General Pathology for Dental Students PDF

-2- General Pathology For dental students first edition 2024  The Contents Page  Introduction of pathology............................................

-2- General Pathology For dental students first edition 2024  The Contents Page  Introduction of pathology.....................................................................  Inflammation........................................................................................ 1  Pathogenesis of inflammation................................................... 3  Types of Acute inflammation.................................................. 13  Chronic inflammation..............................................................21  Cell injury............................................................................................ 25  Types of cell injury…………………………………………...27  Reversible cell injury............................................................... 28  Irreversible cell injury.............................................................. 35  Repair.................................................................................................... 42  Types of repair......................................................................... 46  Complications of wound healing............................................. 51  Healing of injury bone.............................................................. 52  Infectious diseases………...................................................................56  Bacterial infections………………………………....................56  Fungal infection.........................................................................61  Osteomyelitis..............................................................................62  Disorders of Immunity…..…............................................................. 65  Cellular adaptation..............................................................................74  Neoplasia ……………….……………………………..………………79  Benign & malignant tumors ……….……………....................83  Carcinoma and sarcoma...........................................................87  Examples of malignant tumors.................................................87  Disturbances of Circulation...……………........................................89  Disturbances of body fluids...................................................89  Disturbances of blood flow......................................................91  Introduction of pathology Pathology Pathology Is the scientific study of disease. It is concerned with the causes and effects of disease, and the functional and structural changes that occur. Changes at the molecular and cellular level correlate with the clinical manifestations of the disease. Understanding the processes of disease assists in the accurate recognition, diagnosis and treatment of diseases. Disease is an alteration from the normal function/ structure of an organ or system, which manifests as characteristic groups of signs and symptoms. Diseases are often classified as either congenital or acquired disorders. Congenital diseases are present from birth, causes can be either genetic or non-genetic, whereas acquired disorders result of factors originating in the external environment. Acquired causes can be any of the following: 1. Trauma 2. Infections 3. Radiation injury 4. Chemical injury 5. Circulatory disturbances 6. Immunological disturbances 7. Degenerative disorders 8. Nutritional deficiency diseases 9. Endocrine disorders 10.Psychosomaticfactors 11. Iatrogenic disease 12. Idiopathic disease Most of diseases are due to a combination of causes, and they are, therefore, said to have a multifactorial etiology.  Inflammation Definition: - is A local protective response of living vascularized tissues to stimuli (Injurious agents), aiming to eliminate or limit the spread of injurious agent Add the suffix ―itis‖ to organ name Examples:- - Tonslitis, Rhinitis, hepatitis, colitis, gastritis , cystitis Except: - - pleurisy is inflammation of pleura - Pneumonia is inflammation of lung Function of inflammation: - Bring elements of the immune system to the site of injury and prevent further tissue damage. Effects of Inflammation 1- Disposal and isolate of the irritants 2-Disposal of the consequences of injury (e.g. necrotic cells). 3-Neutralize & inactivate the toxins 4- Prepare for healing (Repair) 5-It may have adverse effects as 1. Pain 2. Inflammatory swelling compression or obstruction vital organs e.g encephalitis 3. Hypersensitivity ( e.g. Allergy) 4. Autoimmune disease 5. Thrombosis Causes of inflammation 1) Microbial infections→ Bacteria& their toxins, viruses, fungi and parasites 2) Physical irritants → Burns, excess cold, ultraviolet light, irradiation -1-  3) Mechanical irritants → Trauma 4) Chemical irritants. →Strong alkali, strong acid, inorganic poisons 5) Tissue necrosis→ Ischemia resulting in a myocardial infarction. 6) Foreign body→ Bullet, fragments of bullet. 7) Immunological reaction→→ hypersensitivity, autoimmune disease Systemic symptoms 1. Fever due to irritation of thermoregulatory center by :- TNF, IL-1& IL-6 2. Constitutional symptoms: nausea, malaise and anorexia 3. High erythrocyte sedimentation rate (ESR) 4. Changes in WBCs counts A. Leucocytosis (increased number of WBCs) ⚫ Bacteria ----------- Neutrophils ⚫ Parasites ---------- Eosinophils ⚫ Viruses ------------Lymphocytes B. Or Leucopenia (decreased number of WBCs) ⚫ Some viral infections, salmonella infections. 