Pathology Flashcards
Define Aetiology and Pathogenesis ?
Aetiology = the cause of disease
Pathogenesis = mechanism of how a disease develops
What are the seven different causes of cell injury ?
Causes of cellular injury
- Hypoxia = reduced oxygen supply / heart respiratory failure, anaemia
- Physiological agents = trauma, extreme cold, extreme heat and UV radiation
- Chemicals, drugs, toxins = poisons arsenic, 1080
- Infectious agents = viruses, bacteria, fungi
- Immunological dysfunction = autoimmune disease, hypersensitivity (allergy)
- Nutritional deficiencies/ imbalances = hypervitaminosis A, scurvey
- Genetic disorders = haemophilia, von willebrand disease
Although the causes of cell injury are numerous the general mechanisms of injury are few identify these five mechanisms ?
The five mechanisms of cell injury
- ATP depletion
- altered protein synthesis
- nucleus damage
- membrane damage
- cytoskeleton damage
Describe the mechanism of cellular injury ATP depletion ?
ATP depletion
- mitochondria require oxygen to generate cellular energy
- hypoxia is one of the most common and important causes of cellular injury - results in acute swelling
The mechanism
- decrease oxidative phosphorylation and results in a decrease in ATP
- decrease in ATP triggers a switch to anaerobic glycolysis
- increase anearobic glycolysis
- resulte in a decrease in glycogen stores and PH
- decrease enzymatic activity
- chromatin clumping
- decrease in ATP causes a failure of K+/P+ pump influx of Na+, Ca2+ ions and cell and organelle swelling.
- detachment of ribosomes from RER - reduced protein syntheiss and lipid deposition can occur
Excessive ATP depletion
- severe disruption of cell membranes fragmentation
- influx Ca2+
- lysosome rupture and enzyme release
- severe changes to the nucleus (pyknosis, karyorrhexis, karyolysis).
This eventually leads to cell death 2-24 hrs post injury - may still be reversible within the first 60 mins.
Describe the mechanism of Membrane damage in cellular injury ?
Membrane damage
- the selective permeability barrier
- cellular function due to loss of the structural base for enzymes/receptors
- both the plasma membranes and organelle membranes can be damaged
- cell injury membrane damage is similar to changes already described for ATP depletion
results in swelling if sevre proceeds to death
Describe free radicals and the three mechanisms by which they cause cellular damage ?
Free radicals
Common cause of membrane damage, highly reactive oxygen species cause lipid peroxidation
Free radicals have unpaired electrons and are oxidising agents
Mechanism
- lipid peroxidation = of cell membranes (poluunsaturated fats) creates a chain reaction of free radical generation causing extensive membrane damage
- DNA damage single strand breaks
- Protein damage oxidation of amino acids
Oxidative stress = imbalance between free radical production and free radical scavenging.
What are the three main causes of membrane damage ?
Three main causes of membrane damage
Free radicals
- common
- highly reactive oxygen species cause lipid peroxidation
- unpaired electrons highly unstable may injure cells
Direct damage
- chemicals, bacterial toxins, viruses and immunological injury
Hypoxia
- ATP depletion (impaired energy supply)
- causes altered membrane permeability (Na+/K+ pump)
What are free radicals and describe three ways in which they cause cell damage ?
Free radicals
what
- highly reactive oxygen species with unpaired electrons
- O2-, H2O2, HO
- continuously produced by biological systems
- scavenging mechanisms - antioxidants
- oxidative stress is caused by an imbalance between free radicals and antioxidants
Damage to cells
- lipid peroxidation = oxidation of polyunsaturated fatty acids creating a chain reaction of free radical generation causing extensive cell membrane damage
- DNA damage = cause single strand breaks
- Protein damage = oxidation of amino acids
Identify the two types of reversible cell injury ?
There are two types of reversible cell injury
- Hydropic degeneration
- Fatty acid change
Describe hydropic degeneration ?
