B2 Flashcards
Define thrombosis
A pathological process which denotes the formation of a blood clot in intact vessels due to inappropriate activation of normal haemostatic process
State the cause of thrombosis
VIRCHOW’s TRIAD :
I) Endothelial injury
- over loss of endothelium exposes subendothelial ECM —> leads to platelet adhesion , release of tissue factor ( factor III , procoagulant ) and reduces local production of PGI2 ( anticoagulant ) and plasminogen activators ( anticoagulants )
- may be induced by hypertension, bacterial products , radiation injury , hypercholesterolemia, homocystinuria , toxins of cigarette smoke.
2) Abnormal blood flow
-turbulence contributes to arterial & cardiac thrombosis by causing endothelial injury or dysfunction
- stasis contributes to development of venous thrombi
- How?
I) turbulence & stasis promotes endothelial cell activation & enhanced procoagulant activity by altering endothelial gene expression
II) stasis allows platelets & WBC to come into contact with endothelium when the flow is sluggish
III) stasis also prevents washout of activated clotting factors & inhibits inflow of clotting factor inhibitors
- example : hyperviscosity syndromes eg polycythemia; sickle cell anemia which cause vascular occlusion resulting in stasis
3) Hypercoagulability
- defined as the alteration of coagulation pathways that predispose affected person to thrombosis
- may be genetic ( example : Factor V mutation , prothrombin gene mutation ) or acquired ( oral contraceptive use , hyperestrogenic state of pregnancy , tumors , smoking & obesity )
Describe the Pathogenesis of arterial & venous thrombosis
Arterial
- due to formation of atheromatous plaque on the intimal surface of any artery —>enlarges —> protrudes into lumen —> causes turbulence in blood flow & loss of intimal endothelial cells ->exposure to subendothelial ECM —> cause fibrin deposition & platelet clumping with RBCs —> thrombus formation
Venous
- occurs at valves which protrude into the vessel lumen & produces a degree of turbulence
- veins can get damaged by trauma , stasis & occlusion
- coralline / laminated growths are seen
Atheromatous —> accumulation of macrophages ( foam cells ) , lipids , debris , calcium and CT
Venous thrombosis are more serious than arterial thrombosis as they can embolize & leads to ( ……………..)
Venous thrombosis are more serious than arterial thrombosis as they can embolize & leads to ( pulmonary infarction & death (pulmonary embolism) )
Compare and contrast arterial & venous thrombosis
Arterial thrombosis
- formed in areas of active blood flow
- caused by atherosclerosis & turbulent blood flow
- appearance : alternating lighter layers of platelets & fibrins with darker red cell rich layer
Venous thrombosis
- formed in areas of sluggish / static blood flow
- caused by venous stasis
- appear dark-red with greater concentration of red cells
- Ill-defined laminations (lines of Zahn )
: lines of Zahn
—> pale : platelets
—> dark red : fibrin , RBCs , Leucocytes
Describe the possible fates of thrombus
1) Propagation
- thrombus grows in size —> expand to obstruct the entire lumen
2) Embolization
- thrombus dislodges to distal sites in the vasculature & form embolus
- arterial thrombus leads to systemic embolism
- venous thrombus leads to pulmonary embolism ( most dangerous )
3) Dissolution
- thrombi is removed by fibrolytic activity , typically occurring within the first day or two
- as the thrombi ages , it becomes more resistant to fibrinolysis due to continued polymerisation
4) Recanalization
- older thrombi get organised by ingrowth of endothelial cells , SMC & fibroblast
- capillary channels form within the old thrombi, creating conduits along the length of the thrombus & reestablishing the continuity of the original lumen .
Describe the clinical effects of thrombi
1) Obstruct arteries & veins
2) Acts as possible source of emboli ( others bring amniotic fluid , gases & fat )
Arterial thrombi
- can embolize & cause tissue infarction
- can also obstruct critical vessels (eg : coronary & cerebral )
Venous thrombi
- most occur in the superficial or deep veins of the leg
- leads to local congestion & swelling predisposing the overlying skin to infection & ulcers
- deep venous thromboses ( DVTs) occur in the larger leg veins above the knee joints ( eg : popliteal, femoral & iliac veins ) — more prone to embolize
- may embolize to lung & cause death ( pulmonary embolism )
Define the term embolus
An embolus is a detached , intravascular solid , liquid or gaseous mass that is carried by blood to a site distant from the point of origin.
