General Pathology Flashcards
Main features of reversible cell injury (4)
Cellular swelling (hydropic change), blebbing of cell membrane, clumping of chromatin, fatty changes in hypoxic injury
Events in necrosis
Unprogrammed cell death
Lysozymes cause loss of membrane integrity and leakage of cellular contents –> digestion and denature proteins –> inflammation –> healing and repair (with architectural changes)
Microscopic changes in necrosis (6)
Nuclear: karyorrhexis, karyolysis, pyknosis
Cytoplasmic: eosinophilia, glassy homogenous
Necrotic cells disappear and replaced by myelin figures and then fatty acids
Coagulative Necrosis cause, tissue changes, complications (5)
Most common type
Wedge-shaped yellow area due to infarct (except of the brain)
Tissue architecture preserved
Gangrenous necrosis due to ischemia
Wet necrosis due to superimposed bacterial infection
Liquefactive Necrosis cause, manifestation (2)
Leukocyte enzymes digest tissue into liquid viscous e.g. in hypoxic brain injury
Formation of pus in acute inflammation –> abscess and cavitation
Caseous Necrosis cause, appearance (2)
Chronic granulomatous inflammation
Creamy-cheese appearance
Fat Necrosis causes, outcomes (2)
Fat digestion by lipase e.g. acute pancreatitis, breast trauma
Fatty acid combines with Ca2+ –> saponification (visible white chalky areas)
Fibrinoid Necrosis pathology (1)
Immune complex deposited in vessel wall (microscopic)
Apoptosis definition, features, mechanisms (2), physiological stimuli (3), pathological stimuli (3)
Programmed Cell Death through dedicated set of genes
No inflammation induced
Mitochondrial pathway (Bcl-2 pathway) and Death receptor pathway (TNF + FAS) –> cascade activation of DNA fragmentation
Physiologic: embryological development, withdrawal of hormones, death of immune cells (ageing, deletion of proliferative cell population)
Pathologic: DNA damage, misfolding of proteins, immune reactions
Apoptosis microscopic changes (3)
Shrinking cell, DNA fragmentation with formation of apoptotic bodies (that are engulfed by macrophages)
Autophagy
“Self-eating” as a survival mechanism during stress
Autophagic vacuoles –> autophagolysosome –> lysosomal enzyme digestion
Types of cellular adaptation and examples of each (4)
Hyperplasia – e.g. hormonal during pregnancy or puberty; BPH or endometrial
- controlled process, disappears once proliferative signals subside
Hypertrophy – e.g. muscle training, hormonal during pregnancy (gravid uterus or lactating breast); LVH
Metaplasia (increases risk of dysplasia but potentially reversible) – e.g. cervix transformation zone; Barrett’s oesophagus (squamous –> glandular) , Smoking (columnar –> squamous)
Atrophy – e.g. senile due to intracellular accumulation of lipofuscin; disuse muscle, denervating, pressure, ischemia, malnutrition
Pathways of intracellular accumulation (3)
Increased production/ decreased metabolism, genetic defect in metabolism, abnormal exogenous substance
Examples of intracellular accumulations (4)
Lipid –> TGs in fatty liver due to alcohol, DM, starvation; cholesterol esters e.g. atherosclerosis, xanthoma, cholesterolosis
Protein –> Reabsorption droplets in PCT in severe proteinuria, Russell bodies (excess Ig) in plasma cells, alpha-1 antitrypsin deficiency
Glycogen –> glycogen storage diseases, mucopolysaccharidoses, gaucher (glucocerebrosidase deficiency)
Pigments –> carbon, lipofuscin (brown atrophy; repeated free radical injury), melanin, hemosiderin (from Hb, frequent blood transfusion, metabolic diseases)
Subcellular changes (4)
Intracellular accumulations, pathologic calcification, hyaline changes, fatty infiltration
Pathological calcification, appearance (1), types (2)
Basophilic deposits
Dystrophic: normal Ca2+, in necrotic or injured tissues e.g. atheroma, TB granuloma, damages valves