Hydropic degeneration
- reversable cell injury
- acute cell swelling due to fluid influx
- injured cells are incapable of maintaining ion and fluid homeostasis
- vacuolar degeneration
- Hist cells at the interface of the normal and necrotic areas become pale, swollen and finely vacuolated
Describe fatty acid change ?
Fatty acid change
- reversable cell injury
- cell swelling due to lipid accumulation
- occurs with hypoxic or toxic cell injury
- frequently a more chronic change than hydropic degeneration
Seen most commonly in the liver - organ central to lipid metabolism (hepatic steatosis)
What is the role of calcium in irreversible cell injury ?
Calcium and irreversible cell injury
Calcium activates varous enzymes, proteases, ATPases and phospholipases resulting in
- membrane damage
- damage to cytoskelton
- degradation of chromatin
- degradation of proteins
- decrease in ATP
At what point dose cell injury become irreversible ?
Irreversible cell injury is associated with a dritical change
- severe damage to mitochondria no ATP production
- severe damage to cell membranes
- leakage of cellular contents
- swelling and rapture of lysosomes
- large amorphous bodies in mitochondria
- influx of calcium into the cell
- profound nuclear changes
- all eventually leading to cell death
Identify a number of agents which may accumulate inside of cells ?
Identify the four mechanisms by which agents may accumlate within cells ?
Describe the four mechanisms in which lipids may accumulate ?
Accumulation of lipid within cells
Accumulation of triglycerides, cholesterol, choleserol esters and phospholipids in cells.
- Varaible causes
- decreased oxidation or use of FFA
- impaired synthesis of apoprotein (not apoprotein is required to to transport lipid)
- impaired ability to combine lipids and protein to form lipoprotein (rare)
- impaired release (secretion of lipoproteins from the hepatocyte (uncommon)
- common in liver, heart and skeltal muscle
- hepatic lipidosus, hepatic steatosis
How do you recognise an accumulation of lipid within cells during hepatic steatosis ?
Lipid accumulation / hepatic steatosis
Grossly the liver will appear swollen slightly yellow with a greesy texture.
Histologically, the lipid vacuoles become sharply defined and displace the nucleus to one side.
What factors could lead to an accumulation of glycogen within cells, and describe the morphology ?
Glycogen
Glycogen is normally stored in the liver and muscle cells
Excess accumulation could result from
- diabetes mellitus
- excess corticosteroids
- in glycogen storage disease, glycogen accumulates as a result of a defective enzyme
Accululation of glycogen appears
- grossly the liver appears swollen, pale brown and mottled
- Histologically irregular, clear vacuoles within the cytoplasm
- PAS stain (periodic acid shift) glycogen stains bright pink +ve
How would you identify the accumulation of protein within a cell ?
Protein accumulation
- Histologically proteins are eosinophilic
- Russel bodies = cytoplasmic globules (retained immunoglobulins) found with a MOTT cell.
What is the difference between a exogenous and endogenous product accumulating within cells ?
Exogenous
- from outside the body
- substances eg minerals, lead
Endogenous
- products of abnormal metabolism
- eg lysosomal storage disease
Identify ?
Infectious agents -
- viral inclusion bodies
- may be intracellular or intracytoplasmic (or both) eg rabies, canine distemper, parvovirus, herpes etc
- exogenous
Identify ?
Lead poisoning
Where would we see melanin in a Veterinary pathology setting ?
Melanin in pathology
Chronic injury / endocrine skin disease
- hyperpigmentation of the skin
- extra melanin pigment
Congenital melanosis
- no clinical impairment
Neoplasia
- melanoma / melanocytoma
Identify what is this cellular accumulation
Lipofuscin
- observed in neurons, cardiac myocytes (post mitotic cells)
- wear and tear pigment
- often seen with aging - indicating the age of a cell
- endogenous pigment
- golden coulour
Identify this cellular accumulation ?
Haemosiderin
A intracellular storage complex - found mainly in macrophages
When do we observe Haemosiderin in pathology
- when there is increased RBC red blood cell destruction ‘haemolysis’
- chronic congestion
- iron infections
Grossly = see a brownish tinge (eg lungs, bruised skin)
Histology = golden brown granules (Perl’s Prussian blue)
Differentiate between physiological and pathological adaptations of cells ?