Describe thromboembolism ( aetiopathogenesis , clinical effects , consequences )
- may be pulmonary or systemic
Pulmonary thromboembolism’s
I) aetiopathogenesis
- commonly ( 95%) originate from the deep vein of the leg ( DVT ) proximal to the popliteal fossa -> travel to right side of heart —> lodge in main truck of pulmonary artery or the bifurcation of pulmonary arteries ( saddle embolus ) —> pulmonary infarct & death
II) significance
- most emboli are small —> get reorganized
- if >60% pulmonary circulation is blocked , right heart failure & sudden death will occur
- emboli obstruction of medium sized arteries leads to haemorrhage due to anoxia , but will not cause infarction due to dual bronchial circulation
- multiple small emboli can cause pulmonary hypertension with right heart failure ( Cor pulmonale)
II) systemic
- commonly arise from intracardiac mural thrombi ( 80% ) , aortic aneurysm , fragmented valvular vegetations, thrombi overlying ulcerated atherosclerotic plaques ( basically in the arteries )
- lodges anywhere in blood circulation eg lower extremities (75%) , CNS ( 10%) , organs — whereas venous emboli typically lodge in the lungs
Describe air/gas embolisms
I) Aetiopathogenesis
- may be caused by IV infusion of air bubbles , chest wall injuries , obstetric or laparoscopic procedures
- causes gas bubbles to form in the circulation —> coalesce to form frothy masses to obstruct vascular flow
- Examples :
I) Decompression sickness / the bends —> in areas of great pressure examples : underwater , gases dissolved in tissue & fluid . Upon rapid resurfacing , gases expand in the tissue & bubbles out of the solution in the blood to form gas emboli which can lead to tissue ischemia ;
II) Caissons disease —> more chronic form of decompression sickness —> persistence of gas emboli in skeletal system leads to multiple foci of ischemic necrosis , common sites are the femoral heads , tibia & humeri.
Describe amniotic fluid embolism
I) Aetiopathogenesis
- A complication of labor & immediate post-partum period
- ruptured uterine vessels or placental membrane —> causes amniotic fluid to enter into maternal circulation
II) Clinical signs & symptoms
- dyspnoea , cyanosis , seizure , shock & coma
- pulmonary edema & DIC may occur after due to release of thrombogenic substances in amniotic fluid
- diffuse alveolar damage occur later
- squamous cells , hair , fat and mucin may be found in maternal circulation
Describe fat embolism & fat embolism syndrome ( aetiopathogenesis , clinical symptoms )
I) Aetiopathogenesis
- due to trauma to long bones ( eg : vigorous CPR ) , soft tissue crush trauma & burns
- cause release of microscopic fat globules into blood vessels —> leads to mechanical obstruction & biochemical injury of endothelium ( fat embolism syndrome )
I) Mechanical obstruction
- due to presence of fat emboli itself & also associated RBC & platelet aggregation , causing the occlusion of cerebral & pumonary microvasculature
II) biochemical injury
- due to release of fatty acids —> cause local toxic injury to endothelium
- platelet aggregation & granulocytes recruitment ( with release to proteases , ROS & eicosanoids ) —> futher damaged to vascularity.
** usually fat embolism ( 90% ) are cleared away with little clinical manifestations but 10% develop fat embolism syndrome
II) Clinical symptoms
- anemia due to increase in phosphatidase A enzyme & RBC aggregation
- thrombocytopenia
- neurological symptoms
Define infarction
An area of ischemic necrosis caused by occlusion of either arterial supply or venous drainage in a particular tissue
State the causes of infarcts
1) Thromboembolism’s ( 99%)
2) Tumors causing compression of a vessel
3) Twisting of vessel
- eg : testicular , ovarian torsion , bowel volvulus
4) Local vasospams
State the classification of infarcts
1) Based on Color
I) red infarcts
II) white infarcts
2) Based on presence of microorganism
I) bland - No m/o
II) septic - m/o present
Red infarcts commonly occur in :
I) ( …………..)
II) (………….)
III) (…….)
White infarcts commonly occur in :
I) (…………….)
Red infarcts commonly occur in :
I) ( venous occlusion ( testicular , ovarian torsions ) )
II) ( loose tissue ( lungs ) , in which blood can collect in infarcted zones )
III) ( tissue with dual circulation ( lungs , SI ) )
White infarcts commonly occur in :
I) ( arterial occlusion in solid organs ( heart , kidney , spleen ) in which the tissue density limits the seepage of blood from adjacent patent vascular beds )
Describe the morphology of an infarct
( applies to both red and white infarct )
1) Gross
- wedges shape with the occluded vessel located at the apex and serosal surface of the organ forming the base.
