Pathology Flashcards
What are features of malignant cells?
enlarged cells High nuclear to cytoplasmic ratio Variability in size of nucleus and cells Speckled chromatids More than 1 nuclei Hyperchromatism Mitotic figures - mercedes benz sign
What cells are in carcinoma?
All cells that are not epithelial tissue or glandular
What cells are included in sarcoma?
Soft tissue
Bone
Histologically what would coeliacs disease look like?
Blunting of villi
Decreased goblet cells
Lots of inflammatory cells at top of villi
What is signet ring carcinoma and what causes the characteristic shape?
Rare form of highly malignant adenocarcinoma that produces mucin. Epithelial malignancy
The nuclei are pushed towards to the edge of the cell
What would make a benign mole into a malignant mole?
Growth in dermis and epidermis
What is adenocarcinoma?
glandular lumina surrounded by malignant epithelial cells
What are Reed-Sternberg cells indicative of and what do they look like?
Giant cells found in Hodgkins lymphoma. Usually derived from B cells
Owls eyes appearance
What are HER receptors?
Human Epideramal Growth Factor Receptor (1 or 2)
What are the 7 stages of producing a slide?
1 - Fixation 2 - Cutting up 3 - Embedding into wax 4 - Microtome cutting 5 - H&E staining (others also available) 6 - Mounting onto slide 7 - Diagnosis
What is autolysis?
Tissue autolysis is self digestion that begins when the blood supply is cut off
Cells and tissue architecture is also destroyed
What effects do fixatives have when blocking autolysis?
1 - inactivate tissue enzymes and denature proteins
2 - Prevent bacterial growth
3 - Harden tissue
What colour does Haematoxylin stain?
Nuclei - Purple
What colour does Eosin stain?
Cytoplasm and connective tissue pink
What is the cell injury response pathway to harmful stimuli?
Homeostasis -> Cellular adaptation -> Cellular injury -> Cell death
What is the problem with cellular adaptation?
Increase in size is the usual adaptation
Increase in size = more nutrients & O2 therefore at risk of cellular damage again which could be reversible or irreversible
What is the difference between hypoxia and ischaemia?
Hypoxia - blood has reduced O2
Ischaemia - insufficient blood supply, supplying less O2 to the tissues
What are the 4 types of hypoxia?
Hypoxaemic hypoxia
Anaemic hypoxia
Ischaemic hypoxia
Histiocytic hypoxia
What is hypoxaemic hypoxia?
Arterial content of O2 is low
Caused by:
Reduced inspired pO2 at altitude
Reduced absorption secondary to lung disease
What is anaemic hypoxia?
Decreased ability of Hb to carry O2
Caused by:
Anaemia
CO poisoning
What is ischaemic hypoxia?
Interruption to blood supply
Caused by:
Blockage of a vessel
Heart failure
What is histiocytic hypoxia?
Inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes
Caused by:
Cyanide poisoning
What is anoxia?
No O2 in the blood
What happens at the molecular level in hypoxia?
Ischaemia -> Decreased mitochondrial OxPhos -> Dec. ATP production -> (1) Dec. Na pumping (2) Inc. Glycolysis (3) Detachment of ribosomes from ER
1) Influx of Ca, H2O, Na. Efflux of K+ -> cellular swelling, blebs
2) Dec pH & glycogen -> Clumping of nuclear chromatin
3) Dec. protein synthesis -> Lipid deposition
What happens in prolonged hypoxia leading to irreversible damage on a cellular molecular level?
Ca influx from a variety of sources:
(1) ER (2) External as inc membrane permeability (3) Mitochondrion
Increased calcium activates cytosolic enzymes:
ATPase - dec ATP
Phospholipase - Dec phospholipids
Protease - Disruption of membrane and cytoskeletal proteins
Endonuclease - Nuclear chromatin damage
When are free radicals produced?
Normal metabolic reactions - OxPhos
Inflammation - oxidative burst of neutrophils
Radiation - H2O -> OH (free radical)
Contact with unbound metals within the body (iron and copper) - haemachromatosis and Wilson’s disease
Drugs and chemicals - liver during metabolism
How does the body control free radicals?
Anti-oxidant scavengers - donate electrons to free radical Vitamins A,C,E
Metal carrier and storage proteins (transferrin, ceruloplasmin): sequester free iron and free copper
Enzymes - Superoxide dismutase, Catalase, Glutathione peroxidase
What is the function of Heat shock proteins?
In cell injury heat shock response aims to mend mis-folded proteins and maintain cell viability
Unfoldases or chaperonins are examples
Define oncosis
Cell death with swelling, the spectrum of changes that occur in injured cells prior to death
Define Necrosis
In a living organism the morphologic changes that occur after a cell has been dead some time - seen after 12-24 hours
What are the two types of necrosis?
Coagulative
Liquefactive
What is coagulative necrosis?
Cellular death caused by ischaemia or infarction
Injury damages structural proteins and lysosomal proteins thus blocking proteolysis
Protein denaturation > Release of active proteases
-Protein denaturation and clumping
-Tissue becomes firm and cells keep their structure giving them a ghost like appearance
-Occurs in all tissues except brain
What is liquefactive necrosis?
Ischaemia in loose tissues: presence of many neutrophils - pus formation
Partial or complete dissolution of dead tissue and transformation into a liquid
Enzyme degradation > Enzyme denaturation
Loss of tissue and cellular profile.
Hydrolytic enzymes cause dissolution of cellular organelles
Occurs in Brain as there is no structural integrity of the tissues
What are two special types of necrosis that aren’t coagulative or liquefactive?
Caseous
Fat necrosis
What is caseous necrosis?
White, soft, cheese looking material is formed hence name
Contains amorphous (structureless) debris
Microscopically - uniformly eosinophilic centre of necrosis surrounded by a collar of lymphocytes and activated macrophages
Particularly associated with infections: TB is a prime example and granuloma’s
What is fat necrosis?
Acute inflammation of adipocytes, could be due to trauma.
Damaged cells release digestive enzymes - lipases, which breaks down lipid -> free fatty acids
Anucleated adipocytes w/ deposits of calcium - saponification
What does gangrene mean?
Necrosis visible to the naked eye
An appearance of necrosis (wet and dry)
What does infarction mean?
Necrosis caused by reduction in arterial blood flow
- A cause of necrosis -(if untreated)-> Gangrene
What does infarct mean?
An area of necrotic tissue which is the result of loss of arterial blood supply
- An area of ischaemic necrosis
What is the difference between wet and dry gangrene?
Dry - necrosis modified by exposure to air (coagulative necrosis) - i.e. umbilicus in babies - dry, crisp appearance
Wet - necrosis modified by infection (bacteria, septicaemia) - release proteases which liquify the surrounding area (liquefactive necrosis)
What is gas gangrene?
Rapidly spreading gangrene affecting injured tissue infected by bacterium found in soil and accompanied by the production of foul-smelling gas
Form of wet gangrene - anaerobic Clostrium perfringens
What is the difference between thrombosis and embolism?
Thrombosis - pathological blood clot abnormally obstructing blood flow
Embolism - is a detached solid (clot), liquid (fat,) or gas (air) carried away from site of origin by blood and causing an obstructing of blood flow
Why are some infarcts white?
Solid organs - occlusion of an end artery (sole source of blood to an organ)
Often wedge shaped - blood from lots of vessels merge into 1 vessel = heart, spleen, kidney
Coagulative necrosis
Why are some infarcts red?
Haemorrhagic infarct
Loose tissue - poor stromal support
Dual blood supply - 2 arteries supplying organ/ tissue. The blood will fill dead tissue but not enough to reperfuse it and salvage it.
Numerous anatomoses
Prior congestion i.e. haemorrhagic transformation from ischaemic stroke.
Raised venous pressure
Re-perfusion - there are limits of when to reperfuse after which the risk of causing haemorrhaging could lead to a red infarct
What is ischaemic-reperfusion injury?
Paradoxically, if blood flow is returned to a damaged but not yet necrotic tissue, damage sustained can be worse than if blood flow hadn’t been returned.
Possible causes:
-Increase production of free radicals
-Inc. no. of neutrophils - inc inflammation and inc tissue damage
-Delivery of complement proteins and activation of complement pathway = inc. inflammation
What are the problems with dying cells for example in tumour lysis syndrome?