Cell adaptations
Physiological adaptation
- occur in normal body conditions
- usually beneficial
- eg pregnancy, building of muscle
Pathological adaptation
- changes occur due to a disease condition
- usually detrimental for the host
- eg injury
The cellular response to an altered steady state is limited, how can these cells respond ?
Cell response to an altered steady state is limited
Reversable cell injury
- return to normal function (once stress or injury ceases)
- extent and duration of injury is not excessive
Adapt
- to the changed conditions
- can occur after sublethal persistant stress or injury
Irreversable cell injury
- leads to cell death
- occurs after severe or prolonged injury
The cellular response depends upon the extent, duration and cell type
Define stable, labile and permanent cell division ?
Cell division
Permanent
- terminally differentiated
- non dividing cells eg skeletal muscle, cardiac muscle and neurons
Stable
- conditionally dividing cells
- liver, kidney, endothelium of blood vessels, fibroblasts
Labile
- constantly having to renew / mutiple via stem cells
- skin, intestine, urogenital, lining of exocrine glands
Define hypertrophy, where is this likely to occur and why ?
Hypertrophy an increase in the size of cells.
- size increases by an increase in the number and size of organelles
- occurs in most organs and tissues
- more common in permanent and stable cells - which undergo litle replication
- eg striated and cardiac muscle
Define hyperplasia ?
Cellular adaptation
Hyperplasia = an increase in the number of cells
- increased mitotic division implied
- most common in labile cells that routinely proliferate and readily become hyperplastic
- eg epithelium, GIT, glands
What stimuli could induce hypertrophy ?
The cellular adaptation of hypertrophy is stimulated by
Hypertrophy can occur in response to several different stimuli
- mechanical or demand
- pathological eg increased workload
- hormonal eg oestrogen and pregnancy
- compensatory loss of a paired organ or part of an organ
- xenobiotic eg liver cells increase in size after chronic exposure to drugs
Xenobiotic = chemical substances which are foreign to animal life
Describe stimuli which would cause a hyperplasia response ?
Traditionally hyperplasia is divided into physiological and pathological responses
Physiological
- hormonal eg pregnancy
- compensatory
Pathological
- excessive hormonal stimulation (endometrial hyperplasia)
- chronic irritation
Define Atrophy ?
Atrophy
Decrease in size or amount of cells, tissue or an organ
- occurs after normal growth has been reached
- caused by a decrease in size and or number of cells as a result of gradual and continuous injury
Physiological atrophy also called ‘involution’
eg thymus with age, uterus atrophy post partuition
Describe the pathological causes of atrophy ?
The pathological causes of atrophy
- Nutrient deficient - starvation, reduced blood supply
- reduced workload - reduced skeletal muscle mass
- disuse - limb immobilisation following injury
- denervation - forelimb muscle atrophy after radial nerve paralysis
- pressure - may cause atrophy of adjacent tissues
- loss of hormonal stimulation - eg prolonged corticosteroid treatment
Define metaplasia ?
Cell adaptation metaplasia
Replacement of one cell type with another
- it is not the transformation of individual cells
- stem cells differentiate along a different path, and may eventually replace the original cell type
- may be reversible in some cases, if the cause is withdrawn
- can be preneoplastic - indicating an increased risk of neoplasia
Identify the causes of metaplasia ?
The cause of metaplasia
Usually an adaptive change to withstand an adverse environment
- eg cigarette smokers, vitamin A deficiency in birds
Define hypoplasia ?
Hypoplasia
Not a true cell adaptation - due to abnormal development
Is the failure of an organ to attain its full size eg enamel
Define Aplasia ?
Aplasia
Not a cellular adaptation as it is due to abnormal development
Failure of an organ to develop
Define dysplasia ?