- serosal surface may have overlying fibrinous exudates
- margins of the infarct defined by a narrow rim of hyperaemia
2) Histological
- coagulative necrosis
- areas of inflammation ( IF cells , edema ) followed by tissue repair ( granulation tissue ) which is ultimately replaced by scar tissue
- neutrophils present within 12 hrs, followed by macrophages within 3 days then fibroblasts & scar tissue formation by 1st week
- in brain it is liquefactive necrosis
Describe the factor that influence infarct development
1) Nature of blood supply to the organ
- organs with dual blood supply are less susceptible to infarcts ( lungs , pulmonary & bronchial arteries ; liver hepatic artery & portal vein; hand & forearm , radial & ulnar arteries )
2) Rate of occlusion
- slowly developing occlusion are less likely to cause infarction as there is enough time for development of collateral blood supplies
- example : small interarteriolar anastamoses that interconnect the 3 major coronary arteries, if 1 major artery is slowly occluded ( eg : encroaching atherosclerosis plaque ) , blood flows is increased in the collateral sufficient to prevent infarction
3) Vulnerability of tissue to ischemia
- how long the tissue can withstand a lack of blood supply
- neurons —> more susceptible to infarction when deprived of blood supply ( 3-4 min )
- myocardial cells - die after 20-30 mins of ishchemia
- fibroblasts within myocardium — remains viable after many hours of ischemia
4) O2 content of blood
- conditions like cyanosis , hypoxia , anemia increases likelihood of infarction , especially if blood flow is occluded.
Define shock
A state of systemic tissue hypoperfusion resulting from decreased cardiac output and or decreased effective circulating blood volume
Classify the types of shock
1) Hypovolemic
- due to decrease blood or plasma volume
- ex: massive haemorrhage , burns , vomiting , diarrhea
2) Cardiogenic
- due to decreased cardiac output
- ex: myocardial infarction , cardiac tamponade , cardiac arrhythmia , pulmonary embolism
3) Septic
- sepsis cause the massive outpouring of inflammatory mediators
- systemic vasodilation and pooling of the blood is seen
- flushing of the skin is seen — in all other forms of shock vasoconstriction ( pallor ) is seen so as to preserve blood supply to vital organs.
- ex: bacterial infections
4) Neurogenic
- loss of vascular tone
- due to anaesthesia, spinal cord injury
5) Anaphylactic
- due by IgE mediated hypersensitivity reactions
- causes systemic vasodilation & increased vascular permaebility
Describe the pathogensis of shock
1) Initial , non progressive stage
- reflex compensatory (neurohormonal ) mechanism are activated to increase BV & BP ( eg baroreceptor reflex, ADH release , sympathetic stimulation, release of catecholamine, activation of RAAS system )
- blood is routed to vital organs ( brain , kidneys , heart )
- net effect : tachycardia, peripheral vasoconstriction leading to pallor , renal conservation of fluid
2) Progressive stage
- tissue experience significant hypoxia —> ATP depletion —> anaerobic respiration takes over —> lactic acid buildup —> pH of blood decrease & impairs vasomotor responses —> causes vasodilation & pooling of the blood
- this leads to decreased effective circulatory blood volume & favours anoxic injury to endothelial cells , leading to DIC
- can be reversed by proper treatment
- effects : oliguria , mental confusion
3) Irreversible stage
- occurs following severe cellular & tissue injury
- death usually occur even if hemodynamic defects are corrected
- widespread cell injury —> leakage of lysozymes leads to necrosis —> multi organ failure
Describe the organ changes in shock ( morphology )
** hypoxic tissue injury is seen due to lack of perfusion to tissue
1) Kidney
- gross :
I) Cortex : enlarged , pale & widened
II) medulla : red congested & cyanotic
iii) Corticosteroids-medullary junction : well defined
- histology : necrosis of tubular epithelial cell are seen ( ischemic acute tubular necrosis )
2) Brain
- gross :
I) overall it become enlarged , swollen , with muddy discolouration
II) Gyri are widened , sulci are narrowed
III) demarcation between gray & white matter are I’ll defined in cut section
3) Heart
- subendothelial haemorrhage & necrosis is seen
4) Lungs
- gross : heavy , firm , red , boggy
- histology : accumulation of pale pink fluid in alveolar space , fibrin deposition , presence of alveolar hyaline membrane ( composed of fibrin & necrotic epithelial cells )
5) Adrenal gland
- cortical cell lipid depletion
6) GIT
- Petechial haemorrhage on serosal surface is seen
Define edema
Abnormal accumulation of fluid in the tissue space (edema ) or body cavities ( effusion )
Describe the Pathogenesis of edema
4 reasons :
1) Due to increased hydrostatic pressure
- results from impaired venous return (CCF , constrictive pericarditis , venous thrombosis , lower extremity inactivity ) and arteriolar dilation ( heat , neurohumoral dysregulation )
- for ex : in CCF , CO is reduced —> renal hypoperfusion —> RAAS system activated to increase salt & H2O retention —> but CO does not increase to compensate for extra blood volume in CCF —> lead to severe edema
2) Due to decreased colloidal oncotic ( osmotic ) pressure
