Jason's ACP Revision Notes PDF

1 TERMINOLOGY................................................................................................................................................................... 3 GENERAL PATHOLOGY........................................................................................................

1 TERMINOLOGY................................................................................................................................................................... 3 GENERAL PATHOLOGY......................................................................................................................................... 4 BAP-L2 CELL INJURY & CELL DEATH...................................................................................................................................... 4 BAP-L3 SUBCELLULAR INJURY AND CELLULAR ADAPTATION....................................................................................................... 6 BAP-L5 ACUTE INFLAMMATION........................................................................................................................................... 8 BAP-L6 CHRONIC INFLAMMATION..................................................................................................................................... 10 BAP-L7 HEALING, REPAIR AND REGENERATION..................................................................................................................... 12 BAP-L13 & 14 MOLECULAR MECHANISMS OF NEOPLASIA..................................................................................................... 14 BAP-L15 CLASSICAL TUMOURS.......................................................................................................................................... 18 BAP-L18 & 19 HAEMODYNAMIC DISTURBANCES................................................................................................................. 20 BAP-L33 AMYLOIDOSIS.................................................................................................................................................... 23 GI AND HBP PATHOLOGY................................................................................................................................... 25 BAP-L34 HEAD AND NECK PATHOLOGY............................................................................................................................... 25 BAP-L35 OESOPHAGEAL PATHOLOGY................................................................................................................................. 27 BAP-L39 GASTRIC PATHOLOGY.......................................................................................................................................... 29 BAP-L38 NON-NEOPLASTIC DISEASES OF SMALL AND LARGE BOWELS....................................................................................... 32 BAP-L39 POLYPS AND NEOPLASMS OF SMALL AND LARGE BOWELS.......................................................................................... 35 ACP-L21 & 22 HBP PATHOLOGY...................................................................................................................................... 38 CARDIOVASCULAR SYSTEM................................................................................................................................ 49 ACP-L8 PATHOLOGY OF VESSELS........................................................................................................................................ 49 ACP-L9 & 10 PATHOLOGY OF THE HEART............................................................................................................................ 52 RESPIRATORY SYSTEM....................................................................................................................................... 58 ACP-L18 PATHOLOGY OF LUNG INFECTIONS........................................................................................................................ 58 ACP-L19 OBSTRUCTIVE AND RESTRICTIVE LUNG DISEASES...................................................................................................... 61 ACP-L20 PATHOLOGY OF LUNG AND PLEURAL TUMOURS....................................................................................................... 64 UROGENITAL SYSTEM........................................................................................................................................ 67 ACP-L23 & L24 MEDICAL RENAL DISEASES......................................................................................................................... 67 ACP-L25 TUMOURS OF KIDNEY AND URINARY TRACTS........................................................................................................... 72 ACP-L26 PATHOLOGY OF PROSTATE AND TESTIS................................................................................................................... 74 BREAST & ENDOCRINE PATHOLOGY.................................................................................................................... 77 ACP-L33 BREAST PATHOLOGY........................................................................................................................................... 77 ACP-L36 & L37 ENDOCRINE PATHOLOGY........................................................................................................................... 81 NEUROPATHOLOGY........................................................................................................................................... 85 ACP-L35 DISEASES OF SKELETAL MUSCLES........................................................................................................................... 85 ACP-L44 HEAD INJURY..................................................................................................................................................... 87 ACP-L46 CNS TUMOURS................................................................................................................................................. 90 ACP-L47 CEREBROVASCULAR DISEASES............................................................................................................................... 92 ACP-L48 DEMENTIA........................................................................................................................................................ 95 GYNAECOLOGICAL PATHOLOGY......................................................................................................................... 98 ACP-L49 GYNAECOLOGICAL PATHOLOGY I........................................................................................................................... 98 ACP-L50E GYNAECOLOGICAL PATHOLOGY II...................................................................................................................... 102 ORTHOPAEDIC PATHOLOGY............................................................................................................................. 104 ACP-L51 NON-NEOPLASTIC BONE DISORDERS.................................................................................................................... 104 ACP-L52 JOINT DISEASES................................................................................................................................................ 107 ACP-L53 BONE TUMOURS.............................................................................................................................................. 111 ACP-L45E SOFT TISSUE TUMOURS................................................................................................................................... 112 HAEMATOLOGY............................................................................................................................................... 112 ACP-L1 NORMAL HAEMATOPOIESIS................................................................................................................................. 113 ACP-L2 COMPLETE BLOOD COUNT AND ABNORMAL BLOOD CELL MORPHOLOGY...................................................................... 114 ACP-L3 CYTOPENIA AND APPROACH TO ANAEMIA............................................................................................................... 117 ACP-L4 IRON DEFICIENCY ANAEMIA.................................................................................................................................. 119  2 ACP-L5 MEGALOBLASTIC ANAEMIA.................................................................................................................................. 122 ACP-L6E HAEMOLYTIC ANAEMIA..................................................................................................................................... 124 ACP-L7E GENETIC DISORDERS OF HAEMOGLOBIN............................................................................................................... 128 ACP-L38 & L16 APPROACH TO HAEMATOLOGICAL MALIGNANCIES & INVESTIGATIONS............................................................. 