignant neoplasms
may progress to invasive disease
screening may allow detection and treatment of the disease before the development of carcinoma
invasion of neoplasia
defining feature of a malignant neoplasm
enables neoplastic cells to spread directly through tissues and gain access to blood vessels and lymphatic channels
dependent upon- decreased cellular adhesion, abnormal cellular motility, production of enzymes with a lytic effect on the surrounding tissues
metastasis
process by which a malignant tumour spreads from its primary site to produce secondary tumours at distant sites
may occur via blood vessels (haematogenous), lymphatics, across body cavities (transcoelomic), along nerves or as a result of direct implantation during surgery (iatrogenic)
metastasis cascade
detachment
invasion
intravasation
evasion of host defences
arrest
extravasation
vascularisation
mechanism for neoplasia invasion of basement membrane
invasion of a basement membrane then invasion of extracellular matrix
proteases- matrix metalloproteinases (collagenase, cathepsin D, urokinase-type plasminogen activator)
cell motility
tumour cell motility
tumour cell derived motility factors
breakdown products of extracellular matrix
intravasation of neoplasm
collagenases
cell motility
neoplasm evasion of host immune defence
aggregation with platelets
shedding of surface antigens
adhesion to other tumour cells
extravasation of neoplasm
adhesion receptors
collagenases
cell motility
growth at metastatic site
growth factors
tend to be autocrine, positive feedback
angiogenesis of new metastases
angiogenesis promoters- vascular endothelial growth factors, basic fibroblast growth factor
angiogenesis inhibitors- angiostatin, endostatin, vasculostatin
Routes of metastasis (lungs)
tumours invade veins and lymphatics as arteries have thick walls, so tumours travel to lungs via right side of heart
sarcomas and any common (non-colonic) cancers tend to metastasise in the lung
Routes of metastasis (Liver)
tumours from colon travel via portal vein to liver where the capillaries act as a filter
colon, stomach, pancreas, carcinoid tumours of the intestine
Routes of metastasis (Bone)
Prostate breast thyroid lung kidney