- plasma proteins ( albumin ) responsible for colloidal oncotic pressure
- loss of plasma protein eg : glomerulopathies , malnutrition , liver cirrhosis , protein-losing gastroenteropathy leads to edema
3) Due to decreased lymphatic drainage
- lymphoedema occur due to localised obstruction of lymphatic drainage which can be caused by neoplasia , inflammation or radiation therapy
4) Due to salt & H2O retention
- excessive retention of salt by activation of RAAS system leads to edema as hydrostatic pressure in vessel increase ( due to increased BV ) and also reduced plasma oncotic pressure
- sodium retention occurs in scenarios like m renal hypoperfusion ( activates RAAS system ) , excessive salt intake with renal insufficiency , increased tubular reabsorption of sodium
Classify edema
Local edema
1) Acute inflammatory edema
2) Hypersensitivity (allergic ) edema
3) Edema of venous obstruction
4) Lymphatic edema
Generalised edema
1) Cardiac edema
2) Renal edema
3) Nutritional edema
4) Hepatic edema
Describe the clinical features of renal edema & its possible causes
1) Periorbital edema
2) Pitting edema
Causes
1) Acute chronic glomerulonephritis
2) Nephrotic syndrome
Describe the causes & morphology of pulmonary edema
Causes
- left ventricular failure
- renal failure
- ARDS
- Pulmonary infection
- Hypersensitivity reaction
Morphology - Gross : I) lungs 2-3 times larger II) edema confined to lower lobes III) upon section , escape of frothy , serosanguinous fluid presenting a mixture of air , edema fluid & extravasated red cells
- Histology :
I) accumulation of fluid about the septal arteries with widening of septa
II) granular pink coagulate ( proteinaceous fluid ) within the alveolar spaces
Papilledema refers to the swelling of the ( ………. )
It is a sign of increased ( ……….. )
(………… ) problem may arise , including ( ………………………………………………………………..)
Papilledema refers to the swelling of the ( optic disc )
It is a sign of increased ( intracranial pressure )
( Vision )problem may arise , including ( short flickers of gray vision , blurred or double vision , decreased FOV or ability to see colors )
Describe the morphology of cerebral edema
Gross
- wide gyri with flattened surface
- narrow sulci
- on section , white matter may appear soft & gelatinous
- on section , peripheral gray matter is also widened
- On section , ventricles are compressed
In cardiac edema , the most common cause is ( ……………………. )
It is characterised by ( ………………………………………………………………………………………………… )
In cardiac edema , the most common cause is ( congestive heart failure )
It is characterised by ( dependent edema , which is the accumulation of edema in the subcutaneous tissue of the lower parts of the body also sacral edema )
Compare and contrast exudate and transudate
Exudate
- Oedema associated with increased vascular permaebility
- Inflammatory edema
- High protein content ( > 4g/dl ) , has high fibrinogen
- high specific gravity
- > 7.3 pH
- High LDH
- Highly cellular ; rich in polymorphs
- pus seen in pyogenic infections
Transudate - Filtrate of blood of plasma ; no increased in permaebility - Non - inflammatory edema - Low protein content , mainly albumin - <7.3pH - Low LDH X Few cells , mainly mesothelioma cells - Fluid in congestive cardiac failure
Define amyloidosis
A condition associated with a number of hereditary and inflammatory disease in which extracellular deposits of fibrillation proteins are responsible for tissue damage and functional compromise
Describe the Pathogenesis of amyloidosis
- results from the misfolding of proteins , causing them to become insoluble , aggregate and deposit as fibrils in the extracellular tissue
- they can be normal proteins that have an inherent tendency to misfold OR mutant proteins that are prone to misfolding & subsequent aggregation
- normally , misfolded proteins are degraded intracellular lay in proteosome or extracellular lay by macrophages
State the classification of amyloidosis with their associated amyloid proteins & associated disease
Describe the non-specific and organ specific ( kidney , heart ,GIT , BV ) clinical manifestations of amyloidosis
Non specific
- weakness , weight loss , light-headedness & syncope
Organ specific
1) Kidney
- proteinuria , nephrotic syndrome , renal failure & uremia
2) Heart
- present as restrictive cardiomyopathy or conduction disturbance ( leads to arrhythmia )
3) GIT
- may be asymptomatic
- macroglossia & inelasticity of tongue —> dysarthria & dysphagia
- depositions in stomach & intestine may leads to malabsorption , diarrhea & digestion problems
4) Vascularity
- fragile BV
- sometimes AL amyloid can bind to factor X & inactivated it —> massive bleeding
Describe the diagnosis of amyloidosis
Congo red
- fat aspirates can be stained with Congo red & viewed under polarised microscope — yellow green birefringence is seen
- pink-red-deposits seen under light microscopy
Bone marrow
- bone marrow aspirates show monoclonal plasmacytosis
Serum & urine electrophoresis and immuneelectrophoresis
Commonly biopsies site
A) Kidney
B) rectal tissue
C) gingival tissue
Define pathologic calcification
- the abnormal tissue deposition of calcium salts together with smaller amounts of iron , magnesium and other mineral salts.