130 ACP-L11 ACUTE LEUKAEMIA........................................................................................................................................... 133 ACP-L14 & L15 MYELOPROLIFERATIVE NEOPLASMS........................................................................................................... 135 ACP-L13 APLASTIC ANAEMIA, MYELODYSPLASTIC SYNDROME AND PAROXYSMAL NOCTURNAL HAEMOGLOBUINURIA..................... 139 ACP-L12 MULTIPLE MYELOMA & LYMPHOPROLIFERATIVE DISORDERS.................................................................................... 142 ACP-L17 LYMPHOMA.................................................................................................................................................... 145 ACP-L32 PATHOLOGY OF LYMPH NODES, SPLEEN AND THYMUS............................................................................................ 148 ACP-L27 BLOOD COAGULATION AND HAEMOSTASIS............................................................................................................ 150 ACP-L28 BLEEDING DISORDERS....................................................................................................................................... 152 ACP-L29 THROMBOTIC DISORDERS.................................................................................................................................. 156 ACP-L30 ADVERSE TRANSFUSION REACTION...................................................................................................................... 160 ACP-L31 COMMON BLOOD PRODUCT AND PRE-TRANSFUSION TESTING.................................................................................. 162 ACP-L39 HAEMATOPOIETIC STEM CELL TRANSPLANTATION.................................................................................................. 164 ACP-L42 & L43 BLOOD CANCER CYTOGENETICS................................................................................................................. 166  3 Terminology Pathological terms Definitions General pathology Hyperplasia Increase in cell number Hypertrophy Increase in cell size Metaplasia Replacement of one type of epithelium with another, potentially reversible Dysplasia Disordered growth and maturation of an epithelium, potentially reversible Hamartoma Disorganised overgrowth of tissue indigenous to that site Pus Purulent exudate consisting of necrotic cells, neutrophils and oedema fluid Abscess Focal collection of pus in a walled cavity Cardiovascular pathology Atherosclerosis Focal accumulation of lipid & proliferation of smooth muscle cells within tunica intima of arteries Infarct Ischaemic necrosis Aneurysm Localised, permanent dilatation of artery or vein HBP pathology Cirrhosis Diffuse regenerative nodules with bridging fibrous septa Haematology Thrombus A solid mass of platelets, fibrin (and other components of blood) that forms locally in a vessel Embolus A detached intravascular solid, liquid or gaseous mass that is carried by blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction Thromboembolism Dislodged thrombi that act as emboli  4 GENERAL PATHOLOGY BAP-L2 Cell injury & cell death cause of cell death: trauma, toxin, infection, autoimmune system Cellular responses to injury Wall pale = fibrosis; dark = gangrene Within certain limits, injury is reversible, and cells return to their stable baseline; however, if the stress is severe, persistent, or rapid in onset, it results in irreversible injury and death of the affected cells. cell death Reversible injury the deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed Cellular swelling: first manifestation; ion pump failure → accumulation of Na+ and water → ultrastructural changes o Blebbing of cell membrane o Swelling of cell, mt, ER o Nuclear alterations, with clumping of chromatin Fatty changes: occurs in hypoxic injury; reduced enzyme activity → failure to metabolise fat → cytoplasmic 3 phenomenon of irreversible death: lipid vacuole in non-fatty tissue the inability to restore mitochondrial function Irreversible injury (cell death) the loss of structure and functions of the plasma mem- brane and intracellular membranes the loss of DNA and chromatin structural integrity. Necrosis necrosis = cell death (5 types: liquuefactive, caseous, fat, coagulative, gangrenous) Unprogrammed cell death, always pathological 如缺⾎、接觸毒素、各種感染和創傷引起的損傷 Lysozymes of dying cells + lysozymes of leukocytes recruited in inflammation → loss of membrane integrity + leakage of cellular contents (K+, enzymes → detection) → inflammation → healing and repair [BAP-7] Microscopic changes Nuclear changes: pyknosis (shrink and condense, increased basophilia), karyorrhexis (fragmentation), karyolysis (dissolved, faded basophilia) Cytoplasmic changes: increased eosinophilia Fates of necrotic cells: disappear, replaced by myelin figures and then fatty acids, which can also bind Ca2+ to become calcified Macroscopic changes Describing general patterns instead of explaining underlying mechanisms Type of necrosis Description Coagulative (MC) Found in infarcts (localised area of coagulative necrosis) of all solid organs, except brain arterial block — ischemia Tissue architecture preserved for days: intra-cellular acidosis denatures digestive enzymes of dry gangrene: diabetic foot dying cells, and digestion only occurs until recruitment of leukocytes wet gangrene: ischemic bowel disease Gangrenous necrosis: a form of coagulative necrosis due to ischaemia, e.g. foot gangrene Wet gangrene: superimposed bacterial infection Liquefactive Necrotic enzymes are digested into liquid viscous, e.g. hypoxic injury to brain (?mechanism) brain, lung, liver Formation of pus in acute inflammation, e.g. bacterial infection occur in brain when vessle is occluded Caseous Creamy-cheesy appearance giant cell = macrophage granuloma, yellow white Often in form a granuloma: necrotic centre enclosed with a distinctive inflammatory border Fat Fat destruction by lipase, e.g. pancreatic lipase in acute pancreatitis release of pancreatic lipase in acute pancreatitis breast, pancreatitis Fat digestion → fatty acid combines with Ca2+ → fat saponificationfat + alkaline = soap — visible chalky area Fibrinoid Immune complex deposited in arterial wall, binding with fibrin leaked out of vessel eg. antigen and antibodies Mechanism of Ischemic Necrosis Arterial occlusion with local hypoxia Mitochondrial ATP depletion Cell membrane Na/K ATPase pump failure Fluid influx into cytosol Cell swelling Enzyme outflux  1. Mitochondrial pathway/Intrinsic apoptosis 細胞淍亡 = programmed cell death Growth factor withdrawal = pathway of cell death in which cells activate enzymes that degrade the BAX/BAK dimer on mitochondrial membrane cells’ own nuclear DNA and nuclear and cytoplasmic proteins Cytochrome C enters cytosol 2. Death Receptor pathway/Extrinsic 5 Apoptosis Fas/CD95/Type 1 Tumor Necrosis Factor Receptor on cell membrane Programmed cell death via activating dedicated sets of genes Activated cytotoxic T-cells express FasL Fas-FasL triggers cytoplasmic death domains Energy dependent 1. 但與壞死始終是病理過程的徵兆不 同，apoptosis 也發⽣在healthy tissue。它的作⽤是在正常發育 Not induce inflammation 過程中消除不需要 的細胞並維持恆定的細胞數量，因此它不⼀定與病理性細胞損傷有關 2. The dead cell and its fragments are cleared with little leakage of cellular contents —> Physiological stimuli so apoptotic cell death does not elicit an inflammatory reaction 没有發炎 3. 最終結果是 apoptotic cell death is the clearance of apoptotic bodies by phagocytes. o Embryological development o Withdrawal of GFs/ hormones for turnover of proliferative tissue o Cell deletion in proliferative cell population prevent autoimmune disease o Death in immune cells, e.g. neutrophils in acute inflammation, lymphocytes in lymphoid follicles o Aging Pathological stimuli o DNA damage, e.g. irradiation, cytotoxic drugs o Accumulation of misfolded proteins, e.g. A peptide in Alzheimer’s disease (AD), CFTR in CF o Immune reactions, e.g. autoimmune, CTL-mediated apoptosis, tumour (to avoid overpopulation of cancer cells that compete for nutrients) o Atrophy of parenchymal organs after duct obstruction Necrosis Apoptosis Stimuli Pathologic Physiologic or pathologic Gene activation No Yes Morphology Enlarged cell Shrinking cell Cytoplasmic eosinophilia Apoptotic bodies Nuclear changes: pyknosis → Fragmentation karyorrhexis → karyolysis Induced inflammation Yes 固縮→核碎裂→核溶解 No - in keeping with its role in certain physiologic processes Autophagy ⾃噬 o Survival mechanism during cell stress, e.g. nutrient deprivation o Autophagic vacuoles (ribosome-free ER) → autophagolysosome → lysosomal enzyme digestion o Defective autophagy implicated in AD Necrosis 1. Pyknosis 固縮: characterized by nuclear shrinkage and increased basophilia; the DNA condenses into a dark shrunken mass 2. Necrotic cells show increased eosinophilia — Eosin 紅⾊ (i.e., they are stained red by the dye eosin)  6 BAP-L3 Subcellular injury and cellular adaptation Cellular adaptation Reversible changes