Metastatic: high Ca2+ (hyperPTH, Vit-D related disorders, CKD, bone destruction, sarcoidosis), at normal tissues
Hyaline Changes morphology (1), examples (2)
Homogenous, glassy pink material on H&E
Intracellular: Mallory Denk bodies, Russell Bodies
Extracellular: Hyalinised arteriosclerosis, amyloid in AD
Fatty infiltration associations (1), morphology (1)
Associated with myopathy
Tissue infiltrated and replaced with fat cells
Mechanism of acute inflammation (5)
- Increase in blood flow (vasodilation induced by cytokines and histamines) –> produce heat and erythema
- Increase vascular permeability due to contraction endothelial cells - short-lived - (mediated by cytokines) or by direct endothelial injury –> form exudate and cause swelling
1+2 –> decrease in local blood flow leading to stasis –> facilitating margination of leukocytes
- Neutrophil recruitment: margination –> rolling (selectin, low affinity) –> adhesion (beta integrin, high affinity) –> transmigration –> chemotaxis (along gradient of chemokine, complements, LTB4)
(6-24 hrs neutrophils; 24-48 hrs macrophages) - Neutrophil action at site of injury – phagocytosis (ROS and NO in phagolysosome)
Complement System pathways (3)
Complements are soluble proteins circulating in blood
Classical Pathway – Ag-Ab complex fixes C1
Lectin Pathway – MBL or Ficolins on microbes activate C1
Alternative Pathway – bacterial polysaccharides or other cell wall components trigger, involves properdin, factor B and D
Complement System effects (3)
Inflammation: C3a and C5a (induced histamine release and assist chemotaxis)
Opsonisation: C3b (coats cell wall)
Lysis: C5b trigger formation of MAC
Vasoactive amines examples (2), properties and actions (2), when released (3)
Histamine and Serotonin
Preformed, released mainly by mast cells – fast action (vasodilation and permeability)
Released when:
- physical injury
- binding of IgE to Fc receptors on mast cells (type I hypersensitivity)
- C3a and C5a
Arachidonic acids metabolites examples (2), released by (2), actions (5)
PGs and LTs, released by mast cells and leukocytes
Vasodilation, increase permeability, bronchospasm, chemotaxis, inhibition of inflammation
Cytokines, Chemokines examples (2), produced by (2), effects (4)
TNF, IL-1, IL-6, produced by inflammatory cells e.g. macrophages, lymphocytes
Local effects: activation of endothelial cells for migration and attract leukocytes
Systemic effects: fever, leukocyte production, insulin resistance
Manifestations of acute inflammation grossly (4), types of inflammation and their morphology (3)
Redness, heat, swelling and pain
Suppurative inflammation: purulent exudate with neutrophils, necrotic debris, oedema fluid (pus); abscess is focal collection of pus
- morphology: necrotic focus + neutrophils + surrounding dilated vessels and fibroblasts
- replaced by connective tissue and scarring
Serous inflammation: irritation of serous lining causing filling of potential spaces e.g. pleural, pericardial, peritoneal (not infected)
Fibrinous inflammation: more severe injuries causing increased permeability –> extravasation of fibrinogen –> form fibrin deposits in EC space
- resolution or organisation (exudates replaced by ingrowth of fibroblasts and BV)
Outcomes of acute inflammation (3)
Complete resolution (limited injury, macrophages remove debris and microbes with lymphatics resorbing fluid)
Healing by connective tissue replacement (scarring and fibrosis)
Progress to chronic inflammation (persistent or interrupted healing)
Chronic inflammation causes (3), morphologic features (3)
Persistent infections (TB, syphilis), Immune-mediated inflammatory diseases, Prolonged exposure to offending agent (silicosis, atherosclerosis)
Morphology:
- mononuclear cells (macrophages, lymphocytes, plasma cells)
- tissue destruction
- attempts at healing (angiogenesis and fibrosis)