Describe the types of pathological calcification
1) Dystrophic
- occur in areas of necrosis of all types ( caseous , coagulative , liquefactive )
- Not related to calcium levels
- Deposition of calcium is localised
- ex: calcification of heart valves leading to aortic stenosis , atherosclerosis , tuberculous lymph nodes
2) Metastatic
- occurs in normal tissue secondary to hypercalemia
- deposition of calcium occur throughout the body but principally affects the interstitial tissues of the vasculature , kidneys ( nephrocalcinosis) , lungs and gastric mucosa
- hypercalcemia may be due to :
I) excess PTH ( tumours)
II) Excess bone resorption ( Paget’s disease , immobilisation , tumors )
III) Vitamin D related disorder ( Vit D intoxication and sarcoidosis )
IV) renal failure — phosphate retention leads to secondary hyperparathyroidism in order to elevate Ca levels in serum
Describe the morphology of pathological calcification
Gross
- calcium salts appear as fine , white granules or clumps
Histological
- basophillic , amorphous , granular deposits that may be intra or extracellular
- heteroecious bone may sometimes be seen
- psammoma bodies : single necrotic cells deposited with calcium in layers having laminated appearances
Define neoplasia
An abnormal mass of tissue , the growth of which exceeds and is uncoordinated with that of normal tissue and persists in the same excessive manner after cessation of the stimuli which evoked the change
Describe the components of neoplasm
1) Parenchyma
- consists of the proliferating neoplastic cell
- determines the nature of the tumours
- If parenchyma is excessive , neoplasm is soft & fleshy
- ex : oral carcinoma — squamous cell present , liver cancer — hepatocytes present
2) Stroma
- consists of blood vessels , CT and immune cells
- If stroma is excessive ( desmoplasia ) , tumor is stony hard (scirrhous)
Compare benign & malignant tumors
Benign tumours
- Slow growth rate
- Low mitotic activity
- No invasion
- Never metastases
- Circumscribed or encapsulated border
- Expansile ( expand in size but not invasive )
Malignant tumours
- rapid growth rate
- high mitotic activity
- have invasion
- frequent metastases
- poor defined or irregular
- invade into surrounding structure
Anaplasia is a ( ………….. ) — malignant neoplasms that are composed of ( ………… ) cells are said to be anaplastic . It is hallmark of malignancy
The morphologic features of anaplasia are :
( ……………………………)
Anaplasia is a ( lack of differentiation ) — malignant neoplasms that are composed of ( poorly differentiated ) cells are said to be anaplastic . It is hallmark of malignancy
The morphologic features of anaplasia are :
( I) Pleomorphism ( variation in nuclear size & shape )
II) Increased mitosis
III) Hyperchromatism
IV) Tumor giant cells formation
V) Abnormal nuclear morphology )
Describe the morphology of tumors ( gross , histological )
Gross
- tumors can be :
I) sessile
II) Fungatingg/ exophytic / cauliflower- like
III) Ulcerative / excavative
IV) Annular / encircling / napkin-ring like growths
V) Sessile
VI) Polyp
- in malignant tumours , the tumours is irregular , poorly -circumscribed and may be seen invading other while in benign tumors they are usually well- circumscribed with a capsule
***** sessile & pedi curated tumou - benign tumours usually , the rest are all malignant tumours.
Histology I) Hyperchromasia II) Pleomorphism III) presence of giant tumor cells IV) abnormal ( increased ) mitosis V) malignant tumors — anaplastic , benign tumours — well differentiated
Benign tumours of mesenchymal origin usually end with the suffix (………… )
Example ( ……………………)
Malignant tumors arising from mesenchymal origin are usually called ( ……………)
Example ( …………….. )
Malignant tumours arising from epithelial origin are usually called ( ………….. )
Example ( ………………….. )
Benign tumours of mesenchymal origin usually end with the suffix ( -oma )
Example ( fibroma , osteoma , squamous cell papilloma ) except : hematoma , melanoma , lymphoma )
Malignant tumors arising from mesenchymal origin are usually called ( sarcomas )
Example ( chondrosarcoma , leiosarcoma )
Malignant tumours arising from epithelial origin are usually called ( carcinomas )
Example ( squamous cell carcinoma , basal cell carcinoma , transitional cell carcinoma )
Mutations in these classes of genes can cause cancer. Mention theses genes
1) Growth -promoting proto-oncogenes
2) Growth-suppressing tumors suppressor genes
3) Apoptosis regulating genes
4) DNA repair genes
Describe the models that are used to explain the heterogenecity of tumor cells ( cancer stem cell model and the clonal evolution model )
Cancer stem cell (CSC) model
- tumors consists of cells that can initiate tumors (CSC) and cells that arise from CSCs but cannot form tumors
- cancer stem cells are a rare subset of tumors cells that have the ability to self renew & generate diverse tumor cells
- CSCs may have different sensitivities to radiation or chemotherapy
Clonal evolution model
- mutant tumor cells with a growth advantage ( cause by mutations ) are selected and expanded
- different tumors cells can get different mutation which give rise to different sub population which can further mutate & divide , causing heterogencity.