in number, size, phenotype, metabolic activity, or functions in response to changes in environments Pathologic adaptations allow cells to escape injury [BAP-L13] Hyperplasia 增⽣: increase in cell size and cell number o Increase in cell number epithelium commonly o Usually occur together with hypertrophy o Physiological (hormonal hyperplasia during pregnancy) or pathological (BPH, endometrial hyperplasia that may develop into CA endometrium) benign prostate hyperplasia Hypertrophy 肥⼤: increase in cell size but not cell number o Increase in cell size o Physiological (hormonal hypertrophy during pregnancy, muscle growth from training) or pathological (LVH due to increasing demand → HF) Atrophy left ventricle hypertrophy o Decrease in cell number and size o Accompanied by autophagy o Physiological (senile atrophy due to intracellular accumulation of lipofuscin) or pathological (skeletal muscle atrophy due to disuse or cachexia) Metaplasia 化⽣Replacement of one type of normal epithelium by another type of mature epithelium o Change in cell type, potentially reversible o Increased risk of dysplasia [BAP-L15] 發育不良 o Physiological (cervix) or pathological Barrett's oesophagus: replacement of squamous epithelium with glandular epithelium due to chronic irritation of gastric acid Smoking: replacement of columnar cells with more protective squamous cells) Other cellular and sub-cellular changes Intra-cellular accumulation Pathways of accumulation Normal endogenous substance - increased production or decreased metabolism, e.g. fatty liver Abnormal endogenous substance - genetic defect in metabolism, e.g. storage disease Abnormal exogenous substance, e.g. carbon pigment Lipid Triglycerides: fatty liver due to alcohol, DM or starvation; most appears harmless except acute alcoholic foamy liver, acute fatty liver of pregnancy, Reye syndrome and metabolic syndrome Cholesterol esters: atherosclerosis, xanthoma (nodules commonly formed in tendons), cholesterolosis Proteins Reabsorption droplets in PCT during severe proteinuria: vesicles containing proteins accumulate as they saturate reabsorption mechanism Russell bodies (excessive Ig production) found in plasma cells α1-antitrypsin deficiency Glycogen, complexes of carbohydrates/proteins/lipids Glycogen storage disease, e.g. type II (Pompe) Mucopolysaccharidoses Gaucher disease: glucocerebrosidase deficiency Pigments Exogenous: carbon (phagocytosed by alveolar macrophages) Endogenous o Lipofuscin: brown atrophy; indicative of repeated free radical injury and lipid peroxidation o Melanin: adjacent basal keratinocytes and macrophages can accumulate the pigment o Hemosiderin: derived from Hb; accumulates in frequent blood transfusion, genetic disease  7 Pathological calcification Dystrophic Found in necrotic or injured tissue, e.g. atheroma, caseous granuloma in TB [Ca2+] normal Metastatic Can be found in normal tissues [Ca2+] high, due to hyperparathyroidism, vitamin D-related disorders, sarcoidosis, CKD, bone destruction Hyaline changes Homogeneous, glassy pink material in H&E staining, usually because of protein Intracellular: Mallory bodies in liver, Russell bodies in plasma cell Extracellular: hyalinised arteriosclerosis, amyloid in AD, collagen fibrous tissue in old scars Fatty infiltration Associated with myopathy Tissue infiltrated/ replaced by fat cells 1. Inflammation is a response of vascularized tissues to infections and tissue damage that brings cells and mol- ecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents. 2. 發炎是⾎管組織對感染和組織損傷的反應 3. 急性發炎characterized by exudation of fluid and plasma proteins (edema) and emigration of leukocytes, predominantly neutrophils 8 BAP-L5 Acute inflammation Overview To get rid of offending agents, e.g. infection, necrotic tissues, foreign body, hypersensitivity Outcome: o Controlled inflammation: transient loss of function, imperfect tissue repair, systemic reaction (e.g. fever, malaise, sepsis) o Uncontrolled inflammation: autoimmune Mechanism neutrophil! 1. Increase in blood flow One of the earliest manifestations Induced by mediators e.g. histamine → vasodilation (increased overall blood flow) → erythema (red + heat) Increased capillary diameter + loss of fluid (point 2) → stasis (decreased local blood flow) → leukocytes (neutrophils) accumulate along the endothelium 2. Increased vascular permeability (swelling) Contraction of endothelial cells: histamine and other cytokines (bradykinins, LTs, etc); rapid and short-lived (min) Endothelial injury: direct damage in severe injury; rapid, may be long-lived (hours) → exudate (c.f. transudate) 3. Leukocyte recruitment margination —> rolling —> adhesion to endothelium —> migration through endothelium —> chemotaxis Margination: leukocytes accumulated in periphery due to stasis Rolling: adhesion molecules of low affinity (selectin family) expressed on endothelium activated by cytokines Adhesion: integrin family (higher affinity) Transmigration: stimulated by cytokines Chemotaxis (in tissue) o Leukocytes migrating towards site of injury along a chemical gradient of Bacterial products Cytokines, esp. chemokine family Complements, esp. C5 LTB4 o Move by remodeling cytoskeleton o Secrete mediators that recruit and activate more leukocytes o Neutrophils in first 6-24 hours, monocytes (macrophages) in 24 to 48 hours 4. Neutrophil action (phagocytosis) Intracellular killing by ROS & NO within phagolysosome (phagosome + lysosome) Degraded by lysosomal enzymes  9 Chemical mediators and regulators of inflammation Complement system [BAP-L24/CPY] Activation pathway o Classical pathway: fixation of C1 to Ag-Ab complex o Alternative pathway: triggered by bacterial polysaccharides and other cell wall components; involve a set of plasma proteins including properdin and factors B & D o Lectin pathway: lectin binds to mannose residues on microbes --> classical pathway in the absence of Ab Effects o Inflammation: C3a and C5a (anaphylatoxins) induces histamine release from mast cells; C5a assists chemotaxis o Opsonisation: C3b coats (opsonises) microbe's cell wall --> assist phagocytosis by neutrophils / macrophages o Cell lysis: formation of membrane attack complex (MAC) --> create hole --> disrupt osmotic balance Vasoactive amines Histamine & serotonin Preformed, released mainly by mast cells → fast, immediate action Released (degranulation) when: o Physical injury o Immune reactions involving binding of IgE to Fc receptors on mast cells - type I hypersensitivity o C3a, C5a (anaphylatoxins) Arachidonic acid metabolites PGs, LTs Vasodilation, increase permeability, chemotaxis, bronchospasm, inhibition of inflammation Cytokines, chemokines (TNF, IL-1, IL-6) Produced mostly by inflammatory cells, e.g. lymphocytes, macrophages Local effects: activation of endothelial cells (for migration) and leukocytes Systemic effects: fever, leukocyte production, insulin resistance, etc Manifestation of acute inflammations Suppurative inflammation [BAP-6] Pus: purulent exudate consisting of neutrophils, necrotic cells and oedema fluid Abscess: focal collections of pus in a walled cavity Morphology: neutrophils + necrotic tissues + surrounding dilated vessels & fibroblasts (attempted repair) Soon completely replaced by connective tissue → scarring Serous inflammation Potential spaces filled with fluid due to irritated lining cells Pleural effusion, pericardial effusion, ascites (peritoneum) Fibrinous inflammation As a consequence of more severe injuries → increased permeability Resolution: exudates removed by macrophages Organisation: exudates incompletely removed, replaced by an ingrowth of fibroblasts and BV → scarring  1. 慢性發炎 occur when acute inflammation/initial response fail to clear the stiumulus, which progress to chronic inflammation 10 BAP-L6 Chronic inflammation Causes of chronic inflammation Persistent infections: TB, syphilis, certain viral and fungal infection Immune-mediated inflammatory diseases: hypersensitivity, autoimmune diseases Prolonged exposure to offending agents: silica (silicosis), cholesterol crystals (atherosclerosis) Other mild forms of chronic inflammation: AD, atherosclerosis, metabolic syndrome Morphologic features Infiltration of mononuclear cells: macrophages, lymphocytes, plasma cells Tissue destruction: by persistent offending agents / inflammatory cells Attempts in healing: angiogenesis + fibrosis Acute vs chronic inflammations Acute Chronic Onset Minutes to hours Days to weeks Inflammatory cells Neutrophils also called polymorphonuclear leukocyte Lymphocytes, plasma cells, macrophages, 多形核⽩⾎球 fibroblasts 淋巴球 Vascular changes Vasodilation, increased permeability Angiogenesis → granulation tissue Signs Local: classic signs of red, heat, swelling, Local: tissue necrosis, fibrosis, scar pain Systemic: low-grade fever, weight loss, Systemic: high fever anaemia Cells & mediators Macrophages Professional phagocytes, dominant in most chronic inflammations Tissue macrophages (histiocytes, e.g. Kupffer cells; larger, long life span) vs monocytes (t1/2 in blood = 1 day) Extravasation