Dysplasia
Not a true cellular adaptation as it is due to abnormal cellular development
- disorderly arrangemnet of cells which can cause abnormal architecture of a tissue/ organ
- reflects abnormal cellular organsisation and development
eg hip dysplasia, chondrodysplasia (dwarfism)
Identify the four stages of wound healing ?
What is the difference between a granuloma, granulomatous and granulation tissue ?
Summarise the differences between acute and chronic inflammation ?
Describe four different scar types ?
Define the term neoplasia and tumor ?
Terms
Neoplasia = a new growth
- an abnormal mass, composed of cells originally derived from normal tissues
- uncoordinated and excessive growth
- unresponsive to normal growth controls
- persist after cessation of stimuli
Tumor = original meaning swelling
- now associated with neoplasia or cancer
- can be benign or malignant
Define the terms cancer and oncology ?
Terms
Cancer
- common term for malignant tumors
- Cancer is a collection of diseases characterised by
- uncontrolled growth of cells
- leading to an invasion of surrounding tissues and spread (metastasis) to other parts of the body
Oncology
- study of tumors or neoplasm
What is meant by saying tumors are clonal ?
Tumors are clonal
The entire population of neoplastic cells within an individual tumor arise from a single cell that has acquired a genetic change.
clonal expansion - transformation of a normal neoplastic cell can be caused by
- chemical, physical or biological agentsthat directly and irreversable alter the cells genome
- characterised by the loss of some or all the cells specialised functions
- aquisition of new biological functions
Tumors remain independant on the host for nutrition and blood supply
A tumor consist of what two components ?
A tumor consist of two components
- proliferating neoplastic cells (paranchyma)
- supportive stroma
- made of blood vessels and connective tissue
- tumor - stromal interactions modulate growth and differentiation
What factors determine the namming of a tumor ?
Tumor naming depends upon
- whether the tumor is malignant or benign
- also reflects the cell type of origin
Benign
- end oma
Malignant
- mesenchymal end sarcoma
- epithelial end in carcinoma
Remember there are always exceptions to the rules
Differentiate between malignant and benign tumors ?
Provide the name of a benign tumor ?
Name a benign proliferation resembling blood vessels ?
Name a benign proliferation of adipocytes ?
Name a benign tumor of smooth muscle ?
Name abenign tumor of glandular epithelium ?
Adenoma
Name a host specific benign proliferation of skin : stratified squamous epithelium ?
papilloma
Name a benign proliferation of the mucosa stratified squamous epithelium ?
polyp
How would you name a malignant tumor of the epithelium or the mesenchymal tissue ?
How would you name a malignant proliferation of cells in the mesenchyma of the heart ?
Name a malignant proliferation of squamous epithelial cells ?
carcinoma (produce keratin)
- produce central keratin pearls
Describe the mechanism which results in lipid accumulation in fatty change ?
Mechanism of fatty change
- Excessive delivery of free fatty acids to the liver (GIT dietary excess)
- Decreased oxidation of FFA (mitochondrial injury)
- Impaired protein sysnthesis (apoprotein)
More uncommon
- impaired ability to combine triglycerides and protein to form apoprotein
- impaired release / secretion of lipoproteins from hepatocytes.
Identify the two processes responsible for the changes of necrosis ?
Mechanisms of necrosis
1) Denaturation of proteins
due to reduced PH in severely injured and dead cells
2) Enzymatic digestion of cell components
- Autolysis self digestion by lysosomal enzymes of dead cells
- Heterolysis lysosomal enzymes from immigrant leukocytes
Necrosis initiates an inflammatory response in adjacent tissues
Define postmortem autolysis ?
Postmortem autolysis
Cells that die along with the rest of the animal (somatic death)
Describe the histological changes observed in necrosis ?
Histology of necrosis
Cell nucleus
- Pyknosis
- Karyorrhexis
- Karyolysis
Cell cytoplasm
- increase eosinophilia (increased binding of eosin to denatured proteins)
- Pale ghost like appearance (enzymatic digestion of cytoplasmic proteins)
Define pyknosis, karyorrhexis and karyolysis in necrotic cell change ?