- all cells in the dominant populations have a similar potential for initiating tumor growth ( No CSC-like ability )
- hence neoplasms are said to be clonal proliferation due to their presumed single cell origin
** Bith are not mutually exclusive as CSCs themselves can undergo clonal evolution — hence more dominant CSCs can emerge if a mutation confers if a mutation confers more aggressive properties
State & briefly describe the hallmark of cancer
1) Sustaining proliferative signalling
- cancer cells produce their own growth factor which they are responsible to — unlimited proliferation + cell growth ( eg : glioblastoma secrete PDGF and also express PDGF receptor )
- cancer cell can also activate nearby normal cells in the stroma to release GF
2) Evading growth suppressor
- due to mutation of tumor-suppressor genes
3) Activation invasion & metastasis
- local invasion of ECM
- Spread to distant sites via lymph & circulatory system ( vascular dissemination )
4) Enabling replicative immortality
- most cells have limited number of cell division due to shortening of telomeres
- cancer cells can maintain the length of telomeres with help of telomeres
5) Resisting cell death
- caused by mutation in apoptosis regulating genes
6) Inducing angiogenesis
- tumors require blood supply to ensure adequate O2 and nutrients for growth
7) Avoiding immune destruction
- tumor cells downregulate tumor antigens on cell membrane
8) Deregulating cellular energetic
- cancer cells switch from oxidative phosphorylation to aerobic glycolysis
- all glucose used instead for nucleic acid & lipid synthesis at the expense of ATP production
9) Genome instability and mutation
10) Tumor - promoting inflammation
State the classification of proto-oncogenes based on their function
A) Genes coding for growth factors
- eg : sis gene coding for PDGF
B) Genes coding for growth factor receptor
- eg : erb-b gene coding for epidermal growth factor receptor ( EGFR)
C) Genes that code for intracellular signal transduction molecule
- eg : ras gene coding for Ras protein
D) Genes that code for nuclear-binding transcription factors
- transcription factors binds to DNA to stimulate transcription for gene
- eg : C-myc gene
E) Genes that codes for cell cycle regulator
- eg m cycling & cdks , kinase inhibitor
F) Genes that code for apoptosis inhibitor
- eg : bcl2
Describe the oncogene activation by gene amplication with an example
- seen in neuroblastoma
- ~200 copies of MYCN gene is seen within a neuroblastoma
- MYCN is a oncogenic transcript or factor
Describe the oncogene activation by chromosome rearrangement with example
1) Follicular lymphoma
- translocation of IgH enhancer from chromosome 14 to chromosome 18 , induces massive transcription of bcl2 ( anti-apoptotic ) ( t (14:18) IgH: Bcl2 )
2) Chronic myeloid leukaemia
- result in formation of Philadelphia chromosome
- formed by the fusion of BCR gene of chromosome 22 and ABL gene of chromosome 9, resulting in production of hybrid protein which has constitutively active tyrosine kinase — increase cell division
- treated with tyrosine kinase inhibitor — imatinib
State some examples of tumor suppressor genes
RB: codes for retinoblastoma protein
P53: guardian of genome
- APC
- BRCA1
Describe the mechanism of action of RB protein and how it’s mutation can lead to cancer
- tumor suppressing protein
- when cell proliferation is inactive , RBC is in non-phosphorylated / activated form , it binds E2F , preventing the expression of S phase genes
- when cell proliferation occurs , binding of cyclin D1 to cdk4 leads to formation of a protein-kinase complex , which cause phosphorylation of Rb, causing it to disassociate with E2F .
- When E2F is unbound , S phase genes can be expressed / transcribed , leading to cell proliferation.