of monocytes similar to neutrophil emigration, within 24 hours Pathways of macrophage activation Sequence of activations not well known Classically activated macrophage (M1) o Induced by endotoxins from microbes (TLRs), T-cell derived signals, e.g. IFN-γ, foreign substance o Microbicidal (phagocytosis) and inflammation Alternatively activated macrophage (M2) o Cytokines other than IFN-γ, e.g. IL-4, IL-13 - may inhibit M1 activation o Tissue repair, fibrosis, anti-inflammatory effects Functions Phagocytosis: by releasing ROS, proteases (collagenases, elastases) Initiate tissue repair - scar formation, fibrosis Secrete inflammatory mediators: cytokines, eicosanoids Antigen presentation to T cells, respond signals from T cells - feedback loop in cell-mediated immune response Fate: die or wander off into lymphatics (after inflammation stops), persist +/- fuse to form giant cells induced by IFN-γ (chronic inflammation) Lymphocytes Dominant in autoimmune and hypersensitivity diseases If activated, tend to be persistent and severe T lymphocytes CD4+ T cells (Th) promotes inflammation by secreting cytokines Th cells Cytokines - immune cells recruited Diseases Th1 IFN-gamma - macrophages by classical pathway Bacterial & viral infections, Th17 IL-17 - neutrophils autoimmune disease Th2 IL-4, IL-5, IL-13: eosinophils, macrophages by Allergic reaction, helminthic alternative pathway parasitic infection  11 Plasma cells Plasma cells → B cells after contact with Ag at lymphoid organs or site of chronic inflammation → secrete Ab against specific Ag Morphology: clock face, off-centre nucleus, basophilic Other cell types Neutrophils: dominant cell type in acute inflammation, but can also continue to persist in chronic inflammation – acute on chronic Eosinophils o Parasitic infection, type 1 HSR (IgE mediated) o Recruited by chemotaxis o Release major basic protein (MBP) that destroys parasites but also some epithelial cells o Morphology: bright red granules in cytoplasm (eosinophilic) Histological appearance Constant features: lymphocytes + collagen Necrosis caused by causative agent + inflammation Formation of granulation tissue and scar [BAP-L7] Granulomatous inflammation o A form of chronic inflammation, a cellular attempt to contain an offending agent that is difficult to eradicate; may in turn cause organ dysfunction (e.g. TB) o Focal accumulation of epithelioid cells (activated macrophages) + giant cells (cytoplasmic fusion of macrophages) + rim of lymphocytes +/- central caseous necrosis o Macroscopic differentiation Caseating granuloma (TB): central necrosis, e.g. TB, syphilis Non-caseating granuloma: without central necrosis, e.g. leprosy, Crohn’s disease o Microscopic differentiation Foreign body granulomas: contain foreign bodies that preclude phagocytosis due to its size, does not incite any inflammatory response - foreign body-type giant cell Immune granulomas: contain insoluble particles that are poorly degradable (e.g. microbial cell wall), induce a cell-mediated immune response - Langhans type giant cell (nuclei arranged in periphery in a horseshoe pattern) Types of chronic inflammation Recurrent acute: repeated episodes of acute inflammation followed by incomplete healing and repair, e.g. cholecystitis, pyelonephritis, chronic gastritis associated with H. pylori Primary chronic: e.g. transplant rejection Outcomes of chronic inflammation Abscess: pus in a walled cavity (collagen fibres produced by fibroblasts) which permits bacteria to multiply but not antibiotics to get access; drainage will not collapse abscess Chronic regeneration: possible derangement of tissue architecture after repeated episodes of inflammation, e.g. cirrhosis (may impair blood flow and bile drainage) Metaplasia: redifferentiation upon chronic epithelial damage, e.g. chronic smokers, chronic gastritis Fibrosis of serosal surfaces: fibrinous adhesions → granulation tissue → fibrous adhesion (symphysis) in serosal surfaces (e.g. pleura, pericardium, peritoneum) → inflammation localised, but loss of mobility Scarring [BAP-L7] o Collagen produced by increasing fibroblasts o Complications: Loss of function Contractures and obstructions: inelastic and shortens → decreased movement, stenosis Adhesions: union of 2 surfaces that are normally separate → prevent normal movement  12 BAP-L7 Healing, repair and regeneration Regeneration vs repair Regeneration Proliferation of cells to replace damaged cells, by undamaged cells and stem cells Tissue with high proliferative capacity, e.g. GI tract, skin, haemopoietic system Some parenchymal organs, e.g. liver o Parenchyma: functional part of an organ; in the context of tumour: neoplastic component o Stroma/ mesenchyme: structural part of an organ Repair Regeneration + scar formation by collagen deposition For tissues incapable of regeneration, or ECM not intact (heavily damaged) Functional loss, but provide structural stability for the injured tissues to perform function Factors affecting healing Tissue proliferating activity Definition Example Implication Labile tissue Cells proliferate throughout Surface epithelium (skin) life Columnar epithelium (GIT) Transitional epithelium (urinary tract) Cuboidal epithelium (exocrine ducts) Stable tissue Minimal activity normally Parenchymal cells of liver, kidney, Kidney removal causes Rapid growth upon injury pancreas - limited capacity except liver hypertrophy & hyperplasia Mesenchymal cells, e.g. fibroblast, SM of contralateral kidney Endothelial cells Liver: cell cycles initiated Leukocytes by cytokines, then HGF Permanent Non-dividing Neurons tissue Replaced by scar formation Cardiac, skeletal muscles Stem cells Characteristics: self-renewal capacity, asymmetric replication Types: embryonic SC (pluripotent, from inner cell mass), adult SC (found within an organ/ tissue, limited self- renewal & differentiating potential, e.g. subventricular zone of brain → ?tumourigenesis, base of crypt of GIT) Stem cell niches: specialised microenvironment where stem cells are found Growth factors Polypeptides that drive cell proliferation Act in autocrine, paracrine or endocrine manner Main source: macrophages, lymphocytes (as part of inflammatory process), stromal cells Extracellular matrix Basement membrane + interstitial matrix If damaged → repair can only be accomplished by scar formation Functions: o Mechanical support for cell anchorage and migration o Control cell proliferation o Scaffold for tissue renewal o Establish tissue microenvironment Scar formation In severe & chronic tissue injury, or damage in non-dividing cells → replacement with connective tissues Steps in scar formation: o Removal of destroyed tissue by phagocytosis o Granulation tissue: angiogenesis + migration of fibroblasts Angiogenesis: VEGF, FGF, MMPs that degrade ECM to permit vessels; from existing vessels or migrate from bone marrow o Scar formation: deposition of ECM proteins by fibroblasts: TGF-ß, PDGF, FGF o Connective tissue remodelling: MMPs  13 Factors that influence tissue repair Systemic o Nutrition, e.g. vit C o Metabolic status, e.g. diabetes o Blood supply, e.g. atherosclerosis o Glucocorticoids: inhibit TGF- production & fibrosis Local o Infection o Mechanical factors, e.g. constant local pressure o Foreign body, e.g. suture o Size, location, type of wound, e.g. joint area which requires constant moving Healing of skin wounds Epithelial regeneration (epidermis healing) + connective tissue scar formation (dermis healing) Inflammation (24h) → proliferation (3-7 days) → maturation (weeks) Primary intention Secondary intention Tertiary intention Wound Clean, uninfected incision with Larger wound, abscess, ulcer Contaminated wound good apposition of edges Action Re-epithelialisation closes the Wound left open Wound left open wound with thin scar formation ↑ inflammation, granulation tissue, → Treated with repeated collagen deposition → ↑ scar debridement + abx formation → surgically closed Wound contraction by myofibroblast Pathological aspect of wound healing Inadequate scar formation Wound dehiscence: wound rupture, e.g. abdominal wound in post-abdominal surgery due to increased intra- abdominal pressure Ulceration: inadequate vascularisation due to atherosclerosis, DM Excessive formation of repair components Hypertrophic scar: accumulation of excessive collagen, but within the boundary of original wound Keloid: hypertrophic scar beyond boundary of original wound, more common in African Americans Wound contracture Exaggerated wound contraction Common sites: palms, soles, anterior thorax Deformities of wound and surround tissues, compromise joint movement Fibrosis in parenchymal organs Excessive deposition of collagen and other ECM components Induced by chronic injurious stimuli, e.g. inflammation of liver → cirrhosis May lead to organ dysfunction and failure: structural + functional derangement  14 BAP-L13 & 14 Molecular mechanisms of neoplasia Hallmarks for cancer Activation of oncogenes Proto-oncogenes: normal genes involved in functions related to growth and