Describe the appearance of coagulative necrosis ?
Coagulative necrosis
Denaturation of proteins is the prominent process - therefore enzymes are unable to digest cellular components
Cell outline and archetecture intact.
Cytoplasm is uniformly eosinophilic (pink), nucleus may be pyknotic, karyorrhectic, karyolytic or absent.
- often seen in hypoxic injury
- often seen in kidney, liver and muscle (not brain)
Describe the morphological changes that occur during necrosis ?
Morphology of necrosis
- requires 24-48 hrs to appear grossly
- pale, soft
- friable = (easily crumbled)
- shrply demarcated from viable tissue by a zone of inflammation (histologically)
Necrotic tissue varies widely in appearance both grossly and histologically
Describe liquifactive necrosis ?
Liquifactive necrosis
Cells are lysed and necrotic tissue is converted to a fluid phase.
- final stages of brain parenchyma (large amounts of lipid and lytic enzymes)
- pyogenic pus forming bacterial infections outside the CNS
- centre of absesses or other collections of neutrophils
Describe caseous necrosis ?
Caseous necrosis
Dead cells form friable, granular white/yellow mass : alike cottage cheese
- often involve poorly degradable bacterial components
- dystrophic calcification (central lesion)
- cell outline is lost (architecture disrupted)
- necrotic debris mostly composed of nuclear and cytoplasmic remnants of dead leukocytes
- surrounded by granulomatous inflammation (macrophages)
- fibrous connective tissue capsule
Describe gangrenous necrosis ?
Gangrenous necrosis
Initial lesionis coagulation necrosis
Moist gangrene = contaminated saprophylytic bacteria putrefaction
Gas gangrene = tissue becomes infected with anearobic bacteria (Clostridium sp)
Dry gangrene = necrotic tissue dries out and becomes mummified extremeties eg frost bite, ergot, fescue toxin
Describe fat necrosis ?
Fat necrosis
Enzymatic necrosis of fat
- activated pancreatic enzymes released during pancreatis or damage to pancreatic duct
- destruction of surrounding tissue by lipases from pancrease
- often get dystrophic calcification
- traumatic when fat is crushed (pelvic canal in heifers)
- idiopathic necrosis (unknown cause)
Detail the mechanisms underlying apoptosis ?
Describe what you would observe histologically with apoptosis ?
What is dystrophic calcification ?
Dystrophic calcification
calcium salts depositied in tissue
- deposition occurs locally in damaged, dying or dead tissue
- occurs despite normal serum calcium levels
- eg heart, skeletal muscle
- significance it indicates previous injury
- grossly looks white and has a gritty feel when incised
Basophilic blue fine granule dumps
Describe metastatic calcification ?
Metastatic calcification
calcium salts deposited in tissue
deposition in otherwise normal tissue
- secondary to hypercalcaemia
- eg renal failure - calcium deposition
- gastric mucosa, kidney, alveolar
Describe the differences you would observe histologically in cells undergoing apoptosis or necrosis ?
Describe the main histological differences between a benign and malignant neoplasm ?
Histological differences benign and malignant neoplasm
Differentiation
Rate of growth
Local invasion
Metastasis
Describe how we use differentiation to distinguish between benign and malignant neoplasm ?
Differentiation
- the extant to which neoplastic cells resemble corresponding cells morphologically and functionally
- poorly differentiated cells are a hallmark of malignancy
- Anaplasia = lack of differentiation
- cells display pleomorphism (marked different size and shape of cells)
- large cell, irregular size and shape, hyperchromatic dark nuclei, multinucleated, disorganised
Describe how we use growth to differentiated between benign and malignant neoplasms ?
Growth rate differentiation
Benign
- grow slowly
- progressive growth
- rare mitotic figures
Malignant
- grow rapidly - often outgrow blood supply leading to necrosis
- erratic growth (may appear slow)
- OFTEN NUMEROUS MITOTIC FIGURES (in the process of division)
How do we use local invasion to differentiate between benign and malignant neoplasms ?