A sudden release of potassium can potentially be pro-arrhythmic
Sudden release of urea - cause confusion, kidneys not able to handle this amount of urea
(also hyperphosphataemia and hypocalcaemia are features of TLS)
What enzyme is measured during/ after MI and why?
Troponin
1st enzyme to leave and longest half life
Define apoptosis
Cell death with shrinkage, induced by a regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins
The process requires ATP (whereas necrosis doesn’t)
Pathological and/or physiological
When does apoptosis occur pathologically?
Cytotoxic T cell killing of virus-infected or neoplastic cells
When cells are damaged, particularly with damaged DNA
Graft vs host
What are the 3 stages of apoptosis?
Normal cell -> Condensation -> Fragmentation -> Apoptotic bodies
Initiation -> Execution -> Degradation & phagocytosis
What are the two mechanisms that cause initiation and execution of apoptosis?
Intrinsic and extrinsic
Both result in activation of caspases:
Enzymes that control and mediate apoptosis
Cause cleavage of DNA and proteins of the cytoskeleton
How is the intrinsic pathway of apoptosis initiated?
Initiation comes from within the cell
Triggers: -cellular stress -Irreparable DNA damage - Withdrawal of growth factors or hormones
How is the intrinsic pathway of apoptosis carried out?
p53 protein is activated and this results in the outer mitochondrial membrane becoming leaky
Cytochrome C is released from the mitochondria and this causes activation of caspases
How is the extrinsic pathway of apoptosis initiated?
Signals from other cells
Triggers: -cells that a danger, e.g. tumour cells, virus-infected cells
How is the extrinsic pathway of apoptosis carried out?
One of the signals if TNFalpha
- Secreted by T-killer cells
- Binds to cell membrane receptor (death receptor)
- Results in activation of caspases
Why are apoptotic bodies phagocytosed?
Cells shrink -> apoptotic bodies -> proteins expressed on the surface -> phagocytes and neighbouring cells recognition -> degradation within phagocyte/ neighbour
What are the 3 stages of necrosis of the nucleus in greek and what do they mean?
Pyknosis - condensation of chromatin
Karyorrhexis - fragmentation of the nucleus
Karyolysis - dissolution of cell nucleus
What are the 5 main groups of intracellular accumulations?
Water and electrolytes Lipids Carbohydrates Proteins Pigments - exogenous and endogenous
When is hydropic swelling seen?
Intracellular oedema seen with viral infections
Why does hypoxia cause fluid to accumulate in cells?
Hypoxia -> No OxPhos -> reduced ATP production -> Na/K ATPase does function to remove Na -> Water follows Na and so cells swell
When do lipids accumulate in cells?
Often seen in the liver - due to major organ of fat metabolism. Causes: Alcohol, Diabetes mellitus, Obesity, Toxins
Cholesterol: cannot be broke down and is insoluble, elimination through the liver (bile), excess stores in cell in vesicles. Accumulation in smooth muscle cells and macrophages in atherosclerotic plaques - foam cells.
Present in macrophages in skin and tendons of people with hereditary hyperlipiaemias = xanthomas
In what 2 conditions do proteins accumulate (hepatic)?
Alcoholic liver disease - Mallory’s hyaline (damaged keratin filaments which are intracytoplasmic proteins)
Alpha1-antitrypsin deficiency - liver produces incorrectly folded A1-antitrypsin
When do pigments accumulate in cells?
Carbon/coal dust/soot - urban air pollution
Inhaled and phagocytes by alveolar macrophages
Anthracosis and blackened peribronchial lymph nodes
Usually harmless unless in large amounts
Tattooing - phagocytosed by macrophages in dermis but remains there - some pigment reaches draining lymph nodes
Haemosiderin: iron storage molecule - derived from Hb. Systemic iron overloading - haemosiderin is deposited= haemosiderosis - haemolytic anaemias, blood transfusions and hereditary haemochromatosis
What are the 4 mechanisms of intracellular accumulations?
1 - abnormal metabolism
2 - alterations in protein folding and transport
3 - deficiency of critical enzyme
4 - inability to degrade phagocytosed particles
Why does calcification occur in metastatic disease?
Due to hypercalcaemia secondary to disturbances in Ca metabolism
Hydroxyapatite crystals are deposits in normal tissues throughout the body
Usually asymptomatic but it can be lethal
Can regress if the cause of hypercalcaemia is corrected
What causes hypercalcaemia?
Increased secretion of PTH resulting in bone resorption:
Primary - parathyroid hyperplasia/ tumour
Secondary - renal failure and retention of phosphate
Ectopic - secretion of PTH-related protein by malignant tumours (e.g. carcinoma of the lung)
Destruction of bone:
Primary tumours of bone marrow e.g. leukaemia, multiple myeloma
Diffuse skeletal mets
Paget’s disease of bone - accelerated bone turnover
Immobilisation
What is pepper pot skull and hypercalcaemia indicative of?
Multiple myeloma
What enzyme do germ cells and stem cells have that regular cells don’t that allows them to technically become immortal?
Telomerase - maintains length of the telomeres which usually prevent further cell division
What do Mallory’s hyaline look like under microscope when stained with H&E?
Pink filaments in hepatocyte cytoplasm
What are neutrophils also known as?
Polymorphs
Polylobated nucleus is the cause
What is diapedesis?
The movement of cells in the blood passing through an intact blood vessel typically during inflammation
Microscopically describe what a macrophage would look like
Eccentric nucleus which can be round, kidney shaped or slipper shaped
Often lots of cytoplasm which can appear vacuolated
Describe what a eosinophil would look like microscopically
Granular red cytoplasm
Bilobed nucleus
Describe what a granuloma would look like microscopically and what causes it?
Langerhans type giant cell Epithelioid histiocytes (modified, immobile macrophages) Cellular attempt to remove offending agent - T-lymphocytes strongly activated/ activating macrophages - persistent antigen presentation low level
What cells would line the outside of a foreign body?
Foreign body giant cell
Multinucleated cell that surround the foreign body
What does petechiae look like?
Tiny haemorrhages that can be seen on the skin (<3mm)
What are lines of Zahn?
A thrombus that has lines of zahn is caused by layers of red blood cells and fibrin and other layers of platelets
Characteristic of thrombi that form particularly in the aorta
What are the layers of an atherosclerotic plaque?
Fibrous cap
Necrotic core with cholesterol clefts
Calcification
What are foam cells and where are they usually found?
Type of macrophage that takes up LDL’s into itself and lives primarily in blood vessels. With all the lipids it takes on a foam appearance.
What is the difference between metaplasia and dysplasia?
Metaplasia: Change of one epithelium to another type Reversible once the stimulus has ceased Adaptive process Dysplasia: Development of abnormal cell types - usually in the epithelium Irreversible Alteration of genetic material therefore phenotype also changes
What is transcoelomic spread?
Spread of a malignancy into a cavity that occurs by penetrating the surface of the space. E.g. peritoneum, pericardium, pleural cavity
What type of cancer is most common with asbestos fibres in the lung?
Malignant mesothelioma
What is Kaposi’s sarcoma?
Disease of the endothelial cells and blood vessels that causes masses on the skin
Form of cancer associated with HIV and also classic Kaposi’s is associated with diabetes
What does pleomorphic mean?
Variability in size, shape and staining of cells and/or their nuclei
What does nuclear hyperchromasia mean and what does it indicate?
Nucleus is darker in colour
Associated with malignant cells
What does the tumour marker CA 27.29 indicate?
Breast cancer
Associated also with colon, gastric, hepatic, lung, pancreatic, ovarian, prostate
What does the tumour marker CEA indicate?
Colorectal cancer
What does the tumour marker CA 19.9 indicate?
Pancreatic cancer, biliary tract cancer
What are 5 features of acute inflammation (not cardinal signs)?
Immediate Short duration Innate Stereotyped (same response every time) Limits damage
What is inflammation?
Vascular and cellular response - accumulation of exudate and neutrophils in tissue
Controlled by a variety of mediators - (derived from plasma or cells
Protective - cause local and systemic complications sometimes
What are the clinical cardinal signs of inflammation?
Rubour - redness Calor - heat Tumour - oedema Loss of function Dolor - Pain
What changes occur in vessels and surrounding tissues in acute inflammation?