Main differences between acute and chronic inflammation (4)
Onset, Inflammatory cells involved, Vascular changes, Signs (chronic inflammation: scar, fibrosis, necrosis, low grade fever, weight loss, anaemia)
Macrophages in chronic inflammation, activation pathways (2), functions (4), fate (2)
Classically activated macrophage (M1)
- induced by T cell derived signals e.g. IFN-gamma or endotoxins from microbes (ROS and NO increase phagocytic activities)
- microbicidal and inflammation
Alternatively activated macrophage (M2)
- other cytokines e.g. IL-4, IL-13
- may inhibit M1
- tissue repair, fibrosis and anti-inflammatory effects (IL-10, TGF-beta)
Functions:
- phagocytosis (ROS, NO and proteases)
- secrete inflammatory mediators (initiate and propagate inflammation e.g. IL-12, IL-23 to activate T cells)
- antigen presentation to T cells (and respond to signals from T cells)
- initiate tissue repair
Fate:
- die or cleared into lymphatics
- persist with local proliferation and tissue destruction (+/- giant cell formation)
Macrophages vs Monocytes, lifespan, site of residence,
Tissue macrophages e.g. Kupffer cells, microglia, sinus histiocytes, alveolar macrophages – larger with longer lifespan
Monocytes - in blood, t1/2 = 1 day, extravasate into tissue within 24 hrs
Lymphocytes in chronic inflammation, mechanism of actions (4)
Dominant in autoimmune and hypersensitivity
CD4 cells secrete cytokines to promote inflammation
Th1 –> IFN-gamma activate M1
Th17 –> IL-17 recruit neutrophils (by inducing secretion of other chemokine)
Th2 –> IL-4,IL-5, IL-13 activate eosinophils, M2
Th1 and 17 –> bacterial and viral diseases, autoimmune
Th2 –> allergic reactions, helminthic parasitic infection
Bidirectional interaction between macrophages and lymphocytes (macrophage activate T cells which recruit more macrophages)
Plasma cells function (1), morphology (3)
Secretion of Ab against specific Ag after B cell contact with Ag at tissues
Morphology: clock-face, off centre nucleus, basophilic
Other cell types in chronic inflammation (3)
Neutrophils (persist from acute inflammation)
Eosinophils (parasitic or IgE mediated inflammation, recruited by eotaxin, release MBP, very eosinophilic)
Mast cells (plethora of cytokines can promote or limit infl reactions)
Histology of chronic inflammation (3)
Lymphocytes and Collagen
Necrosis
Granulation tissue and scarring (no dilated vessels)
Granulomatous Inflammaton, cause (1), definition (1), macroscopic features (2), microscopic types and how to differentiate (2)
Presence of cellular agent that is difficult to eradicate
Focal accumulation of epithelioid histiocytes and giant cells with a rim of lymphocytes (+/- central necrosis)
Grossly, caveating (TB, syphilis) vs non-caseating (leprosy, Crohn’s - cobblestone mucosa, sarcoidosis)
Microscopic differentiation: foreign body granuloma (no inflammation, foreign body type giant cell with nuclei dispersed in cytoplasm) vs immune granuloma (cell-mediated immune response to pathogen, langerhans type giant cell with horseshoe nuclei)
Types of chronic inflammation (2)
Recurrent acute (incomplete healing and repair) and primary chronic (e.g. UC, granulomatous, transplant rejection)
Outcomes of chronic inflammation (5)
Abscess
Chronic regeneration leading to derangement of tissue architecture
Metaplasia as a protective mechanism
Fibrosis of serosal surfaces - fibrinous adhesions –> granulation tissue –> fibrous adhesions (symphysis) –> loss of mobility
Scarring - increased collagen deposition –> cause loss of function, contractures, adhesions
Regeneration vs Repair, definition (1), tissue type (1)
Regeneration is replacement of damaged cells by undamaged cells and stem cells, in tissue with high proliferative capacity e.g. GI, skin, haematopoietic
Repair is regeneration + scar formation, in tissues incapable of regeneration or tissues that have damaged ECM –> leads to some functional loss