proliferation Oncogenes: mutated form of proto-oncogenes Functions Implications GF (ligands) Overexpression of PDGF-b in astrocytoma GF receptors EGFR mutation in CA lung Amplification of HER2 in CA breast Signal transduction KRAS mutation in CA colon/lung Transcription factor C-MYC translocation in Burkitt's lymphoma Cell cycle regulator Amplification of cyclin D1 in HNSCC, CA oesophagus and breast Activation mechanisms o Dominantly transforming: mutation of 1 allele can lead to transformation o GOF mutation, e.g. KRAS o Translocation, e.g. MYC in Burkitt's lymphoma o Amplification Inactivation of tumour suppressor gene (TSG) TSG: encode proteins that are growth inhibitory and block transformation pathways Knudson's two-hit hypothesis: both alleles of TSG must be inactivated for tumour development, i.e. "recessive cancer gene" o As shown in retinoblastoma: high risk in heterozygous RB mutation in germline vs low risk in heterozygous RB mutation in a single retinoblast Gene Function Tumours associated Rb Regulate cell cycle: inactivate E2F which promotes Retinoblastoma, osteosarcoma, etc cells to enter S phase, i.e. G1-S checkpoint p53 Cell cycle arrest at G1 phase Most human CA Apoptosis in response to DNA damage TGF- receptor Growth inhibition: TGF-β → SMAD4 CA colon: mutation in TGFBRII and SMAD4 APC Inhibition of signal transduction Inherited: FAP, CA colon Somatic: CA colon, stomach, etc E-cadherin Cell adhesion Inherited: familiar gastric cancer Somatic: CA stomach  15 Aberrant apoptosis BCL2 family inhibits apoptosis, BAX family promotes apoptosis Relative concentration of BCL2/ BAX determines apoptotic fate, e.g. o P53 mutations in various CA o Overexpression of BCL2 in leukaemia o Overexpression of BCL2 caused by translocation in follicular lymphoma o BAX mutations in CA colon Major mechanism of chemo resistance Defects in DNA repair DNA repair Function Mechanism Implication Mismatch repair Replication errors MSH2 recognises Lynch syndrome: germline (MMR) MLH1-PMS1 excise, mutation causes MSI resynthesize, ligate Excision repair Damage from exogenous NER: chain of nt replaced Mutation of XP gene (NER) in mutant BER: a single nt replaced xeroderma pigmentosum Nucleotide excision repair (NER): bulk lesions Base excision repair (BER): simple lesions Double strand X-ray damage BRCA1 & BRCA2 mutations in breakage (DSB) 80% of familial CA breast repair Immortalisation by telomerase activation Telomeres o At chromosome ends o Functions: prevent DNA loss during replication & control replication potential o Specific sequences TTAGGG, with specific proteins (hTERT) o Shorten during cell division → arrest/ apoptosis Telomerase o Elongate telomeres o Not expressed in most somatic cells o High activity in tumours Angiogenesis, invasion and metastasis  16 Carcinogenesis Involve multiple, stepwise genetic changes: 6-7 independent driver mutations over several decades Clonal evolution: originated from a single ancestral cell + continuous evolution of subclones → tumour heterogeneity, e.g. non-antigenic, metastatic, invasive Two-phase carcinogenesis Initiation Promotion Irreversible Reversible Constant DNA damage Selective growth advantage for initiated cells → outgrowth No dose threshold Dose-response relationship Normal phenotype Altered phenotype E.g. chemical carcinogens, radiation, virus E.g. phorbol esters, hormones, phenols Carcinogen Oncogenic virus Acute transforming viruses containing viral oncogenes: not found in human CA Chronic oncogenic viruses o Insertional mutagenesis: activation of proto-oncogenes/ inactivation of TSG, e.g. HPV-16/18 o Enhance polyclonal expansion of infected cells, e.g. HTLV-1 o Immunosuppression, e.g. HIV (Non-Hodgkin's lymphoma) Human papilloma virus (HPV) CA cervix, HNSCC High-risk HPV (e.g. HPV-16, 18) o Expression of E6: bind and degrade p53 & BAX; activate telomerase o Expression of E7: bind to Rb and displace E2F, activate cyclin E & A o A necessary but insufficient factor for CA cervix → other genetic changes are necessary for transformation Low-risk HPV (e.g. HPV-6, 11) o Its E6/E7 bind much less efficiently and low affinity → genital condyloma (warts) Epstein-Barr virus (EBV) Primary EBV infection: o Early in Asian → asymptomatic o Late in Western (teenage) → developed immune system → infective mononucleosis (fever) Persist in majority as a lifelong, asymptomatic infection of a B-lymphocyte pool Failed immunoregulation → mutation of one clone → Burkitt's lymphoma  17 Human T-cell leukaemia virus type 1 (HTLV-1) The only retrovirus that causes human cancer Endemic in Japan Genome contains pX region → TAX protein → o ↑Expression of cytokines, cytokine receptors and co-stimulatory molecules --> ↑CD4+ T cells o ↓Function of TSG, e.g. p16, p53 Chemical carcinogens Direct-acting agents: require no metabolic conversion, e.g. chemotherapy Indirect-acting agents: o Require metabolic conversion to become carcinogenic, e.g. CYP450 - polymorphic → susceptibility varies o Polycyclic hydrocarbons (smoking): CA lung o Aromatic amines (rubber): CA bladder o Nitrosamines: GI cancer, NPC o Aflatoxins (moldy nuts & grains): HCC Radiation Non-ionising radiation (UV) Form thymine dimer (T^T) → point mutations in oncogenes & TSG → overwhelm NER Cumulative exposure --> SCC, basal cell carcinoma Intense intermittent exposure --> melanoma Ionising radiation (X-ray, gamma ray, radioactive substance) Damage directly and indirectly (form ROS) Examples of tumour suppressor genes & associated cancers All mutations are inherited in an autosomal dominant (AD) fashion Gene Associated cancers APC Inherited mutation: familial adenomatous polyposis Somatic mutation: CA colon, stomach TGF- Inherited mutation: familial stomach cancer Somatic mutation: CA pancreas, CRC RB1 Inherited mutation: retinoblastoma, osteosarcoma Somatic mutation: retinoblastoma, osteosarcoma, CA breast, lung, colon VHL Inherited mutation: von Hippel-Lindau syndrome (cerebellar haemangioblastoma, retinal angioma, bilateral RCC, bilateral phaeochromocytoma) WT1 Inherited mutation: Wilms tumour Somatic mutation: Wilms tumour TSC1 & TSC2 Inherited mutation: tuberous sclerosis (hypopigmented skin lesion – ash leaf spots, MR, seizure, harmatoma, e.g. angiomyolipoma, cardiac rhabdomyoma) NF1 Inherited mutation: neurofibromatosis type 1 (phaeochromocytoma, Wilms tumour, neurofibrosarcoma) Somatic mutation: neuroblastoma NF2 Inherited mutation: neurofibromatosis type 2 (bilateral acoustic neuroma, meningioma) Somatic mutation: acoustic neuroma, meningioma BRCA1/2 Inherited mutation: CA ovary, female breast (BRCA1), male breast (BRCA2) p53 Inherited mutation: Li-Fraumeni syndrome (CA breast, brain tumour, leukaemia, sarcoma) Somatic mutation: MC gene producing cancer PTEN Inherited mutation: Cowden syndrome (multiple harmatoma syndrome, with increased risk of CA breast, follicular thyroid cancer, etc), type 1 endometrial carcinoma  18 BAP-L15 Classical tumours Terminology Neoplasm/ tumour Benign Malignant Epithelial -oma -carcinoma* Mesenchymal -oma -sarcoma Hemato-lymphoid -oma Germ cell Mature (cystic) teratoma of ovary Teratoma: derived from > 1 germ cell layer; at or close to midline Precursor cells -blastoma: mostly in children, except glioblastoma *Carcinoma in situ is a pre-malignant condition (except urothelial bladder TCC [ACP-L25]) Malignant tumours with -oma: o Haemato-lymphoid: lymphoma, multiple myeloma o Germ cell: teratoma, seminoma o Melanoma o Mesothelioma o Glioma Muscles: rhabdomyo- (skeletal muscle), leiomyo- (smooth muscle) Reporting a tumour Diagnosis Characteristics Benign Malignant Differentiation Well differentiated Varied: from well-differentiated to anaplasia Growth rate Usually slow - circumscribed Increased, atypical mitosis - mitotic count, proliferation index Mitotic figures rare Nuclear atypia: high N/C ratio, hyperchromasia, pleomorphism, prominent nucleoli Necrosis (overrun blood supply) - eosinophilic, homogenous Neo-vascularisation - haemorrhage Invasion (local) Well demarcated Stromal invasion - desmoplastic reaction (growth of spindle- May be encapsulated like fibrous tissues)^ Lymphovascular invasion Perineural invasion Metastasis Absent Hallmark of malignancy* (distant) Lymphatic spread: regional LN → distant LN Haematogenous spread Transcoelomic spread: through peritoneum, pleura, pericardium ^Urothelial transitional cell caricoma (TCC) as an exception: malignant even without stromal invasion yet (i.e. carcinoma in situ) *Basal cell carcinoma (BCC) as an exception: invade but do not metastasize Staging and grading o Staging: how far → prognosis; TNM (pathological, clinical) o Grading: how fast → aggressiveness; higher grade usually means lesser degree of differentiation Margin status Potential for target therapy Standard description of tumour Squamous cell carcinoma Adenocarcinoma Architecturally, it is composed of Squamous differentiation Glandular differentiation proliferation of tumour cells with In a desmoplastic stroma In a desmoplastic stroma Tumour cells are arranged in Infiltrative