Changes in blood flow - temperatures - Transient vasoconstriction (seconds) then vasodilation (inc overall blood flow)
Vascular phase- Movement of fluid into tissues - oedema - inc. hydrostatic pressure reduced oncotic pressure (in blood vessels)
Cellular phase - Inflation of inflammatory cells into tissue
What is the problem with movement of fluid out of the vessel but you also want this in acute inflammation?
Stasis
Increased viscosity of the blood -> reduced flow through vessel -> stasis -> inc contact time with bacteria/ causative agent of acute inflammation
What are the types of interstitial fluid and what are their causes?
Exudate - occurs in inflammation, protein rich - don’t contain fibrinogen, increased vascular permeability
Transudate - fluid loss due to increased capillary hydrostatic pressure or reduced oncotic pressure, no change of vascular permeability, occurs in heart failure/ hepatic failure/ renal failure (damaged tubules-protein loss - red. oncotic pressure)
What are mechanisms of increasing vascular permeability?
Endothelial contraction - histamine and leukotrienes
Endothelial cytoskeleton reorganisation - Cytokines, IL-1 TNF
Direct injury - chemical and toxic burns
Leukocyte dependent injury - enzymes and toxic oxygen species from leukocytes
What is the primary WBC involved in acute inflammation?
Neutrophil
What are some features of a neutrophil?
Trilbed nucleus
A granulocyte
Part of innate immune system
How do neutrophils escape vessels?
Margination= Stasis causes neutrophils to line up at edge of blood vessels along the endothelium
Rolling = neutrophils roll along endothelium sticking to it intermittently
Adhesion = Neutrophils stick more avidly to the site of injury - increasing affinity as gets closer to site of injury
Emigration (diapedesis) = Neutrophils follow through the blood vessel wall
What are the 2 adhesion molecules used by neutrophils to bind to the endothelium?
Selectins = endothelial cell surface (ICAM-1) unregulated by chemical mediators Integrins = On neutrophil cell surface (Integrins B2 on leukocytes) binds to endothelial surface
How do neutrophils move through the interstitium?
Chemotaxis -
Movement along a chemical gradient of chemoattractants
Rearrangement of neutrophil cytoskeleton
Pseudopods formed which help it move along endothelium and then emigrate
What do neutrophils do in acute inflammation?
Opsonisation - facilitates recognition of toxin
Toxin covered in C3b and Fc (Fc domain on antibodies - IgG is the most important - only if a bacteria has been encountered before) - opsonins
Receptors for C3b and Fc on neutrophil surface triggers phagocytosis
What are 2 killing mechanisms of neutrophils?
Oxygen dependent - ROS and RNS
Oxygen independent - Lysozyme, Hydrolytic enzymes, Defensins (punch holes in bacterial cell membranes)
What are the 2 phases of acute inflammation?
Vascular phase - exudation of fluid into interstitium
Cellular phase - infiltration of neutrophils
How does oedema limit damage?
Dilutes toxins (exudate) Delivers plasma proteins to area of injury - fibrin mesh limits spread of toxin, inflammatory mediators and immunoglobulins Increased lymphatic drainage from area (more extracellular fluid) - delivers antigens to lymph nodes (inducing adaptive immune response)
How do inflammatory cells limit damage?
Removal of toxins and pathogenic organisms
Removal of necrotic tissue
Release of chemical mediators that stimulate and regulates further inflammation
Stimulates pain - encourages rest and limits risk of further damage
What are chemical mediators released by?
Activated inflammatory cells
Platelets
Endothelial cells
What chemical mediators cause vasodilation?
Histamine
Serotonin
Prostaglandins - pyrogens = inc fever and pain
Nitric oxide
What chemical mediators increase vascular permeability?
Histamine
Bradykinins
Leukotrienes
C3a and C5a
What chemical mediators cause chemotaxis?
C5a, LTB4, TNF-alpha, IL-1, Bacterial peptides
What chemical mediators cause fever?
Prostaglandins
IL-1
TNF-alpha
IL-6
What chemical mediators cause pain?
Bradykinin
Substance P
Prostaglandins
What is one local complication of swelling?
Blockage of nearby tubes and ducts
e.g. bile duct/ intestines
What is one local complication of exudate production?
Compression of organs
e.g. cardiac tamponade
What is one local complication of pain and loss of function?
Muscle atrophy - disuse contractures
Psycho-social consequences of chronic pain
What cells increase in number with bacterial infections?
Neutrophils
What cells increase in number with viral infections?
Lymphocytes
What chemical mediators cause the bone marrow to increase production of lymphocytes?
IL-1
TNF
What are acute phase proteins?
C-reactive protein (commonly used blood marker)
A1-antitrypsin
Haptoglobin - binds free Hb - inhibits oxidative activity
Fibrinogen
Serum amyloid A protein - transport cholesterol to liver. Recuits immune cells to inflammation site - induces proteases etc to degrade extracellular matrix
What are 4 acute phase responses that are universal for inflammation?
Malaise
Reduced appetite
Altered sleep
Tachycardia
What are the features of septic shock?
Overwhelming infection Huge release of chemical mediators Widespread vasodilation Hypotension, tachycardia Multi-organ failure
What are the 4 sequelae of acute inflammation?
1 - complete resolution
2 - continued acute inflammation with chronic inflammation -> ABSCESS
3 - chronic inflammation and FIBROUS REPAIR, with some tissue regeneration
4 - death
What is important in allowing damaged tissues to regenerate?
Architecture preservation
What is an abscess?
Accumulation of dead and dying neutrophils
Associated liquefactive necrosis
What are 4 non-ischaemic and non-inflammatory causes of cardiomyopathy?
Hypertrophic
Arrhythmogenic right ventricular cardiomyopathy
Obstructive
Dilated (post viral from inflammation)
What are causes of acute inflammation?
Microbial infections - e.g. pyogenic organisms Hypersensitivity reactions (acute phase) Physical agents Chemicals Tissue necrosis
What is the response of Histamine in acute inflammation?
Immediate early response
Released from mast cells, basophils and platelets
In response to physical damage, immunologic reactions, C3a, C5a, IL-1
What is a systemic effect of acute inflammation that is severe?
In the acute phase response
SHOCK is a response that is severe
A clinical circulatory failure
Microscopically what do neutrophils look like?
Multilobed nucleus
Few organelles
Light pink coloured cytoplasm
Microscopically what do eosinophils look like?
They take up a large amount of eosin inside their cytoplasm.
Eosin is acidic and is attracted to basic components - cytoplasm
As lots of basic products inside the cytoplasm it stains the cytoplasm in deep pink
Microscopically what do macrophages look like?
Large eccentrically placed nucleus, which is kidney bean shaped
Abundant cytoplasm some pink granules in the cytoplasm
What is the difference between leiomyosarcoma and leiomyoma?
Leiomyosarcoma - soft tissue cancer - develop in muscle, fat, blood vessel etc.
Leiomyoma - aka fibroids - benign smooth muscle tumour. Can occur in any organ. Most common place is uterus, small bowel and the oesophagus.
Define chronic inflammation
Chronic response to injury with associated fibrosis
How does acute inflammation become chronic inflammation?
Damage is too severe to be resolved in a few days
Chronic inflammatory cells will be recruited
How does chronic inflammation arise?
May arise de novo e.g.
-some autoimmune conditions e.g. RA
-some chronic infections e.g. viral hepatitis
-chronic low-level irritation
Develop alongside acute inflammation - severe or repeated irritation
What are the major differences between neutrophils and macrophages?
Neutrophils - found in blood, macrophages found in tissues
Neutrophils - granulocytes and macrophages - agranulocytes
Neutrophils - multilobated nucleus, macrophages - spherical nucleus
What is the other name of macrophages?
Blood monocytes
What are the functions of macrophages?
Phagocytosis and destruction of debris and bacteria
Processing and presentation of antigen to immune system
Synthesis of not only cytokines, but also complement components, blood clotting factors and proteases
Control of other cells by cytokine release
Stimulation of angiogenesis
Inducing fibrosis
Inducing fever, acute phase reactions and cachexia
What are the main cell type causing chronic inflammation?
Lymphocytes
Don’t normally cause fibrosis but does in chronic inflammation
What are the basic functions of lymphocytes?
Complex, mainly immunological
B lymphocytes differentiate to produce antibodies
T lymphocytes involved in control (T-helper) and some cytotoxic (CTL) functions
What is characteristic of the nucleus of plasma cells (B-cells)
Clock like morphology of chromatin
Eccentrically placed
What are 2 characteristics of eosinophils?