- Hence mutation of Rb gene ( leads to inactivation ) will cause uncontrolled cell division
Describe p53 and how it’s mutation can lead to cancer
- tumor suppressor gene ( guardian of genome )
- wild type ( normal ) p53 gene detect DNA damage and stops cell cycle progression , giving time for the cell to repair any DNA damage before they divide
- if DNA damage is too severe -p53 remains high —> apoptosis
- if DNA damage is repaired , p53, & p21 decrease -> cyclin-CD4 can phosphorylase RBC to release E2F —> S phase genes turned on & cell proliferation occurs
MOA :
p53 is a tumour suppressor that is induced in response to DNA damage.
p53 activation -> induction of p21 -> inhibition of Rb phosphorylation -> suppression of E2F activity
-Mutation of p53 gene -> no p21 -> phosphorylation of Rb occurs ( gets inactivated ) -> E2F unbound -> transcription of S-phase gene -> uncontrolled cell division
Define Carcinogenesis
Carcinogenesis is the process that results in the transformation of normal cells to neoplastic cells by causing permanent genetic alterations
Describe oncoviruses
Viruses that can cause cancer
- 2 types : DNA & RNA viruses
- DNA viruses :
I) Epstein -Barr virus — associated with nasopharyngeal cancer , Burkitt’s lymphoma
II) hepatitis B&C virus — associated with hepatocellualr carcinoma
2) RNA virus
- retrovirus like human T cell lymphotrophic virus-1 ( HTLV-1 ) — associated with adult T cell leukaemia
III) human papilloma virus ( HPV) — associated with cervical carcinoma and common warts
Describe how DNA and RNA viruses can cause cancer
DNA virus
- upon entering the host cell , genome (DNA) gets integrated into host genome
- results in host cell expression of viral mRNA coding for viral protein
RNA virus
- upon entering host cell , a DNA copy of RNA genome is formed via reverse transcription with reverse transcriptase enzyme
- get incorporated into host genome —> expression of viral mRNA -> viral protein formed
Describe the mechanism of action of chemical Carcinogenesis
Initiation stage
- involves reaction b/w a carcinogen and DNA
- carcinogens include : chemicals , radiation or viruses
- 2 or more carcinogens can acts together as cocarcinogens
Promotion stage
- involves promoters ( hormones , drugs , which stimulate cell proliferation , creating more clonal proliferation of the initiated cell & enhances the carcinogenic process )
- a promoter itself is not carcinogenic
- accumulation of mutations in the clones can leads to development of malignant tumours
Radiation Carcinogenesis involves ( ……………………. ) and ( ………………………)
- Exposure to UV rays is associated with increased incidence of ( ……………………………..)
- The degree of risk depends on the ( …………………..) , (……………….) and (………………) ( darker has lower risk of cancer )
Radiation Carcinogenesis involves ( electromagnetic ( UV , X-ray , y-ray ) and ( particulate ( protons , neutrons , a and B particles ) radiation )
- Exposure to UV rays is associated with increased incidence of ( squamous cell carcinoma , basal cell carcinoma and melanoma )
- The degree of risk depends on the ( wavelength of UV rays ) , ( intensity of exposure ) and ( skin pigmentation ) ( darker has lower risk of cancer )
Hormone such as ( …………….) can leads to mammary and endometrial carcinoma , while ( ………………………. ) can leads to hepatocellular carcinoma.
Bacteria such as ( …………………. ) causes gastric adenocarcinoma and MALT lymphomas
Mycotoxins ( ………………… ) produced by ( …………………… ) causes hepatocellular carcinoma
Parasites like ( …………………. ) causes bladder cancer , while liver flukes — ( ……………………) and (…………………….) causes cholangiocarcinoma
Hormone such as ( exogenous estrogen ) can leads to mammary and endometrial carcinoma , while ( androgenic and anabolic steroids) can leads to hepatocellular carcinoma.
Bacteria such as ( Helicobacter pylori ) causes gastric adenocarcinoma and MALT lymphomas
Mycotoxins ( aflatoxins ) produced by ( Aspergillus flavours ) causes hepatocellular carcinoma
Parasites like ( Schistossoma haematobium ) causes bladder cancer , while liver flukes — ( Opisthorcis viverrini) and (Clonorchris sinensis ) causes cholangiocarcinoma
Describe the multistep theory of Carcinogenesis
- more than 1 carcinogen and 6-7 DNA changes required for the complete neoplastic transformation of a cell
- usually involves at least one active oncogenes and loss of function of several tumor suppressing genes
- involves initiation , promotion which causes the cell to transform and a progression stage that results in the malignant phenotype due to acc of mutations
- once the mutations is established , neoplastic behaviour does not require the continued presence of the carcinogen— hit and run situation
- evidence of the causative agent is usually not identified in the tumor
Theories that account for heterogeneity & differences in regenerative capacity of tumours :
I) Clonal evolution model
II) Cancer stem cell (CSC) model
State the definition of metastasis
It is spread of tumors from a primary sites and their establishments at distant secondary locations
Metastases of epithelial tumors ( carcinoma ) are easier to identify because ( ……………………………………………….. )
Metastases of CT tumors ( sarcomas ) are more difficult to identify because there is a lack of (…………. ) Instead , evidence of ( ………………. ) ; or other histological features such as ( …………….. ) are used to assess metastases.