nests and sheets with Infiltrative irregular and complex keratin pearl glands Cytologically, tumour cells show Malignant cytology with nuclear pleomorphism, hyperchromasia, enlargement, increased n/c ratio and frequent mitosis Tumour cells also show Intercellular bridges Mucin secretion  19 Clinical effects of a tumour Local effect Local effect Example Mass effect (SOL): compression, impingement Brain: midline shift, herniation Blocking lumen Bowel: IO Ulceration, bleed Stomach: GIB Invasion Lung: involve ribs Rupture/ infarct Liver: rupture HCC Secondary infection Biliary: sepsis (due to biliary stasis) Systemic effect Cachexia o Progressive weight loss (fat + muscle), anorexia, anaemia, immunocompromised, poor fitness/ recovery for surgery o Pathogenesis: metabolism, inflammation with cytokines (TNF-α, IL-1) Paraneoplastic syndromes: non-metastatic systemic effects o Endocrine paraneoplastic syndrome Ectopic hormone Typical tumour type Hypercalcemia of PTHrP HNSCC, Lung malignancy PGs RCC SIADH ADH-like hormone Lung Cushing's syndrome ACTH Lung o Hypertrophic osteoarthropathy (HOA) Clubbing, periosteal long bone formation, arthritis Common in CA lung: platelet failed to degrade in lung → its circulating factors lodged in fingertip o Neurological paraneoplastic syndromes Myasthenic syndrome, peripheral neuropathy, polymyopathy Cortical cerebellar degeneration o Vascular phenomenon o Fever: MC presentation o Nephrotic syndrome Dysplasia Disordered growth and maturation of an epithelium, potentially reversible Pre-invasive neoplastic process, without stromal invasion (not yet invade through basement membrane), i.e. tumour in-situ (Tis) Grading: low-(intermediate)-high CA cervix as a classic example [ACP-L49] o Basal layer affected first: highly dividing Tumour-like conditions Hamartoma 錯構瘤 o Overgrowth of disorganised tissue indigenous to that particular site o E.g. lung hamartoma, Peutz-Jeghers polyp Heterotopia: mature tissue in a foreign location o Choristoma: heterotopia that is clinically significant  20 BAP-L18 & 19 Haemodynamic disturbances Thrombosis Definition: intravascular mass attached to the vessel wall that is composed of varying proportions of coagulation factors, RBCs, and platelets Pathogenesis: Virchow's triad [ACP-L29] Examples Remarks Endothelial injury Atherosclerosis Common cause of Vasculitis arterial thrombus Endocarditis formation Circulatory stasis LA dilatation due to MS Common cause of Varicose veins venous thrombus formation Hypercoagulability 1o: protein C deficiency 2o: DIC, antiphospholipid syndrome, malignancy Pathology Lines of Zahn: pale platelet & fibrin layers alternating with darker red cell-rich layers; only present in those that form in flowing blood (i.e. arterial/venous but not postmortem) Microscopy o Arterial thrombus white: platelet-rich, fibrin-poor o Venous thrombus red: RBC-rich, platelet-poor, fibrin-rich Fate of the thrombus Dissolution: newly formed thrombus prone to shrinkage by activation of fibrinolytic factors; old thrombus more resistant Organisation: thrombi invaded by fibroblasts and endothelial cells → new, smaller conduits → o Recanalisation: incorporated into the vessel wall o Digestion: centre of thrombus digested by enzymes from entrapped macrophage; serve as culture medium if bacteria present → weaken the wall (mycotic aneurysm) [ACP-L9] Propagation: enlarged by obtaining additional platelets and fibrin → ↑risk of occlusion Embolism: thrombus s is dislodged and transported elsewhere in the vasculature → obstruction Embolism Definition: detached mass (solid, liquid, gas) that is carried through blood to a distant site Origin Clinical presentations/ definitions Thromboembolism DVT (mostly from LL) Pulmonary embolism: MC from DVT (venous) MI, endocarditis Systemic embolism: MC from heart; tissue infarct Fat embolism Fractured long bone (MC) Marrow fat enters ruptured marrow sinusoids → pulmonary Fatty liver capillaries → embolised to brain, kidneys, etc SOB, tachycardia, renal failure; delirium and coma common Pathology: revealed by oil red O stain Amniotic fluid Amnion Tears in placental membrane +/- uterine vessels → embolism cardiopulmonary collapse + DIC SOB, bleeding (∵DIC) High mortality; survivors present with neurological impairment Air embolism Decompression sickness Rapid ascent in scuba diving converts soluble N2 to gas bubbles in vessels & tissues Bends (severe pain in joints & bones), pulmonary oedema, bleeding, atelectasis Paradoxical emboli ASD/VSD Venous emboli passing through ASD/VSD into systemic circulation  21 Disseminated intravascular coagulation (DIC) [ACP-L29] A thrombohaemorrhagic disorder, causing ischemic damage (fibrin thrombi occludes the microcirculation) + bleeding from GIT, nose and every puncture site Pathogenesis Consumption coagulopathy: pathologic generation of thrombin leads to o Widespread intravascular deposition of fibrin: ↓platelet, schistocytes o Consumption of platelets and clotting factors: ↑aPTT, PT, TT, ↓fibrinogen Activation of fibrinolysis: ↑FDP, D-dimer DIC-associated clinical disorders Obstetric: amniotic fluid embolism, eclampsia Infections: G- septicaemia (MC) Neoplasm: acute promyelocytic leukemia, adenoCA Massive tissue injury: trauma, burns Others: snake venom, shock Oedema Increased fluid in the interstitial space of ECF compartment Pathophysiology Pathophysiology Examples ↑hydrostatic pressure CHF: CVP & water and Na retention ∵CO Constrictive pericarditis Venous obstruction Liver cirrhosis: portal HT ↓oncotic pressure Nephrotic syndrome Malnutrition Protein-losing enteropathy Liver cirrhosis: albumin production Lymphatic obstruction Inflammatory CA breast: lymphatic blockage by malignant cells Lymphoedema after radical mastectomy Capillary permeability Toxins: direct damage of endothelium → leakage Chemical mediators: retraction of endothelial cells Types of oedema Transudate Exudate Mechanism Δ Starling force (hydrostatic/ oncotic) Δ Permeability Protein Low High Fibrinogen Absent Present Cells Few, mesothelial Inflammatory Oedema Dependent, pitting oedema: obey law Non-pitting oedema: viscosity ∵ of gravity protein and cells Congestion & hyperaemia Hyperaemia Congestion Increase in blood volume within a tissue Active process: arteriolar dilation, increased inflow Passive process: impaired outflow, passive vasodilation Red (erythema) Blue-red (cyanosis) Morphology Liver congestion: nutmeg appearance – centrilobular zone necrosis (red/brown) surrounded by uncongested periportal zone (tan-coloured) Pulmonary congestion: engorged alveolar capillaries  22 Shock Systemic hypoperfusion due to reduced effective circulating blood volume (ECV) Type of shock Examples Pathogenic mechanisms Cardiogenic AMI Pump failure PE Extrinsic pressure Cardiac tamponade Obstruction to outflow Arrhythmia Hypovolemic Haemorrhage Inadequate blood Fluid loss volume Septic Bacteraemia G+: LTA G-: LPS (endotoxin) Neurogenic Anaesthesia Loss of vascular tone Spinal injury Anaphylactic Allergy IgE-mediated HSR C', histamine Presentations Vasodilatation: hypotension, weak pulse, cold clammy skin Low CO: tachycardia, oliguria, mental changes ARDS: hyperventilation, pallor/ cyanosis DIC: haemorrhage Stages Non-progressive: perfusion maintained by neurohumoral compensatory mechanisms Progressive: widespread tissue hypoxia, vital organs affected Irreversible: widespread cell injury that death is inevitable Consequences Brain, heart: irreversible damage Kidneys: acute tubular necrosis Lungs: diffuse alveolar damage (shock lung) Adrenals: lipid depletion due to increased utilisation for steroid GIT: mucosal ulcerations, haemorrhages Liver: fatty changes, perivenular necrosis Prognosis Best for hypovolemic and neurogenic types Worst for cardiogenic (no compensatory mechanisms) and septic (hard to gauge cytokines released and DIC) RAAS and ADH system do not cause oedema, but they maintain pre-existing oedema.  