Abundant in parasitic infections and IgE hypersensitivity reactions - allergies
Morphologically - sunglasses on with pinky cytoplasm
What is a giant cell?
Multinucleated cell made by fusion of macrophages
Frustrated phagocytosis
What are the 5 main types of giant cells?
Langhans - TB Foreign body Touton - fat necrosis Giant-cell arteritis Reed-Sternberg cell - Hodgkins lymphoma
What chronic inflammatory cells are mainly found in rheumatoid arthritis?
Plasma cells
What chronic inflammatory cells are mainly found in chronic gastritis?
Lymphocytes
What chronic inflammatory cells are mainly found in Leishmaniasis?
Macrophages
What are the 4 stages of chronic inflammation that lead to a cycle?
Fibrosis -> Impaired function -> Atrophy -> Stimulation of immune response -> back to fibrosis
How do you get impaired function in IBD?
UC - superficial - local effects of inflammation
Crohn’s - transmural - strictures and fistulae -
What does thyrotoxicosis look like microscopically?
Grave’s disease - hyperthyroidism -> decreased colloid and increased fat
What is the basic principle of wound healing?
Close the gap
Replace lost tissue with new functioning tissue or replace it with a scar
What is the mnemonic involved in wound healing?
HIMRES: Haemostasis Inflammation Migration Regeneration Early scar Mature scar
What is regeneration?
Regrowth with no or minimal evidence that there was a previous injury
Healing by primary intention in the skin
What is healing by primary intention?
Healing that occurs when a clean laceration or a surgical incision is closed - margins bought together
Disruption of basement membrane continuity but death of only small number of epithelial and connective tissue cells
Used when little tissue loss
What is healing by secondary intention?
Extensive skin and tissue loss - edges not able to be bought together
e.g. pressure sore
Which cells replicate in regeneration?
Stem cells
Where are the stem cells in the skin, intestines and liver?
Skin - basal layer adjacent to basement membrane
Intestines - mucosa - bottom of crypts
Liver - between hepatocytes and bile ducts
What are the 3 lineages of stem cells in their ability to divide?
Unipotent - only produce one differentiated cell e.g. epithelia
Multipotent - produce several differentiated cells e.g. haematopoietic stem cells
Totipotent - embryonic stem cells - produce any tissue
What are the 3 groups of tissues based on their proliferative activity?
Labile tissues
Stable tissues
Permanent tisses
What are labile tissues?
Short lived cells that are replaced from cells derived from stem cells
E.g. surface epithelia, haematopoietic tissues
What are stable tissues?
Normally low level of replication - can undergo rapid proliferation
Both stem cells and mature cells proliferate
e.g. liver parenchyma, bone, fibrous tissue, endothelium
What are permanent tissues?
Mature cells can’t undergo mitosis and no or only a few stem cells present
e.g. neural tissue, skeletal muscle, cardiac muscle
What one thing does regeneration require in order to occur?
Intact basement membrane
When does regeneration or fibrous repair take place?
Regeneration= collagen framework
Fibrous repair = collagen framework destroyed, on-going chronic inflammation or necrosis of permanent tissues
How does scar formation progress from minutes to years duration?
Seconds-minutes = haemostasis Minutes-hours = acute inflammation 1-2days = chronic inflammation 3 days = granulation tissue forms 7-10days = early scar weeks - 2 years = scar maturation
What is granulation tissue?
New connective tissue + microscopic blood vessels. Typically goes from the base of a wound upwards
Complex of fibroblasts (collagen deposition and myofibroblasts contract), vascular endothelial cells (angiogenesis) and macrophages (removal of dead tissue debris) within a mix of collagen
What is the function of granulation tissue?
Fills the gap
Capillaries supply oxygen, nutrients and cells
Contracts and closes the hole by myofibroblasts
What occurs in tissue regeneration maturation?
Long lasting process - collagen deposition matures and remodels
Myofibroblasts contract and reduces volume of defect
Vessels differentiate and are reduced if not used
Left with a fibrous scar
Which cells are involved in fibrous repair and what is their function?
Phagocytosis of debris - neutrophils and macrophages
Production of chemical mediators - lymphocytes and macrophages
Endothelial cells - proliferation results in angiogenesis (stable tissue type)
Fibroblasts and myofibroblasts - produce extracellular matrix (collagen), responsible for wound contraction
What are 4 growth factors needed in wound repair/ healing?
1 - epidermal growth factor
2 - vascular endothelial growth factor
3 - platelet derived growth factor
4 - tumour necrosis factor
What is the role of cell-cell and cell-stomal contact in wound repair and healing?
Contact inhibition:
- signalling through adhesion molecules - catherine bind cells together and interns bind cells to the extracellular matrix
- inhibits proliferation in intact tissues, promotes proliferation in damaged tissues
If cells have contact in all directions they sense that the tissue is grown and so no need to grow anymore
What occurs in healing by primary intention?
Epidermis regenerates - basal epidermal cells move 0.5mm/day - > deposition of basement membrane -> fuse in midline beneath scab
Dermis undergoes fibrous repair
What occurs in healing by secondary intention?
Epidermis regenerates - deposition of basement membrane
+
Considerable wound contraction required - 1 week later myofibroblasts appear and contract
Substantial scar formation
New epidermis grows from edges to cover the defect
What is the difference between split thickness and full thickness in skin grafts
Split thickness - above the hair bud follicle
Full thickness - below the hair bud follicle
What is the process of bone healing?
1 - haematoma 2 - granulation tissue forms 3 - soft callus 4 - hard callous 5 - lamellar bone
What 5 local factors influence wound healing?
1 - type, size, location of wound 2 - mechanical stress 3 - blood supply 4 - local infection 5 - foreign bodies
What 8 factors influence wound healing?
1- age 2- anaemia, hypoxia, hypovolaemia 3- obesity 4- diabetes 5- genetic disorders 6- drugs- anticoagulants, antimicrobials, anti-rheumatoid drugs, aspirin, NSAIDs 7- vitamin deficiency 8- malnutrition
What are 5 complications of fibrous repair?
Formation of adhesions - compromising organ function or blocking tubes
Loss of function - replacement of specialised functional parenchymal cells by scar tissue (e.g. MI non-contracting tissue)
Disruption of complex tissue - distortion of architecture interfering with normal function
Overproduction of fibrous scar tissue - keloid scar
Excessive scar contraction - obstruction of tubes, disfiguring scars - fixed flexures
What cell produces platelets in the bone marrow?
Megakaryocytes
What factors cause platelet adhesion?
Damage to vessel wall
Exposure of underlying tissues
Platelets adhere to collagen via vWF/ receptor
What substances to platelets release when they are activated?
ADP
Thromboxane
Serotonin
What are natural anticoagulants?
Antithrombin
Tissue factor pathway inhibition
Antithrombin
Activated protein C and protein S
What causes fibrinolysis?
Plaminogen activator activates plasminogen -> plasmin -> breaks down the fibrin clot -> D-dimers
What clotting factors are in the intrinsic pathway?
VIII, IX, X, XI, XII
What clotting factors are in the extrinsic pathway?
VII
What clotting factors are in the common pathway?
V, X, prothrombin (FII)
How would you measure clotting?
Prothrombin time
Activated partial thromboplastin time
What pathways does prothrombin time measure?
Extrinsic and common pathways
What pathways does activated partial thromboplastin time?
Intrinsic and common pathways
What is the function of von Willebrand factor?
Platelet adhesion to the vessel wall
Platelet aggregation
Carries FVIII
In simple terms how does haemophilia A present and what is the clotting factor that is deficient?
X-linked recessive
Congenital lack of FVIII
Diagnosed pre-natally
Bleeding into muscles and joints and post-operatively
Treatment with recombinant factor VIII or desmopressin
In simple terms how does haemophilia B present and what is the clotting factor that is deficient?
Similar presentation to Haemophilia A
Congenital reduction in factor IX
What is von Willebrand’s disease?
Common autosomal dominant Abnormal platelet adhesion to vessel wall Reduced FVIII amount/ activity Quantitative - not enough produced Qualitative - reduced activity/ function
What is hereditary haemorrhagic telangiectasia?