Local invasion for differentiation
Benign
- remain localised to site of origin (discrete lesion)
- well demarcated
- cohesive, expansile growth
- fibrous capsule
Malignant
- progressive infiltration invasion and destruction of surrounding tissue
- do not recognise anatomical boundaries
- typically unencapsulated
Invasiveness is a reliable indicator of malignancy
Using metastasis to differentiate between benign and malignant tumors ?
Metastasis
Metastasis is the single most reliable hallmark of malignancy
M = when colonies of tumor cells take up residence at a distant site from the parent tumor - the neoplasm has migrated to another location
Identify the pathways of tumor metastasis ?
Pathways of metastasis
- Direct seeding - transcoelomic spread in the body cavities / surfaces
- Lymphatics - most carcinomas spread via the lymphatic system
- Blood vessels - typical spread of sarcomas and also seen in carcinomas liver and lungs
For metastasis to occur the neoplasm must have the correct gene combination .
Describe the mechanisms of invasion and metastasis (8 steps) ?
The mechanisms of invasion in metastasis
- Detach - from main tumor mass - reduce cell to cell adhesion
- Adhere and penetrate basement membrane
- Invade extracellular matrix - adhere, migrate, degrade and remodel
- Invade blood vessels lymph nodes (intravasation)
- evade immune system cells - often form small tumor emboli with platelets
- excit from vessel (extravasation)
- colonise new site
- stimulate new blood vessel growth angiogenesis ( to grow and thrive)
Describe the tumour stromal interactions Scirrhous response and cytokine production ?
Tumour stromal interactions
- Successful tumours can co-opt and adapt the environment to their own inferiors means
- tumour cell and stroma interact in a variety of ways (wide range of signalling molecules; growth factors, cytokines, hormones and inflammatory mediators
- modulate growth rate, differentiation state and behaviour of tumour cells (invasiveness, metastatic capability)
Scirrhous response (PDGF platelet derived factor)
- some tumour cells release PDGF which stimulates proliferation of fibroblast, and increased production of collagen
- often seen in epithelial cell tumours
Cytokine production
- Some tumour cells induce stromal cells to produce cytokines which promote tumour proliferation or motility
Describe how tumors evade the immune system ?
The immune response to neoplasms
Neoplastic cells have antigen on their cell surface. These antigens are able to stimulate a immune response, and in some cases this response may lead to regression of the tumour.
However many cells evade the body’s immunosurveillance
- antigen loss of tumour cell
- class one MHC deficient tumour cell
- immunosuppressive cytokines
Provide an overview of inflammation ?
Provide the five cardinal signs of acute inflammation ?
Describe the role of preformed vasoactive amines as part of the chemical response in inflammation ?
Chemical response preformed vasoactive amines
Histamine
- mast cells, basophils and platelets
- increase muscous production and bronchial constriction
- vasodilation and vascular permeability
Serotonins
- platelets of mammals
- important neurotransmitter
- vasodilation and vascular permeability
Describe newly synthesised eicosenoids part of the chemical response in inflammation ?
Newly synthesised eicosenoids - chemical response in inflammation
Arachnidonic acid and metabolitesderived from cell membrane lipids - mediate many aspects of acute inflammation
Prostaglandins
- endothelial cells, mast cells = vasodilation
- fever, pain and increase in vascular permeability
- act upon hypothalamus
Leukotrienes
- vasoconstriction and increase vascular permeability
- LTB4 potent chemotactic agent for leukocytes
- however, an incrase in conc leads to vasodilation
What are the plasma derived (largely from liver) mediators of inflammation ?
Describe the complement cascade = function and activation ?
Compliment cascade
Inflammation activates circulating complement proteins
- synthesised by liver up of 25 complement proteins
- activated by microbes, antibodies, endotoxins and venom
Function
- form membrane attack complexes - perforate membranes of pathogens
- when complement proteins become activated they become activated proteolytic enzymes
- promote chemotaxis and opsonisation
- enhance histamine release from mast cells
- these in turn activate other compliment proteins resulting in powerful enzymatic amplification
- the critical step is activation C3 (most abundant compliment protein)
Describe the three ways in which the compliment cascade can be activated ?