Metastases of epithelial tumors ( carcinoma ) are easier to identify because ( the basement membrane serves as a line of demarcation between the tissue boundaries. if the BM is broken , it means that the epithelial tumours has metastasized )
Metastases of CT tumors ( sarcomas ) are more difficult to identify because there is a lack of( basement membrane ) Instead , evidence of ( vascular or lymphatic permeation ) ; or other histological features such as ( mitotic activity ) are used to assess metastases.
List the pathway of spread of cancer
1) Seeding of body cavities
2) Lymphatic spread
3) Hematogenous spread
Describe the spread of cancer through seeding of cavities & surfaces
- occurs when a malignant neoplasm penetrates a natural ‘ open fields ‘ lacking physical barrier such as the peritoneal , pleural and peepricardial cavities , subarachnoid & joint spaces
- eg , transcoelomic spread which is the dissemination of malignant tumors throughout the surface & organs of the abdominal & pelvic cavities h which are covered by the peritoneum )
- characterised of ovarian carcinomas which can spread to the peritoneum causing a heavy cancerous
Describe the hematogenous spread of cancer & the commonest sites involved
- commonest method of spread by sarcomas — but also seen in carcinomas
- involves are usually small veins due to their thinner walls
Commonest site (LLBB)
- liver
- Lung
- brain
- bone
Hypercalcemia can result from squamous cell carcinomas due to production of ( ……………. ) ,( ……………….) , (………… ) ,( ………)
Hypercalcemia can result from squamous cell carcinomas due to production of ( parathyroid hormone related protein ) ,( TGF-a) , ( TNF ) ,( IL-1)
Explain the clinical effect of tumors
1) Mass effect
- the effects of a growing mass that results in secondary pathological effect by pushing on or displacing surrounding tissue
- eg : pituitary adenoma -> compresses the pituitary gland —> leads to destruction —> hypopitutarism
- eg : thyroid adenoma —> compression of larynx —> blockage of airway ; compression of laryngeal nerves —> affected speech ; hyperthyroidism
- eg ; neoplasms of the guts —> enlarge -> obstruction of GIT ; telescoping of neoplasm & its affected segment into the downstream segment — intussusception
2) hormone production
- more typical of benign tumors as they are well diffentiated
- eg : adenoma of pancreatic islets —> insulin production increase —> fatal hypoglycaemia
- non-endocrine tumors may give rise paraneoplastic syndrome
- - eg : sq cell carcinoma of lung —> hypercalcemia
3) Ulceration
4) Tumor rupture & infarction
5) Cachexia
- the progression loss of body fat & lean body mass accompanied by profound weakness , anorexia , & anemia
Describe cancer cachexia & its mechanism of action
- a clinical effect of cancer
- it is the progression loss of body fat & lean body mass accompanied by anemia , anorexia and weakness
- anemia is caused by an anemia-inducing substrate (AIS) which binds to the cell membrane of RBCs & lowers the influx of glucose & pyrivate kinase activity —> haemolytic anemia
- hampers chemotherapeutic treatment
Mechanism of action
- due to action of cytokines produced by tumor
- eg : TNF , IL-1 , IFN-y
- TNF at high concentration mobilize fat from tissue store & suppress appetite
- IL-1 , IFN-y synergies with TNF
- other factors : proteolysis - inducing factor , lipid mobilising factor increase catabolism of adipose & muscle tissue
- imbalance between factors that regulate muscle Hypertrophy ( IGF ) muscle catabolism —> cachexia
A specimen meant to be biopsied should be immersed in a fixative of ( ………………….. )
The fixative used for Pap smears is ( ……………….. )
A specimen meant to be biopsied should be immersed in a fixative of ( 10% formalin )
The fixative used for Pap smears is ( absolute alcohol )
Describe the immunohistochemistry & its uses and state some immunohistochemistry marker
- use of specific Ab to detect antigens
Uses
1) To categorise undifferentiated malignant tumors
- eg : breast tissue contains of blood vessels , fat and tissue — breast tumors can either angiosarcoma , liposarcoma or breast cancer itself, hence immunohistochemistry can be used distinguish between them
2) To identify the site of origin of metastatic tumors
- IHC detection of organ-specific or tissue specific Ag in a biopsy specimen can help determine the tumor source.
- eg : prostate-specific antigen & thyroglobulin are markers of carcinoma of prostate & thyroid respectively
3) Detection of molecule that have prognostic or therapeutic significance
- eg : IHC detection of hormones receptor ( estrogen / progestorone ) in breast cancer shows good prognosis because they will be responsive to anti-estrogen therapy ( chemotherapy )
IHC markers
I) carcinomas -cytokeratin
II) sarcoma - desman , vimentin
III) lymphoma - CD45 , LCA