Congenital autosomal dominant disease
Dilated microvascular swellings increasing with time
Abnormal blood vessel formation in skin, mucous membranes, brain, liver etc
Can form abnormal arteriovenous malformations
What is an acquired vessel wall abnormality causing bleeding?
Senile purpura
Steroids
Infection e.d. measles, meningococcal infection
Scurvy - Vit C deficiency
What is DIC and what the 4 pathways of each outcome?
Pathological activation of coagulation - loss of appropriate localisation/ limitation/ fibrinolysis
Risk of bleeding and thrombosis together
(1) Fibrin formation + (2) inhibited fibrinolysis -> microvascular thrombosis -> organ failure
(3a) - Consumption of haemostatic factors -> reduced anticoagulant effect -> microvascular thrombosis
(3b) - Consumption of haemostatic factors -> reduced clotting factors + platelets ->haemorrhagic tendencies -> bleeding
(4) Fibrinolysis activated -> reduced clotting factors + platelets -> haemorrhagic tendencies -> bleeding
With DIC what are the triggers causing it to happen?
Malignancy Massive tissue injury Infections - gram negative sepsis Massive haemorrhage and transfusion ABO transfusion reaction Obstetric causes - placental abruption, pre-eclampsia, amniotic fluid embolism
What are the components to Virchow’s triad?
Abnormal clotting
Abnormal vessel wall
Abnormal blood flow
What is the appearance of an arterial and venous thrombus?
Arterial: pale, granular, lines of Zahn, lower cell content
Venous: soft, gelatinous, deep red, higher cell content
What are the 3 outcomes of thrombosis and what happens in each stage?
Propagation - progressive spread of thrombosis, distally in arteries, proximally in veins (direction of blood flow)
Organisation - reparative process, fibroblasts and capillaries, lumen remains obstructed - scar tissue forms
Recanalisation - bloodflow re-establised, one or more channels formed through thrombus
Embolism - part breaks off - travels through bloodstream - lodges at distant site
What are the effects of thrombi in arteries and veins?
Arteries: ischaemia, infarction, depends on site and collateral circulation
Veins: congestion, oedema, ischaemia, infarction
Define embolism
Embolism is a blockage of a blood vessel by a soli
What % level of blood flow obstruction is enough to call a massive PE?
> 60% - rapidly fatal
What are the simple constituents of a primary haemostatic plug?
Platelets
Fibrin
What are 4 key steps to clot formation?
1 - initiation
2 - amplification
3 - propagation
4 - termination
What is thrombin time?
Fibrinogen -> fibrin
Raised TT - heparin, fibrinogen deficiency or abnormality
Define atherosclerosis
Accumulation of intracellular and extracellular lipid in the intimacy and media of large and medium sized arteries
The thickening and hardening of arterial walls as a consequence of atherosclerosis
What are 3 macroscopic features of atherosclerosis?
Fatty streak
Simple plaque
Complicated plaque
What is a fatty streak?
Lipid deposits in intima
Yellow, slightly raised
What is a simple plaque?
Raised yellow/ white plaque
Irregular outline
Widely distributed
Enlarge and the coalesce
What is a complicated plaque?
Thrombosis
Haemorrhage into plaque
Calcification
Aneurysm formation - tunica media involved and loss of elasticity
What are early changes that occur in atherosclerosis?
Proliferation of smooth muscle cells - tunica media
Accumulation of foam cells
Extracellular lipid
What are later changes that occur in atherosclerosis?
Fibrosis + Necrosis, Cholesterol clefts + Inflammatory cells
Disruption of internal elastic lamina extending into media
Ingrowth of blood vessels
Plaque fissuring
Why is plaque fissuring a problem in atherosclerosis?
Link between atherosclerosis and thrombosis is through the fibrous cap
The cap will crack or fall off and will expose collage, VWF, tissue factor -> platelet aggregation
What is a clinical effect of atherosclerosis in the peripheries?
Peripheral vascular disease:
Intermittent claudication - pain in the periphery for example calves when exercising that gets gradually worse due to inadequate O2 supply
What is ischaemic rest pain?
Continuous burning pain of the lower leg or feet
Begins or aggrevated after reaching or elevating the limb
Relieved by sitting or standing
More severe than intermittent claudication
What are polymorphisms in the genes affecting Apo E useful for detecting and why?
Polymorphisms can be used as risk markers for atherosclerosis
Genetic variations in Apo E are associated with changes in LDL levels
What 3 signs are indicative of familiar hyperlipidaemia?
Corneal arcus
Tendon xanthoma
Xanthelasma
What are immediate, early and late complications of splenectomy?
Immediate - haemorrhage
Early - Haemorrhage, infection, raised platelets (thrombosis)
Late - Infections - prophylactic Abx
What are the cell cycle steps in mitosis?
G1 , S , G2 , Mitosis + cytokinesis (M phase)
Can leave the cell cycle and enter G0
What are the 2 cell cycle check points?
End of G1 and G2
What is the R point of the cell cycle?
R point= restriction point
This is the most critical checkpoint
Majority of cells will pass R point and complete cell cycle - point of no return
By what process does cell checkpoint activation alter the fate of the cells?
If activated - DNA repair mechanisms OR apoptosis via p53
What is p53?
The protein which leads to tumour suppression - discouraging of cell proliferation
What are cyclins and CDK function in the cell cycle?
Cyclin A,B,D,E
CDK - Cyclin Dependent Kinase
What cyclins and CKD’s are functioning at different points of the cell cycle?
G1 -Cyclin D/ CDK2
S - Cyclin E/CDK2
G2 - Cyclin A/CDK2
M - Cyclin B/CDK1
What is the retinoblastoma protein?
Retinoblastoma is a cancer of the retina - red eye and white eye are seen on pictures
Usually acts to prevent DNA replication - tumour suppressor protein
Most common primary malignancy in children - almost exclusively found in young children
What factors affect cell population?
Balance of cell proliferation and death
Excessive physiological stimulation can become pathological e.g. prostatic hypertrophy
Proto-oncogenes regulate normal cell proliferation
Proliferation stimulated by growth factors, injury, cell death, mechanical deformation of cells
What are the two types of cellular adaptation response?
Adaptations - reversible changes in number/size/phenotype/function
Physiologic - response to normal stimulation by hormones or chemical mediators
Pathologic - response to stress that allow cells to escape injury
How do cells adapt to stress?
Hypertrophy Atrophy Hyperplasia Metaplasia Dysplasia
Define hyperplasia
Increase in tissue or organ size due to increased cell numbers
Which two cell types does hyperplasia occur in?
Labile and stable tissues - constant regrowth and cells not replaced but can increase cell turnover if required respectively
What are two main causes of hyperplasia?
Hormonal - e.g. oestrogen causing endometrial hyperplasia
Compensatory - e.g. following injury
What is the risk with repeated hyperplasia?
Repeated cell divisions expose the cell to risk of mutations and neoplasia
Name an example of pathological and physiological hyperplasia
Pathological - goitre - thyroid disease
Physiological - proliferation in endometrium by oestrogen or bone marrow - erythrocytes - hypoxia
Define hypertrophy
Increase in tissue or organ size due to increased cell size
In which tissues does hypertrophy occur?
All types but especially in permanent (doesn’t have capacity for hyperplasia)
What factors cause hypertrophy?
Increased functional demand or hormonal stimulation
What are 2 examples where physiological hypertrophy occurs
Skeletal muscle
Pregnant uterus
What is an example of pathological hypertrophy
Cardiomegaly due to increased work load of the heart in IHD/ peripheral vascular disease
Urinary bladder hypertrophy
Define atrophy
Shrinkage of a tissue or organ due to an acquired decrease in size and/or number of cells
Why do tissues atrophy?
Shrink to a size where the cell can still try and survive
Which cells die first parenchymal or stromal in atrophy?
Parenchymal because stroma has stem cells inside still that can potentially be used
Name 4 examples of physiological atrophy
Reduced functional demand/workload = atrophy of disuse - reversible with activity
Loss of innevation = denervation atrophy
Inadequate blood supply - thinning of skin on legs with peripheral vascular disease
Inadequate nutrition - wasting of muscles with malnutrition
Name 4 examples of pathological atrophy
Loss of endocrine stimuli - breast, reproductive organs
Persistent injury - polymyositis
Ageing - senile atrophy - brain and heart
Pressure - tissues around an enlarging being tumour (secondary to ischaemia)
Define metaplasia
Reversible change of one differentiated cell type to another
Phenotypic change of the cells
What causes metaplasia?