Activation of the compliment cascade
Classical pathway
- binding of CL to AB-Ag complexes
alternative pathway
- binding of endotoxin or LPS
Lectin pathway
- plasma manose binding lectin binds to CHOS on microbes activation CL
Describe what the membrane attack complex is composed of ?
Describe the function of complement fragments C3a, C3b, C5a and C5b ?
Describe the plasma derived component the Kinin system ?
The kinin system
Activated by hageman factor 12
- activated by secondary exposure of collagen or basement membrane, when endothelium is damaged
Bradykinin
- vasoactive amine
- vasodilation and increase in vascular permeability (endothelial cell contraction)
- increases sensitivity to pain
- Kallikreins - kininogens - bradykinin
Plays a role in blood pressure and inflammation via the production of bradykinin
Describe the vascular response in inflammation ?
Acute inflammation is a vasocentric process
- characterised by marked vascular changes vasodilation, increased permeability and fluid exudation
- exudation of fluid, plasma proteins
- emigration of leukocytes
What is responsible for this marked vascular response
- mast cell degranulation (BK, PGs and FR) causing vasodilation which in turn increases blood flow.
Provide an overview of the chemical mediators of acute inflammation
Genes of oncogenesis
Proto oncogenes
- help regulate cell growth and differentiation
- when modified in a way initiates or promotes neoplasia are then called oncogenes (promotors of autonomous cell growth RAS)
Tumour suppressor genes p53 (transcription up regulation)
- the gene initiates cell cycle arrest at checkpoints
- allows for time to repair DNA damage
- many tumours have a mutation in p53, preventing cell arrest
Genes coding for DNA repair
- tumours can regain the ability to replicate telomeres - immortality
Genes which code for DNA repair proteins
- cells accumulate potentially mutagenic DNA damage
The development of neoplastic behaviour in a cell is complex, multi step process “stepwise development neoplasia”
Describe the vascular response in acute inflammation ?
The three steps of neoplasia development
Initiation
- cell is primed by a non lethal, irreversible genetic change
- appears morphologically normal
- may remain quiescent for years
Promotion (high risk)
- initiated cell expands to form a preneoplastic lesion or benign tumour
- in response to stimuli called promoting agents
- stimulate proliferation of mutated cells eg. hormones or drugs
- not mutagenic effects are reversable
Progression
- with further epigenetic or genetic alterations a malignant tumour arises from a sub clone
- represents an irreversible change in the nature of the tumour
- complex and poorly understood process
Describe the mechanisms underlying vascular permeability ?
Describe four preneoplastic changes and what induces them ?
Describe some factors which contribute to the development of neoplasia ?
Provide some intrinsic and extrinsic factors which could contribute to the development of neoplasms ?
Describe the importance of angiogenesis with relation to tumour cells ?
Angiogenesis
Continued growth of solid tumour cells absolutely depends on adequate blood supply
- provides oxygen and nutrients to growing tumours
- tumours induce angiogenesis via growth factors and other signalling molecules released from ECM - VEGF and FGF
- blood vessels in tumours are tortuous, irregularly shaped, disorganised, leaky and unstable
Describe the immune response to neoplasms, and tumour evasion of the immune response ?