Factors affecting healing (4)
Tissue proliferative capacity
- labile e.g. epithelium
- stable e.g. parenchyma of liver, kidney or pancreas/ mesenchymal cells, endothelial cells
- permanent e.g. neurons, skeletal or cardiac muscles
Stem cells
- self-renewal capacity, asymmetric replication
- embryonic (pluripotent, inner cell mass) vs adult (multipotent?, organ or tissue e.g. BM, GI, Skin)
- stem cell niches
Growth factors
- polypeptides that drive cell proliferation and gene transcription e.g. EGF, TNF
- from macrophages, lymphocytes, stromal cells
- EGF mitogenic for keratinocytes and fibroblasts and stimulates granulation tissue formation
Extracellular matrix
- basement membrane and interstitial matrix
- repair only by scar formation once damaged
- functions: tissue microenv, scaffold for tissue renewal, control cell proliferation, cell anchorage and migration
Scar formation steps (5)
Clotting and chemotaxis
Inflammation and phagocytosis to remove destroyed tissue (M1 and M2)
Formation of granulation tissue (up to 10 days) – angiogenesis (VEGF, FGF - migration of endothelial cells and degrade ECM to permit vessels) and migration of fibroblasts
Scar formation by deposition of ECM from fibroblasts (TGF-beta, PDGF)
Connective tissue remodelling from 2-3 weeks (MMPs)
Factors that influence tissue repair, systemic (4), local (4)
Systemic: nutrition (e.g. Vit C), metabolic e.g. DM, blood supply, glucocorticoids (weak scars)
Local: infection, mechanical (e.g. constant pressure), foreign body, size/location/type of wound
Healing of skin wounds, stages (3), types of wound and different ways of healing (2)
Inflammation (24h) –> Proliferation i.e. fibroblast migration and re-epithelialisation (3-7 days) –> maturation i.e. ECM deposition and remodelling (weeks)
Primary intention: clean, uninfected wound with well apposed edges –> re-epithelialisation closes wound with thin scar formation (off stitches at stage 2)
Secondary intention: larger wound with complication e.g. abscess, ulcer –> wound left open with more inflammation, granulation tissue and collage deposition –> bigger scar
(wound contraction at stage 3)
Pathological aspects of wound healing (4)
Inadequate scar formation – dehiscence and rupture, ulceration
Excessive repair – hypertrophic scar, keloid scar
Wound contracture – usually at palm, soles, anterior thorax –> deformities of wound and surrounding tissues
Fibrosis in parenchymal organs –> excessive collagen and ECM in chronic injurious stimuli e.g. liver cirrhosis – may cause organ dysfunction and failure
Hallmarks of cancer (Growth and Immortality) - 6
Sustained proliferative signalling
- mutation in genes involved in growth and proliferation
- activation of oncogenes e.g. hyperactivation of RAS increasing transcription of MYC which increases cell cycle progression
- EGFR, HER2, KRAS, Cyclin D1
Evading growth suppression
- inactivation of tumour suppressor genes e.g. hyperphosphorlyation of RB (neg regulator of cell cycle) which decreases binding to E2F –> can promote cell to enter S phage
- p53 mutation affecting ability to respond to DNA damage or cell stress –> decrease p21 transcription –> can’t prevent RB phosphorus –> no S phase block –> no cell cycle arrest for DNA repair or apoptosis
Aberrant apoptosis to resist cell death
- increase antiapoptotic factors e.g. Bcl-2 over expression in leukaemia or follicular lymphoma
- p53 mutations
Deregulating cellular genetics
- Warburg effect
- Oncometabolism –> e.g IDH mutation creating new enzymatic activity which leads to abnormal DNA methylation (hypomethylation increase activity of genes)
Replication immortality
- loss of p53 checkpoint activation in cell cycle after telomere shortening –> NHEJ mediated DNA double stranded repair –> chromosomal instability and mitotic crisis –> reactivation of telomerase leads to immortality