Stressed cells are replaced by different types - to try to preserve the tissue
Can mucosal tissue become bone tissue in metaplasia?
No
There is no metaplasia across germ layers
What tissue type can metaplasia occur across?
Labile or stable tissue types
Name 2 examples of metaplasia
Bronchial pseudo stratified ciliated epithelium -> stratified squamous epithelium
Stratified squamous epithelium in oesophagus -> glandular epithelium
What is aplasia and what are examples of aplasia?
Pathological failure to completely develop - organ, tissue
Thymic aplasia - infections and auto-immune problems
Aplasia of kidney
Also used to describe organs whose cells have ceased to proliferate e.g. aplasia of bone marrow in aplastic anaemia
What is hypoplasia and what are examples of tissues that may have hypoplasia?
Underdevelopment of incomplete development of tissue or organ at embryonic stage due to inadequate number of cells
Not opposite of hyperplasia as it is a congenital condition
Examples - Renal, Breast, Testicles in Klinefelter’s syndrome, chambers of the heart
What is involution
Overlap with atrophy but normal programmes shrinkage of an organ
Uterus after childbirth, thymus in early life, pro and mesonephros
What is reconstitution?
Replacement of a lost part of the body
What is atresia and give 4 examples?
No orifice
Congenital imperforation of an opening
E.g. pulmonary valve, anus, vagina, small bowel
What is dysplasia and what is a problem with it?
Abnormal maturation of cells within a tissue
Potentially reversible
Often pre-cancerous condition
What is a neoplasm?
Abnormal growth of cells that persists after the initial stimulus is removed
What is a malignant neoplasm?
Abnormal growth of cells that persists after the initial stimulus is removed AND invades surrounding tissue with potential to spread to distant sites
What is a tumour?
A clinically detectable lump or swelling
What are 2 subsections of tumours?
Non-neoplastic
Neoplastic
What are 2 subsections of neoplastic tumours?
Benign
Malignant - Primary or secondary carcinomas
What do neoplasms look like under the microscope in terms of differentiation?
Benign - resemble parent tissue - well differentiated
Malignant - Poorly differentiated
Anaplastic - no resemblance to any tissue
What causes neoplasia?
Accumulated mutations in somatic cells
What is the name given to mutation causers?
Initiators
What is the name given to mutations that induce cell proliferation?
Promoters
What does progression refer to in neoplasia?
A neoplasm emerging from a monoclonal population occurs from a process called progression, characterised by the accumulation of yet more mutations
How do inherited mutations affect progression in neoplasms?
Head start as the tissues already have the initiator required to start the process of neoplasia formation and also promoters. All of the cells in the monoclonal population will have the same features together
What are the two genes that are involved in controlling the cell proliferation into neoplasms?
Proto-oncogene and tumour suppressor gene
How do proto-oncogenes lead to neoplasms?
Proto-oncogenes become oncogenes when they are abnormally activated, favouring neoplasm formation
Only 1 is needed to be altered to lead to neoplasm formation
How do tumour suppressor genes lead to neoplasms?
Tumour suppressor genes normally suppress neoplasm formation become inactivated
These act as a brake to cell proliferation
2 have to be altered to form a neoplasm
What is the nomenclature for benign neoplasms
Benign - ending is oma
What is the nomenclature for malignant neoplasms?
Epithelial origin - carcinoma
Stromal origin - sarcoma
What is a neoplasm referred to if it has penetrated through the basement membrane or not?
Invasion - invasive
No invasion - in-situ
What cell lineage is referred to in leukaemia and lymphoma?
Leukaemia - malignant neoplasm of blood-forming cells arising in the bone marrow
Lymphoma - malignant neoplasm of lymphocytes, mainly affecting lymph nodes
What type of cell is referred to as myeloma?
Malignant neoplasm of plasma cells
What is the name of a neoplasm that originates from the testis/ ovaries?
Germ cell neoplasms
What is the name of the tumour that arises from cells distributed throughout the body?
Neuroendocrine
Why is blastoma used to describe neoplasms?
Occur mainly in children
Formed from immature precursor cells
e.g. nephroblastoma
When is the term adenoma used?
A neoplasm of glandular epithelial origin
What is the term used to describe neoplasms that are putting pressure on the body systems?
Tumour burden
What are the 3 steps for a malignant cell to get from a primary to a secondary site?
1 - grow and invade at the primary site
2 - enter a transport system and lodge at a secondary site
3 - grow at the secondary site to form a new tumour (colonisation)
Why is metastasising of cells difficult?
The whole process is inefficient-
Evasion of the immune system is tough when metastasising
Cells destroyed by the process - unstable cells in general
What 3 alterations are required for invasion?
Adhesion
Stromal proteolysis
Motility
How do malignant cells alter their adhesion?
Cell to cell adhesion - reduction in E-cadherin expression
Cell to matrix adhesion - reduction in Integrin expression
How do malignant cells cause stromal proteolysis?
Altered expression of proteases e.g. Matrix Metalloproteinases
What is epithelial-to-mesenchymal transition?
Adhesion, proteolysis and motility create a carcinoma cell phenotype that sometimes appears more like a mesenchymal cell than an epithelial cell
What are the 3 ways of transport to distant sites via three routes?
1 - blood vessels via capillaries and venules
2 - lymphatic drainage
3 - fluid in body cavities (pleura, peritoneal, pericardial and brain ventricles), Transcoelomic spread
What is colonisation in reference to malignancy?
Secondary sites malignant cells must grow - colonisation
Failed colonisation - greatest barrier to successful metastasis
What are micrometastases?
Surviving microscopic deposits that fail to grow
What is the phenomenon called where a person has many micromets?
Tumour dormancy
What are 3 routes leading to tumour dormancy?
1 - Immune attack
2 - Reduced angiogenesis
3 - Hostile secondary site
What determines the site of a secondary tumour?
1 - regional drainage of blood, lymph or coelomic fluid
2 - ‘seed and soil’ phenomenon
What is a cancer niche?
Malignant cells take advantage of nearby non-neoplastic cells which together form a cancer niche
How do carcinomas and sarcomas typically spread?
Carcinomas -> first to draining lymph nodes -> blood-borne distant sites
Sarcomas -> blood stream
What are effects of neoplasms?
Direct local effects = primary neoplasm and secondary neoplasm
Indirect systemic effects = increasing tumour burden - secreted hormones + things that will affect conginition/ personality e.g. in brain tumours
What is a paraneoplastic syndrome?
Side effects of a cancer when the immune system starts attacking normal cells
For benign neoplasms, local effects from the primary and hormonal effects
What are local effects of primary and secondary neoplasms?
1 - direct invasion and destruction of normal tissue
2 - ulceration (discontinuity or break in a membrane) at a surface leading to bleeding
3 - compression of adjacent structures
4 - blocking tubes and orifices
What are systemic effects of neoplasms?
Sarcopenia - loss of muscle mass
Reduced appetite and weight loss (cachexia), malaise, immunosuppression (direct bone marrow destruction), thrombosis (platelet aggregation)
What are 2 ways of carcinogenesis?
Intrinsic factors - heredity, age, sex (hormonal)
Extrinsic factors - environment and behaviour
What are the 5 leading behavioural and dietary risks for neoplasm?
High BMI Low fruit and veg intake Lack of physical activity Tobacco use Alcohol use
What are the 3 categories of extrinsic carcinogens?
Chemicals,
Radiation
Infections
What is a risk of industrial dyes in carcinogenesis?
2-napthylamine an industrial carcinogen used in the dye manufacturing industry -> bladder cancer
What is the effect of tropisms in carcinogenesis?
Certain carcinogens have a tropism where they predominantly affect certain parts of the body
What 3 factors increase the risk of getting a malignant neoplasm caused by a carcinogen?
1 - Long delay between carcinogen exposure and malignant neoplasm onset
2 - Risk of cancer depends on total carcinogen dosage
3 - Organ specificity for particular carcinogens
What is a pro-carcinogen?
Pro-carcinogen -CYP450-> carcinogen
Non-carcinogenic till metabolised
What are carcinogens that act as both initiators and promoters called?
Complete carcinogens e.g. cigarette smoke
What type of radiation is bad for us and why is ultrasound not mutagenic?