23 BAP-L33 Amyloidosis Definition Fibrillar protein that is deposited in extracellular interstitial tissue, resulting in organ dysfunction by pressure atrophy of adjacent cells (but not evoking inflammation) More than 25 distinct proteins Morphology: o EM: linear, non-branching, 8-10nm diameter, varying length o X-ray crystallography: -pleated sheet arrangement Tissue diagnosis Tissues commonly biopsied: rectum, gingiva, omental fat pad H&E: amorphous eosinophilic hyaline in between cells Congo red: orange red pink or red colour to tissue deposit Polarising microscopy: apple green birefringence Immunohistochemistry: antibodies to further differentiate between AA, AL, Aβ EM: differentiate between amyloidosis (non-branching, constant diameter) and other fibrillary diseases (e.g. fibrillary glomerulonephritis) Biochemical forms and pathogenesis Origin Pathogenesis Remarks AL (amyloid Light chains of Ig (γ > κ) Plasma cell dyscrasia Amyloidosis or non- light protein) → ↑Ig or Bence Jones protein amyloidosis condition (renal → defective proteolysis or protein cast nephropathy, light chain misfolding deposition disease (LCDD) → renal failure) AA (amyloid- SAA (serum amyloid-associated Chronic inflammation → ↑IL-1/6 MC worldwide associated fibril) protein), an acute phase reactant → sustained ↑SAA from liver → synthesized and released by liver in defective proteolysis or protein inflammation misfolding A APP (amyloid precursor protein) Found in AD Other possible proteins: ATTR (transthyretin): carrier protein for T4 and vit. A; seen in familial amyloid polyneuropathy and senile amyloidosis Aβ2-m (β2-microglobulin): light chain component of MHC; seen in long-term haemodialysis Procalcitonin: seen in MTC  24 Common types of amyloidosis Type of amyloidosis Disease associations Fibril protein Systemic amyloidosis Plasma cell dyscrasia (1o) Monoclonal gammopathy AL Multiple myeloma (10%) Chronic inflammation (2o) RA, AS, IBD AA TB, osteomyelitis Neoplasm: RCC Haemodialysis-associated CKD → not filtered by dialysis membrane → found in carpal Aβ2-m amyloidosis ligament of wrist → carpal tunnel syndrome Hereditary amyloidosis Familial amyloid ATTR polyneuropathy Familial Mediterranean fever AA Localised amyloidosis Senile amyloidosis Heart (restrictive cardiomyopathy, conduction defects) ATTR Alzheimer's disease Aβ Islets of Langerhans T2DM Amylin Medullary carcinoma of Excessive calcitonin production from thyroid C cells Procalcitonin thyroid (MTC) Sporadic (80%) or familial (20%) Manifestations General Fatigue, SOB, oedema, paraesthesia, weight loss Kidney MC involved and serious Proteinuria with nephrotic syndrome GI Macroglossia → speech and swallowing Diarrhoea → malabsorption CVS Restrictive cardiomyopathy: infiltration of amyloid between myocytes [ACP-L9] Conduction defects Liver Hepatomegaly Amyloid first appears in space of Disse Pressure atrophy of hepatocytes, but functional impairment uncommon Spleen Splenomegaly If white pulp involved: sago spleen appearance If red pulp involved: waxy appearance (lardaceous spleen) Musculoskeletal Commonly found in haemodialysis-associated amyloidosis Bilateral carpal tunnel syndrome, bone cysts, etc Haemostasis Vascular fragility: bleeding, spontaneous or following trivial trauma Factor X deficiency: factor X binds to amyloid fibrils Pinch purpura: amyloid infiltration of small vessels CNS Dementia (AD) Peripheral neuropathy (paraesthesia, muscle weakness) Autonomic neuropathy Prognosis Poorer in systemic amyloidosis than localised disease OS 1-3 years due to late Dx; earlier detection now made possible by immunoelectrophoresis Causes of death: arrhythmia or renal failure Treatment Tx of dyscrasia: for amyloidosis due to plasma cell dyscrasias Anti-TNF: for amyloidosis involving kidneys Haemodialysis, renal transplant: for those with renal failure Autologous bone marrow transplant: for those with preserved organ function  25 GI AND HBP PATHOLOGY BAP-L34 Head and neck pathology Developmental abnormalities Branchial cleft cyst/ sinus/ fistula Failure of obliteration of 2nd branchial cleft Mostly in anterolateral neck Distinguished from cystic LN metastasis Thyroglossal duct cyst Failure of atrophy of thyroglossal duct Midline lesion Diseases of oral cavity Oral inflammatory lesions Aphthous ulcers: could be a/w coeliac disease, IBD, Behcet disease Viral: HSV-1 (latent, reactivating); cold sores [MIC-L36] Fungal: Candida albicans - commensal, but infectious (candidiasis) in infants/ immunocompromised Bacterial: TB Oral pre-cancerous lesion Erythroplakia and leukoplakia Red/ white patches, due to chronic irritation (e.g. dentures), candida, smoking Leukoplakia: considered precancerous unless proven otherwise by histology → dysplasia of squamous epithelium, may proceed to SCC Erythroplakia: much greater risk of malignancy Head and neck squamous cell carcinoma (HNSCC) Aetiology: smoking, alcohol, betel nuts, HPV (high risk types: 16, 18) Sites: lower lip (MC) > floor of mouth > lateral border of tongue Sx: ulcer, dysphagia, odynophagia, throat discomfort, neck mass (metastatic LN) Extent of disease: o Field cancerisation: 100x more likely to develop another primary tumour in the region (synchronous or metachronous) ∵ chronic mucosal exposure to carcinogens (alcohol, tobacco) & continuous mucosa o Metastasis: cervical LN → distant organs HPV-associated HNSCC Increasing trend, but better prognosis Pathogenesis: HPV16/18 → E6/7 oncoproteins → Rb & p53 → compensatory p16 Implications: o P16 immunostain can be used as a surrogate marker o HPV vaccine Pathology: poorly differentiated  26 Diseases of nasal cavity, pharynx, larynx Non-neoplastic conditions Allergic rhinitis Type 1 hypersensitivity Repeated attacks lead to nasal polyp formation Vocal cord nodule/ polyp Found in singers or those who abuse voices Nasopharyngeal carcinoma (NPC) WHO classification: o Keratinising squamous (25%) o Non-keratinising squamous (75%): strongly associated with EBV ▪ Differentiated (15%) ▪ Undifferentiated (60%) o Basaloid squamous Pathology (HK): o Syncytial sheets of undifferentiated, non-keratinising cells o In-situ hybridisation for EBV-encoded RNA (EBER-ISH) +ve Investigations: o Bloods: CBC, EBV DNA o Imaging: CT, MRI o Endoscopy: nasendoscopy +/- biopsy Other risk factors: genetics (Southern Chinese), environmental (nitrosamines, smoking, chemical fumes) Diseases of salivary glands Non-neoplastic conditions Sjogren syndrome Autoimmune destruction of salivary, lacrimal & conjunctival glands by infiltration of lymphocytes & plasma cells Dry mouth: dental caries, candidiasis, dysphagia, dysphasia Dry eyes Sialadenitis Acute inflammation of salivary glands Mostly due to mumps virus Calculi Submandibular > parotid: more serous Blockage, swelling, gland atrophy Neoplasms Involve both major and minor salivary glands (in oral cavity, nasal cavity, trachea, etc) MC in parotid Size inversely proportional to likelihood of being malignant, i.e. sublingual tumours are most often malignant Diseases of jaw bone and teeth Odontogenic keratocyst: locally aggressive, high recurrence rate Ameloblastoma: from odontogenic epithelium, locally invasive but slow-growing  27 BAP-L35 Oesophageal pathology GI histology Obstructive diseases Mechanical obstruction Failure of FG division in 4th week of gestation Oesophageal atresia: congenital absence of lumen; MC occur near tracheal bifurcation Tracheoesophageal (TE) fistula: MC type III (connected to lower oesophagus) Presentation: aspiration pneumonia, regurgitation, severe fluid/ electrolyte imbalance Functional obstruction (Achalasia) Oesophageal motor disorder characterised by triads of o Aperistalsis o Increased resting tone of LES o Incomplete LES relaxation during swallowing Aetiology: o Primary: idiopathic (degeneration of inhibitory neurons) o Secondary: Chagas disease (Trypanosoma cruzi causes destruction of myenteric plexus) Presentations: progressive dysphagia (99%), nocturnal regurgitation, aspiration Complications: candida oesophagitis, lower oesophageal diverticulum, aspiration pneumonia, oesophageal SCC (∵? Chronic stasis of food and bacterial overgrowth) Oesophageal varices Dilated tortuous submucosal veins in lower oesophagus due to portal hypertension Pathogenesis: portal hypertension induces backflow of portal blood to caval system → enlargement of submucosal venous plexus in distal oesophagus → massive hematemesis Fatal: 40% mortality in 1st episode, 50% 1-year rebleeding rate with 40% mortality Oesophagitis Mallory-Weiss syndrome Longitudinal mucosal (superficial) tears of distal oesophagus +/- proximal stomach 5-10% of upper GIB, self-limiting Aetiology: severe retching associated with excessive alcohol intake Pathogenesis: failed reflex relaxation of musculature in prolonged vomiting → reflux of gastric contents Boerhaave syndrome: severe form of MWS; rupture of distal oesophagus → mediastinitis  28 Reflux oesophagitis MC type of oesophagitis: reflux of gastric content +/- duodenal bile into lower oesophagus Presentation: heartburn (mimic angina), dysphagia, regurgitation Complication: minor UGIB, stricture, Barrett oesophagus Histology: o No correlation with symptoms severity, but to assess for Barrett oesophagus o Basal zone hyperplasia (> 15% of full-thickness) o Papillary elongation of lamina propria (>2/3 full thickness) o Leukocytic exocytosis (neutrophil + eosinophil +/- lymphocyte) Barrett oesophagus Replacement of distal squamous epithelium with metaplastic columnar epithelium, identified in o Endoscopic exam: salmon-coloured mucosa at 1cm above OGJ o Histological exam: presence of goblet cells (intestinal metaplasia) + columnar cells Risk factor for oesophageal glandular dysplasia and adenocarcinoma (30 - 100x), but majority do not develop Oesophageal carcinoma Male predominance: 4:1 Age 60-70 Squamous cell carcinoma Adenocarcinoma % of CA oesophagus 90% (c.f. Western countries) 10% Risk factors Lifestyle: smoking, alcohol, hot drinks, nutrition Barrett oesophagus (e.g. vit A, Zn), nitrosamines Oesophageal disease: achalasia, Plummer-Vinson syndrome Tylosis Morphology Mostly in mid third Mostly in distal third Presentations