Angiogenesis
- required for exponential growth of tumour cells (esp hypoxic areas)
- controlled by angiogenic and anti-angiogenic factors –> hypoxia stimulates HIF-1 alpha –> increase VEGF transcription (also by RAS and MYC)
Hallmarks of cancer (Progression) - 3
Invasion and Metastasis
- invasion: loosen cell contacts (e-cadherin), degrade ECM (MMPs), attach to novel ECM components, migration of tumour cells
- metastasis: intravasation after invasion, form tumour embolus, attach to basement membrane, extravasation – usually at first capillary bed encountered, may have organ tropism
Avoiding immune destruction
- expression of CTLA4 or PDL-1 which binds to T cells and induce T cell exhaustion
Malignancy enablers
- genomic instability (defects in DNA repair e.g. MMR in MSH1 or MLH1 mutation, DSB repair in BRCA mutations; also DNA hypomethylation)
- tumour promoting inflammation –> cytokines as GFs, M2 modify microenv to promote growth
Carcinogenesis stages (3)
Multiple genetic changes involving 6-7 driver mutations accumulating over decades
Initiation (irreversible, constant DNA damage, normal phenotype)
Promotion (reversible, selective growth advantage for precursor cells – increase mutations, altered phenotype)
Progression (become more aggressive, proliferation of tumour cells leading to heterogeneity e.g. non-antigenic, metastatic, invasive)
Carcinogens (3) and risk factors (4)
Smoking, Alcohol, Diet, Obesity
Oncogenic virus (15% cancers due to infection)
- HPV-16, 18 –> E6 binds and degrades p53 and activates telomerase; E7 binds to Rb and displaces E2F and activated cyclin E and A –> necessary but insufficient for CA cervix
- EBV –>failed immunoregulation leading to mutation of one clone and Burkitt’s lymphoma; also cause NPCA (40-100%), Hogdkin (30%)
HTLV-1 –> TAX protein increase cytokine expression to increase CD4 T cells, decrease TSG functions
- HBV –> HCC (80%)
- H. pylori –> produce CagA to activate NF-kB to cause inflammation –> CA stomach (80%)
Chemical carcinogens
- direct acting e.g. chemotherapy
- indirect acting e.g. polycyclic hydrocarbons (smoking), aromatic amines (rubber), aflatoxins (fungi)
Radiation
- Non-ionising UV –> form thymidine dimer –> mutation in TSG and oncogenes (cumulative - SCC, BCC or intense intermittent exposure - melanoma)
- Ionising Xray, Gamma ray, radioactive –> direct damage and chromosome breakage/ rearrangement or indirect from ROS
Chronic inflammatory states associated with cancer (5)
Hepatitis Reflux esophagitis IBD Asbestos or Silicosis Gastritis, Ulcers
Tumour suppressor genes, model of mutation (1), cancers associated
Knudson's 2 hit model (acquired +/- germline mutations) --> higher risk in germline mutations APC - CA colon, FAP RB1 - retinoblastoma NF1/NF2 - neurofibromatosis type 1 and 2 BRCA1/2 - CA ovary, female breast (BRCA1) p53 - Li-Fraumeni syndrome PTEN - Cowden syndrome MSH2/MLH1 - HNPCC
Driver v Passenger mutation
Driver mutation causes functional loss and change in cellular behaviour e.g. at TSG or photo-oncogenes
Passenger mutation facilitates cancer development but does not affect cell fitness or behaviour
Neoplasm, definition (1), components (2), terminology for different types of tumours (5)
Abnormal, uncoordinated excessive growth resulting in new tissue mass that is autonomous
Composing of parenchyma of neoplastic cells and supporting stroma
Epithelial - -oma/ -carcinoma Mesenchymal - -oma/ -sarcoma Haematolymphoid - -oma (malignant) Germ cell - teratoma (only benign one is mature cystic teratoma of ovary); also seminoma, yolk sac tumour, embryonal carcinoma, choriocarcinoma Precursor cells - -blastoma
Benign vs Malignant Characteristics
Differentiation, Growth rate and morphological features (4), Invasiveness (3), Metastasis (3)