Ionising is bad for us
Ionising and non-ionising radiation
Ionising - Radon, medical test
Non-ionising radiation - UV, Ultrasound
What infection is carcinogenic and relies upon mutations in the tumour suppressor genes?
Direct carcinogen
Human papilloma virus - cervical carcinoma link
E6 and E7 proteins that inhibit p53 and pRB - mutated
What malfunctioning proteins cause an increases in cervical cancer risk ?
E6 and E7 proteins are produced by the virus but they also inhibit p53 and pRB
Through what basic mechanism does hepatitis B virus infection cause cancer?
Indirect cause
HBV causes chronic inflammation and regeneration
The chronic inflammation itself leads to mutations
What is the 2 hit hypothesis?
For example: first hit delivered through germline in familial cancers and affected all the cells in the body
Second hit is a somatic mutation in one of the cells already having a mutation
The two hits refers to the tumour suppressor genes - both are required to be mutated
Why if a child has retinoblastoma cancer would it be bilateral and in an adult it would likely be unilateral?
Bilateral as this is genetic and all the cells would have a mutation - inherited pattern
Unilateral in adults because this mutation occurred after birth and so only one cell is required to have the mutation in an eye
What is RAS in pathology?
Human oncogene -> mutated in 1/3 of all malignant neoplasms
RAS proto-oncogene encodes a small G protein that relays to the cell to put it past the restriction point in the cell cycle
What type of repair is defective in Xeroderma pigmentosa?
Nucleotide excision repair
Skin is very sensitive to UV damage - develop skin cancer at young age
What type of repair is defective in Hereditary non-polyposis colon cancer (HNPCC)?
Mismatch repair
Autosomal dominant
Germ line mutation
What type of repair is defective in BRCA1 or 2?
Double stranded breaks
BRCA1/2 - tumour suppressor proteins
Why does genetic instability occur in malignant neoplasms?
Chromosome segregation is abnormal
+ whatever the original problem/ mutation = accelerated mutation rate = genetic instability
What are the genes that maintain genetic stability called?
Caretaker genes - class of tumour suppressor gene
Describe the term cancer progression?
Step-wise accumulation of mutations that is steadily increase
What are 6 hallmarks of cancer?
1 - self-sufficiency in growth signals
2 - resistance to growth stop signals
3 - no limit on the number of times a cell can divide
4 - sustained ability to induce new blood vessels
5 - resistance to apoptosis
6 - the ability to invade and produce mets
How do we stage lymphoma?
Ann Arbour staging 1 - 4 depending on diaphragm nodes
Stage 1 - single node region
S2 - two separate regions on one side of the diaphragm
S3 - Spread to both sides of the diaphragm
S4 - Diffuse or disseminated involvement of one or more extra-lymphatic organs
How do we stage colon cancer?
Dukes staging A-D Depending on depth through GI wall, lymph nodes and mets A - Invasion but not through the bowel B - invasion through the bowel wall C - Involvement of lymph nodes D - Distant mets
How do we stage breast cancer?
Richardson
Grading 1-3 depending on tubule involvement, mitoses, nuclear pleomorphism
What is adjuvant therapy?
Treatment given after surgical resection of a primary tumour to eliminate subclinical disease
What is neoadjuvant therapy?
Treatment given before surgery to reduce the size of a primary tumour
In what phase of the cell cycle does radiotherapy best kill rapidly dividing cells?
G2 phase
What is the principal of giving fractional radiotherapy rather than one big dose?
The smaller doses allows normal tissues to recover and but the cancer won’t be able to recover as quickly
Over time the multiple smaller doses is more effective at removing more cells than one big dose
What are the 4 main ways of chemotherapy treatment?
1 - antimetabolites = mimic normal substrates in DNA replication - Fluouracil
2 - Alkylating and platinum based = cross-link the DNA strands together - Cyclophosphamide and Cisplatin
3 - Antibiotics = Inhibit DNA topoisomerase - Doxorubicin or Double-stranded DNA breaks - Bleomycin
4 - Plant-derived = Block microtubule assembly and interfere with mitotic spindle formation - Vincristine
Give an example of hormone based treatment for malignant tumours?
Selective oestrogen receptor modulators - Tamoxifen
Bind to oestrogen receptors - preventing oestrogen binding
TX hormone receptor positive breast cancer
Androgen blockade is used for prostate cancer
How does transtuzumab work?
HER-2 gene -> HER-2 receptor blocking by drug
1/4 of all breast cancers have gross over-expression of HER-2 receptors
How does Imatinib work?
CML shows chromosomal re-arrangement creating an abnormal chromosome in which an oncogenic fusion protein is encoded (BCR-ABL).
Imatinib inhibits this fusion protein
How do nivolumab and ipilimumab work?
Immune checkpoint blockers
Ipilimumab - priming and activation of APC’s and T-cells
Nivolumab - enhances killing of cancer cells by immune system
What hormone is released by testicular tumours that can be tested for?
Human Chorionic Gonadotrophin
What are tumour markers useful for?
Monitoring tumour burden during treatment and follow up
What oncofoetal antigen is released by hepatocellular carcinoma?
Alpha fetoprotein
What specific protein is released in prostate tumours?
Prostate-specific antigen
What is released by ovarian cancer?
Mucin/ glycoprotein CA-125
When are free radicals produced the most?
Chemical and radiation injury
Ischaemia-reperfusion injury
Cellular ageing
High oxygen concentrations
What are the 3 free radicals of importance?
OH- (hydroxyl - most dangerous)
O2- (superoxide)
H2O2 (hydrogen peroxide)
What 3 enzymes remove free radicals
Catalases
Superoxide dismutase
Peroxidases
What is the term used to describe the maximum number of divisions of a cell?
Replicative senescence
Which area of the liver lobule is most susceptible to paracetamol damage and what CYP enzyme breaks it down?
Zone 3
CYP2E1
What is a basic difference between apoptosis and necrosis in terms of local microscopic changes seen?
Apoptosis - no inflammation, single cell dying, intact plasma membrane, apoptotic bodies seen
Necrosis - cells swell before dying but apoptosis shrink only
What do opsonins do?
Coat foreign materials and make them easy to phagocytose
What is complement?
A group of proteins that are assembled locally to produce a bacteria-perforating structure
What are the two subtypes of exudate?
Serous exudate and fibrous exudate
What is serous exudate?
Plasma proteins mostly
Few leucocytes - suggesting no infection by micro-organisms
Clear (no colour)
Contain proteins - no fibrinogen
What is fibrinous exudate?
Significant deposition of fibrin (i.e. a blood clot without RBC)
Fibrin deposited in the space e.g. pleural/ pericardial
What cancer are eosinophils most abundantly present?
Hodgkin’s lymphoma
Why are myofibroblasts bad in hepatic cirrhosis?
Contraction of cirrhotic liver impairs blood flow of portal blood resulting in ascites
What are 2 subcategories of granulomas?
Foreign body granuloma
Hypersensitivity of immune type granuloma
What is sarcoidosis?
A disease with unknown cause in which granulomas are seen in organs throughout the body
Apart from sarcoidosis which gastric condition also produces granulomas?
Crohn’s disease
What cells are primarily seen in rheumatoid arthritis?
Lymphocytes, macrophages and plasma cells
What factors contribute to cellular regeneration in simple terms?
Growth factors in the microenvironment
Cell - to - cell communication
Electric currents and nervous stimuli
What is asymmetric replication?
One daughter cell remains as a stem cell that is totipotent
What nerves can regenerate?
Peripheral nerves
CNS can not regenerate
What muscle type has good regenerative capacity?
Smooth muscle
Striated muscle is limited
How do striated muscle’s regenerate?
From satellite cells - muscle stem cells
What epithelia are exceptions to having very good regenerative capacity?
Lens of the eye
Renal podocytes
What is alport syndrome?
X - linked disease
Type IV collagen abnormal
Glomerular basement membrane, cochlea of the ear and lens of the eye dysfunction
What is autocrine cell communication?
Cells respond to signalling molecules they produced themselves
What is paracrine communication?
Cell produces signalling molecules hat act on adjacent cells
Cells responding are close in proximity but different type
What growth factors are important in wound healing?
Epidermal growth factor - mitogenic for epithelial cells, fibroblasts
Vascular endothelial growth factor - potent inducer of blood vessel development
Platelet derived growth factor - migration and proliferation of fibroblasts
Tumour necrosis factor - induces fibroblast migration proliferation and collagenase secretion
In basics what is the difference between a hypertrophic and a keloid scar?