Dysphagia (solid → liquid), odynophagia Rapid weight loss Dry cough, haemoptysis: tracheal invasion Hoarseness: RLN invasion Hypercalcaemia: PTHrP ~ lung SCLC PVS: triad of oesophageal web, intermittent dysphagia, IDA; unknown pathophysiology Tylosis: AD genetic disorder characterised by hyperkeratosis of palms & soles + oral leucoplakia  29 BAP-L39 Gastric pathology Anatomy and physiology of stomach Inflammations Acute gastritis Definitions: transient mucosal inflammation, which may lead to o Erosion: breach in the epithelium of the mucosa o Ulcer: breach in the mucosa, with extension into submucosa or deeper Aetiology: o Drugs: NSAID (MC), aspirin, chemo o Metabolic: alcohol, chemical, uraemia o Traumatic: NG tube o Severe stress, e.g. severe burns (Curling ulcer) o CNS injury (Cushing ulcer) Clinical presentations: o Asymptomatic o Epigastric pain, n/v o Bleeding: hematemesis, melena, massive blood loss o Acute gastric ulcer: ▪ Curling ulcer: in proximal duodenum, a/w severe burns, trauma ▪ Cushing ulcer: in stomach, duodenum, oesophagus, a/w intracranial disease (direct stimulation of vagal nu.); risk of perforation Chronic gastritis H-pylori-associated Autoimmune % of chronic gastritis >80% 10% Associated diseases Gastric ulcer Pernicious anaemia Duodenal ulcer (~ 100%) Predominant location Antrum ( antral biopsy) Body Pathogenesis Features of HP virulence: Antibodies to parietal cells → loss of H/K Flagella: motility ATPase (achlorhydria ∴ gastrin) Urease: generate ammonia to Antibodies to intrinsic factor → B12 neutralise gastric acid ∴pernicious anaemia Adhesins: enhance adherence to foveolar cells (mucous cells) Toxins (CagA): carcinogenesis Overwhelm mucosal defences → pangastritis Complications Gastric adenoCA, lymphoma Gastric adenoCA Histology HP concentrated in mucous layer Endocrine G cell hyperplasia Chronic +/- active inflammation: Chronic inflammation: lymphocytes lymphocytes +/- neutrophils Diffuse glandular atrophy Glandular atrophy Intestinal metaplasia Intestinal metaplasia  30 Peptic ulcer disease Risk factors: most commonly HP infection or NSAID use Pathogenesis: imbalances of mucosal defences and damaging forces → chronic gastritis → PUD Locations: any portion of GIT o HP infection: D1 of duodenum (MC), antrum o GERD: lower oesophagus o Gastric heterotopia, e.g. Meckel diverticulum o Zollinger-Ellison syndrome (gastrin tumour): multiple ulcers Gross morphology o Mostly solitary, sharply punched-out, slightly elevated around the edges (fibrosis) o Base clear and smooth: peptic digestion; bleeding possible Histology (of 4 layers) NIGS o Necrotic debris o Acute inflammation o Granulation tissue o Fibrosis Gastric ulcer Duodenal ulcer % of ulcer cases 25% 75% Location Lesser curvature D1 of duodenum Anterior portion, then posterior portion Risk of malignancy Small risk – need for biopsy Never – no need for biopsy Clinical presentations Epigastric pain exacerbated by food Epigastric pain relieved by food Complications Bleeding (left gastric artery) Bleeding (GDA) Perforation Perforation Gastric outlet obstruction (GOO), pancreatitis: posterior ulcer Gastric neoplasms Gastric polyps Non-neoplastic (> 90%) Hyperplastic/ inflammatory polyps: in chronic inflammation [BAP-39] Fundic gland polyps: acid → gastrin → glandular hyperplasia Neoplastic Gastric adenoma: risk of adenoCA related to size Malignant neoplasms Carcinoma: 85-90% Lymphoma: 5-10% Mesenchymal tumour (GI stromal tumour): 2% Carcinoid tumour: 0.3% [BAP-39]  31 Gastric adenocarcinoma Epidemiology: incidence, but higher in Asia; routine endoscopic screening in Japan Locations: lesser curvature and antrum (MC) > cardia Risk factors Environment: smoking, smoked food (Japan), diet (nitrosamines), pernicious anaemia, gastric adenoma Host: Helicobacter pylori (HP), EBV Genetics: APC, Lynch syndrome, HDGC, blood group A Gross classification (Borrmann) Type 1: polypoid Type 2: fungating with sharp raised margins Type 3: ulcerated with poorly defined margins Type 4 (linitis plastica): diffuse infiltration due to desmoplastic reaction that stiffens the gastric wall Microscopic classification (Lauren) Association Histological features HER2 amplification Prognosis Intestinal type Most environmental risk factors, Cohesive, gland formation, 10-15% Better (MC) but no family history mucin Diffuse type Hereditary diffuse gastric Discohesive mucinous cells < 1% Worse cancer syndrome (HDGC): E- → Signet ring cell cadherin mutation Linitis plastica Not associated with most risk factors (e.g. HP) Mixed type With both intestinal and diffuse type Clinical findings Cachexia, weight loss (60%) Epigastric pain (50%) Vomiting +/- melena Metastasis: left supraclavicular node (Virchow), umbilicus (Sister Mary Joseph nodule), organs (e.g. ovaries – Krukenburg tumour) Prognosis Depend on TNM staging Early (good survival): limited to mucosa/submucosa Advanced (poor survival): infiltrated into muscularis propria Gastric lymphoma MC extra-nodal lymphoma [ACP-L17] Mostly non-Hodgkin B-cell lymphoma, associated with HP/ EBV o HP eradication therapy treats 70% of case Homing: tend to home back to stomach Classification o Low grade B-cell lymphoma: MALToma, related to HP o High grade B-cell lymphoma: transformed to diffuse large B-cell lymphoma (DLBCL) GI stromal tumour (GIST) Site: stomach > SB > LB Pathogenesis o Originate from interstitial cells of Cajal (ICC) in muscularis propria o GOF mutation of c-KIT or related PDGFRA (95%) Immunohistochemistry c-KIT TKI (Imatinib) for the unresectable/ metastatic tumour  32 BAP-L38 Non-neoplastic diseases of small and large bowels Vascular diseases Ischemic bowel disease Pathogenesis Hypoxic injury phase: little damage Reperfusion injury phase: o ↑O2 supply → ↑ROS o ↑influx of leukocytes and complements → ↑inflammation Watershed zones prone to damage: end of arterial supplies o Splenic flexure (Griffith’s point): SMA & IMA o Sigmoid colon (Sudeck's point): IMA and hypogastric artery Types of infarction Layer involved Pathophysiology Manifestations Mucosal Mucosal layer Systemic hypoperfusion (shock) Abdominal pain, melena Mural Mucosal + submucosal Localised anatomic defects Progress to transmural if not restored Transmural All layers Acute occlusion of a major As above mesenteric artery Perforation, sepsis, shock High mortality > 50% Aetiology Examples Luminal Embolism (MC): AF as MC risk factor; SMA most vulnerable ∵ greatest velocity of blood flow + most acute angle off the aorta Thrombosis: arterial, venous Mural Atherosclerosis Vasoconstriction: 2o to shock or vasoconstrictors Extramural Anatomical defects: volvulus, hernia Haemorrhoid Variceal dilations of anal/ perianal venous plexuses Risk factors: constipation (elevated venous pressure), pregnancy, portal HT (rare) Sx: rectal bleed, pruritus, prolapse mass, pain (thrombosed haemorrhoids) Classification: External Internal Below dentate line Above dentate line, further divided into Grade 1: no prolapse Grade 2: prolapse that can be reduced spontaneously Grade 3: prolapse that can be reduced manually Grade 4: prolapse that cannot be reduced Squamous epithelium Columnar epithelium Pain (if thrombosed) No pain Angiodysplasia (vascular ectasia) Definition: AVM characterised by tortuous dilatations of submucosal and mucosal veins Pathogenesis o Degenerative: incidence increases with age o Mechanical: peristaltic contraction → intermittent obstruction and dilatation of submucosal veins, venules, capillaries → loss of precapillary sphincter function → AVM MC site: caecum & ascending colon (80%) > jejunum & ileum (15%) Associated with ESRF Common cause of recurrent LGIB (20%) o Mostly self-limiting o Massive bleed (15%)  33 Inflammatory diseases Infective enterocolitis Presentations: diarrhoea, sometimes ulceration and inflammation in intestine Caused by bacteria (Vibrio, C. difficile), virus (rotavirus), parasites Intestinal tuberculosis Necrotising granuloma: necrotic centre + epithelioid histiocytes + Langhans giant cell [BAP-L6] ZN stain +ve Pseudomembranous colitis (PMC) Formation of pseudomembrane (layer of inflammatory cells + debris overlying sites of mucosal injury) Pathogenesis: toxins of Clostridium difficile → Dx test [MIC-L32] Treatment: antibiotics, faecal microbiota transplantation (FMT) Inflammatory bowel disease (IBD) Increasing incidence in HK Pathogenesis o Genetics: NOD2 (not in HK!) o Mucosal immune response: Th1/2/17 cells o Epithelial defects: defective tight junctions o Gut microbiota: metronidazole helpful in maintaining remission of CD Crohn's disease Ulcerative colitis Incidence 1/100000 (c.f. 5/100000 in Western) 2/100000 (c.f. 10/100000 in Western) Presentation Abdominal pain Abdominal pain Diarrhoea +/- blood & mucus (only with colon/ Diarrhoea with blood & mucus anal involvement) Risk factors Smoking Smoking/nicotine as a protective factor Sites Whole GIT, but MC in terminal ileum & caecum Rectum +/- colon Skip lesions Continuous lesion Gross Transmural inflammation - thick wall Mucosal/submucosal inflammation - thin wall