Immune response to neoplasms
Neoplastic cell have antigens on the cell surface (proteins, glycoproteins, glycolipids)
- These antigen elicit an immune response
- the inflammation response dose not in general protect against neoplasia
- macrophages, NK cells and cytotoxic T cells
Evasion of the immune response
- antigen loss variant of tumour cell
- class one MHC deficient tumour cell
- immunosuppressive cytokines
Direct effects of neoplasia
A direct effect is when a tumour directly compromises the function of organs in which they arise
- replace normal tissue of organs
- cause pressure atrophy of adjacent tissue
- compress adjacent blood vessels to cause ischaemia (blood restriction) and tissue necrosis
- erosion of blood vessels can cause extensive haemorrhage
- may rupture hollow organs such as the stomach, intestine or urinary bladder
Indirect effects of a neoplasm
Indirect and often remote effects caused by tumour cell products - known as paraneoplastic syndrome (occur in >70% of human patients)
- cachexia
- endocrinopathies
- skeletal syndromes
- vascular and haematologic syndromes
- neurological syndromes
- cutaneous syndromes
Cachexi
Many animals with cancer show notible weight loss and debility
- loss of both muscle and fat
- Aetiological complex - extra calories do not reverse the catabolic state
- anorexia impaired digestion
- nutritional demands of neoplastic tissues / nutrient loss of neoplasm
- metabolic and endocrine derangements
- humoral factor = TNF - alpha, interleukins IL-1 IL-6 and prostaglandins
What are the indirect effects of endocrinopathies with respect to neoplasm ?
Endocrinopathies
Due to an overproduction of hormones
- hyperthyroidism due to thyroid neoplasia
- Cushing’s disease (hyper-adrenocortism) due to pituitary or adrenal neoplasm
There are also a variety of non-endocrine neoplasms which produce hormonally active substances (ectopic hormone production)
- hypercalcaemia or hypoglycaemia are frequently observed due to neoplasm
- A wide variety of carcinomas/sarcomas result in the production of parathyroid hormone. Parathyroid hormone PTH removes calcium from bones, increases intestinal and kidney absorption causing hypercalcemia
- Hypoglycaemia (low blood sugar) is seen with insulinomas - a functional neoplasm of the islet of Langerhans beta cells = results in incoordination, lethargy, weakness and seizures.
Hypertrophic osteopathy
Observed in cats and dogs
- extensive periosteal new bone growth
- occurs with a variety of neoplasms but frequently associated with neoplastic and non neoplastic space occupying thoracic lesions
- the cause is not known - but presumed to be overproduction of growth hormone
Haematological and vascular syndromes
Neoplasia causes a variety of vascular and haematological disorders, cause remains unclear
- anaemia
- eosinophilia
- neutrophilia
- thrombocytopaenia (⅓ of all dogs with neoplasia)
- disseminated intravascular coagulation (DIC)
How to diagnose neoplasia
Clinical signs and symptoms
- generalised lymphadenopathy in lymphoma
- cachexia
- respiratory distress with coughing / pulmonary neoplasm
- lameness in dogs with hypertrophic osteopathy
Blood analysis
- anaemia, leucocytosis (up), DIC
- paraneoplastic syndromes (hypercalcemia)
- specific markers (prostatic specific antigen in humans)
Imaging techniques
- radiography, ultrasound and CT scans
- can detect primary and metastatic neoplasms
A definitive diagnosis is carried out through cytology and histopathology.
Classification and naming of a neoplasm requires microscopic examination of cells - techniques which are routinely practised.
How do we use cytology to identify a neoplasm ?
Cytology
A sample is collected from solid neoplasms, or body fluids for cytology (examination of individual cells)
- stain with a simple rapid stain Diff-Quik
- may also include skin scrapings or impression smears
- in house or sent away to a laboratory
Identifiable features
Cell type involved
Scrutinise for features of malignancy
- degree of cell differentiation
- mitotic index
- evidence of invasion or metastasis
Techniques
- Haematoxylin and eosin - histopathology
- Toluidin blue - mast cells
- Immunohistochemistry - antibodies
- molecular methods PCR
Tumour development
Step wise tumour development - cumulative effect of multiple genetic (and epigenetic) changes over a long time course that creates a tumour.
Many genes are required to direct and control the steps within the normal cell cycle
Oncogenesis = is the complex process by which neoplastic cells develop.
DNA mutations can occur in one or many of the different genes that normally regulate cell growth and differentiation-
- proto oncogenes - regulate cell growth and differentiation
- tumour suppressor genes such as p53 - slow
- genes which code for DNA repair proteins
- telomerases
What are the four actions of thrombin ?