Hypertrophic stays within the bounds of the damage and can regress over time. A keloid scar is the opposite.
In basics what are the 3 stages of haemostasis?
1 - severed artery contacts enough to slow bleeding, veins don’t contract but pressure is much lower
2 - primary haemostat plug of activated platelets forms at the hole in the vessel - seconds to minutes
3 - secondary haemostatic plug forms as fibrin filaments stabilise the platelet plug - 30minutes approx
What is clot retraction?
Actin and myosin filaments within the platelets contract as the platelets die. Clot retraction then pulls the ends of the wound closer together toughening the clot
What activates the function of plasmin?
Tissue plasminogen factor
Why is streptokinase only given once?
Antigenic - formation of antibodies against the drug - risk of immune reaction
What sets fibrinolysis in motion?
Clotting cascade
As the clotting cascade develops further and further the more the fibrinolysis is activated
Why is surgery risky for 7-10days thromboembolism?
Fibrinolytic activity drops and remains low for 7-10 days post surgery - time period coincides with increase risk of post-op thrombosis
What happens to PT and APTT in thrombocytopenia?
Normal as these are clotting cascade function and not platelet function
How would you describe the bleeding pattern seen in thrombocytopenia?
Petechial
What are the 4 classes of causes of thrombocytopenia?
Decreased production
Decreased platelet survival
Sequestration
Dilutional
What are a few examples of causes of decreased platelet production?
Bone marrow infiltrates by malignancy
Drugs
Infections
B12 and folate deficiency
What are a few examples of causes of decreased platelet survival?
Immunologic destruction - Immune thrombocytopenic purpura (ITP)
Non-immunologic destruction - Disseminated Intravascular Coagulopathy (DIC)
What would cause an increased sequestration of platelets?
Enlarged spleen
What is DIC?
Thrombohaemorrhagic disorder occurring as a secondary complication in a variety of conditions
Activator of clotting -> microthrombi formed -> platelets, fibrin, coagulation factors consumed + fibrinolysis activated too -> haemorrhage
What are the causes of DIC?
Sepsis - gram negative - endotoxin produced which activates the clotting cascade
Severe trauma - especially in brain - large amounts of thromboplastin
Extensive burns
Complications of childbirth -> amniotic fluid embolism, retained dead foetus
Malignancy
Snake bite
What is the treatment of DIC?
Treat the cause
Transfusion of platelets, fresh frozen plasma, cryoprecipitates, RBC
Heparin if excess clots
What is the term used to describe anaemia in DIC?
Microangiopathic haemolytic anaemia
What is the difference seen in the location of thrombi in the arterial and venous system?
Arterial - site of endothelial damage
Venous - areas of stasis
Do all 3 factors of Virchow’s triad need to be factors in thrombosis
No - only 2 factors are needed
What effect does smoking have on clotting?
Activates factor 12
What is thrombophlebitis?
Pain when superficial thrombi form and cause associated inflammation in the wall of the vein
What is a thrombus on a cardiac valve called?
Vegetation
Why are thrombi more common on the left heart?
Exposure to greater pressures and therefore micro trauma - exposure to thrombogenic sub endothelial tissues
Can embolisation occur in veins?
No - blood flow is slower as it goes from smaller to larger vessels
What is a paradoxical embolus?
Thromboemboli that form in the systemic veins but embolise to the systemic arteries
How do paradoxical emboli by-pass the lungs?
1 - small emboli pass through arteriovenous anastomoses in pulmonary circulation (also a way that fat droplets pass through the lungs)
2 - larger emboli can only enter the systemic circulation by passing through defects in the interventricular septum or a patent foramen ovale during coughing, lifting or straining
Why does coughing, lifting or straining increase the risk of emboli passing through defects in the heart from R -> L heart?
Increased pressure in R heart ≥ L heart pushing thrombus through the defect
What is the most common emboli that causes TIA?
Atheroemboli - coming from carotid arteries
Which process can increase the chance of an air emboli?
Labour - air enters the uterus and forced into open veins during uterine contractions
What procedures increase the risk of fat/ bone marrow emboli?
Long bone fractures
Liposuction
How do fat emboli cause death?
Fat droplets coalesce over few days -> sucked into gaping veins that have been torn by a fracture
What are the most common locations of a thrombi occurring that cause a PE?
Veins of the thigh and the popliteal vein
What causes gas emboli?
Trauma to neck/ chest
Negative pressure in veins during inspiration -> Air enters veins -> frothy mass stops circulation
Labour
What causes the bends?
Underwater diver is under high pressure -> nitrogen dissolves in body fluids and tissues
If diver surfaces too quickly -> gases come out of solution -> bubbles distort tissues -> emboli in blood.
Nitrogen is highly fat soluble -> persistent bubbles and focal ischaemia in lipid-rich tissues i.e. CNS.
+ skeletal muscle, joints, lungs.
What are potential sequelae with an amniotic embolus?
Causes sudden respiratory distress, hypotension, seizures, loss of consciousness and DIC
Define arteriosclerosis
Hardening of the arteries
Arteries are thickened and lose their elasticity
Define arteriolosclerosis
Hardening of the arterioles
Affects all arterioles but particularly the arterioles of the kidneys
Little to no connection with atherosclerosis and usually occurs secondary to severe HTN or in DM
By what 3 mechanisms does the endothelium prevent thrombosis?
Prostacyclin production
Thrombomodulin production
Expression of heparin-like molecules
What is the most common type of cancer to form in the bowel?
Adenocarcinoma
What is the most common type of cancer to form in the skin?
Squamous cell carcinoma, malignant melanoma, basal cell carcinoma
What is the most common type of cancer to form in the lung?
Adenocarcinoma, squamous cell carcinoma, small cell carcinoma
What is the most common type of cancer to form in the Breast?
Adenocarcinoma
What is the most common type of cancer to form in the prostate?
Adenocarcinoma
What is the most common type of cancer to form in the Pancreas?
Adenocarcinoma
What is the most common type of cancer to form in the brain?
Astrocytoma
What is the most common type of cancer to form in the uterus
adenocarcinoma
What is the most common type of cancer to form in the oesophagus
squamous cell carcinoma, adenocarcinoma
What is the most common type of cancer to form in the stomach
adenocarcinoma
What is the most common type of cancer to form in the thyroid
adenocarcinoma
What is the most common type of cancer to form in the cervix
squamous cell carcinoma
Adenocarcinoma
What is the most common type of cancer to form in the bladder
transitional cell carcinoma
Why can patients get Zollinger-Ellison syndrome from a pancreatic and gastric tumour?
Production of excess gastrin causes excess acid production
Why can patients get carcinoid syndrome?
Metastatic cancer
e.g. Liver mets
Excess production of serotonin and other products which can be detected in the blood and urine
Symptoms of flushing, abdo pain, diarrhoea, nausea and vomiting
In the resp system what are the different classifications of neuroendocrine tumours?
Low grade malignant (typical and atypical carcinoids)
High grade carcinomas (large cell neuroendocrine and small cell lung carcinomas)
Presence of necrosis and mitotic activity
What cancer causes pepper pot skull and also what is the type of lesion present?
Myeloma
Osteolytic lesion
What primary cancer can metastasise to the bone and what type lesion do they cause?
Prostate, breast, transitional cell carcinoma, small cell lung
Sclerotic lesion
What is the difference between lytic and sclerosing metastasis?
Lytic - destroys bone
Sclerotic - builds bone as part of the mets as a protective process
What are the layers of the skin?
Stratum corneum -> lucid -> granulosum -> spinosum -> basale
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What is the clinical and pathological features of familial adenomatous polyposis?
Polyps along the whole colon that can become malignant
Tubular adenomas - most common - adenocarcinomas
APC gene which is a tumour suppressor gene is defective
Autosomal dominant
What is the adenoma-carcinoma sequence?
Stepwise accumulation of mutations both oncogenes and tumour suppressor genes
What is pagets disease of the bone?
Interference in the bone remodelling process - osteoclasts are more active than osteoblasts
New bone laid down is of poorer quality and more brittle
Predisposes to fractures
What type of tumour is most common in the testis and which is likely to be in a young adult?
Most common - seminoma and non-seminomatous
Germ cell tumour most likely as young adult