5. Immunologic reactions - increased level of some substances (C-reactive protein) Local Cardinal Signs Of Inflammation:- 1. Redness 2. Hotness 3. Swelling 4. Pain 5. Loss (or impairment) of function -2-  Types of Inflammation 1. Acute inflammation 2. Subacute inflammation 3. Chronic inflammation Time course of inflammation 1. Pre acute inflammation ----------so fast you hardly known what hit you. 2. Acute inflammation ---------------hours to few days 3. Subacute inflammation ----------- in between 4. Chronic inflammation ------------ weeks to months to years Pathogenesis of inflammation 1- Local vascular changes: - 1- Changes in vascular caliber and blood flow  Transient Vasoconstriction  Permanent Vasodilatation (result of redness and hotness in inflamed area).  Slow circulation (Stasis) 2- Increased vascular permeability (result of swelling, pain & loss of function in inflamed area). 3- Formation of the inflammatory fluid -3-  2- Cellular events 1- Transmigration of leucocytes inside the area of inflammation, leucocytes move out of the blood vessels through sequential steps. leukocytes margination rolling adhesion transmigration ⚫ emigration of: ⚫ neutrophils (1-2 days) ⚫ monocytes (2-3 days) 2- Chemotaxis leucocytes move towards the site of irritant this process mediated by chemical mediators such as ⚫ endogenous signaling molecules →e.g lymphokines ⚫ exogenous →e.g toxins 3- Phagocytosis - leucocytes engulf and destroy the irritant, this process mediated by lysosomal enzymes, free radicals, oxidative burst 4- Passive emigration of RBC - No active role in inflammation (hemorrhagic inflammation). A-Vascular changes: A group of sequential changes occurs in blood vessels ended by formation of inflammatory fluid and prepare for cellular events 1- Change in vascular Caliber:- Transient Vasoconstriction ----------------- then permanent Vasodilatation of arterioles, capillaries and post capillary venules. This lead to marked increase of the blood flow to the inflamed area & increase hydrostatic pressure, which is manifested clinically by local redness and hotness of the affected area. -4-  2- Increased capillary permeability: - It is due to endothelial changes in the form of either I. Endothelial swelling with widening of intra-endothelial gaps of post capillary venules. II. Major endothelial damage involving arterioles, capillaries and venules. This results in leakage of proteinaceous fluid (exudate) which causes inflammatory edema. 3- Formation of inflammatory fluid Vascular changes lead to formation of inflammatory fluid Early →→→Transudate fluid ⚫ Is clear fluid with low protein content (mostly albumin) ⚫ Is an ultrafiltrate of blood plasma due to ↑ hydrostatic pressure with normal vascular permeability. Later→→→Exudate fluid ⚫ Is a filtrate of blood plasma mixed with high protein content, inflammatory cells and cellular debris. ⚫ due to ↑ Hydrostatic pressure + increased vascular permeability -5- Features Transudate Exudate Definition Is A filtrate of blood plasma is An ultrafiltrate of blood mixed with inflammatory cells plasma and cellular debris. Cause Due to increased hydrostatic pressure. with Due to increased vascular normal vascular permeability permeability. Fluid clear fluid turbid fluid Protein types Albumin All plasma protein Fibrin No Present Chemistry Does not coagulate on Coagulates on standing. standing Cells No cells Contains inflammatory cells Specific gravity Low specific gravity High specific gravity. Types of acute inflammatory exudate 1. Serous: - Clear fluid with few cells and fibrin →e.g. in burns -6-  2. Fibrinous: - Turbid fluid rich in fibrin mainly in inflammation of serous sacs →e.g. pericarditis. 3. Pus: Thick, turbid inflammatory exudate rich in leukocytes (mostly neutrophils (living and dead (pus cells). Seen in suppurative inflammations The functions of this inflammatory fluid 1. Dilution of toxins 2. Delivery of antibodies and antibiotic 3. Delivery of nutrients, oxygen and chemical mediators 4. Fibrin network formation for facilitate leucocytes extravascular movement& localization of inflammation 5. Stimulation of immune response through circulation of the exudate into the lymphatic system help in antigen presentation and produce specific immune response 4- Changes in vascular blood flow (hemodynamic changes) ⚫ Slowing of the circulation (stasis) ⚫ Movement of inflammatory fluid exudate into the extravascular tissues results in the concentration of blood cellular element in small vessels& increased viscosity of blood. Explanation of local cardinal signs of inflammation These classic signs are produced mainly by a rapid vascular response ⚫ Redness: due to vasodilation →→→ increase blood flow ⚫ Warm: due to vasodilation →→→ increase blood flow -7-  ⚫ Pain: due to irritation of nerves by chemical mediators or swelling pressure. ⚫ Swelling: due to inflammatory fluid formation ⚫ Loss of Function: due to pain& tissue damage B- Cellular events A group of sequential processes results in formation of cellular exudation & destroy the injurious agent. Normal blood flow in lumen of blood vessels, the cellular elements →flow in the center of the vessel ―laminar flow‖, plasma is flowing adjacent to endothelium, with stasis during inflammation Leucocytes accumulate at the periphery of vessel along the endothelium ( process called Margination) I. Emigration of leucocytes divided into 4 steps 1. Margination 2. Rolling 3. Adhesion to endothelium 4. Diapedesis (trans-migration across the endothelium) 1. Margination:- Increased plasma viscosity due to loss of intravascular fluid→→→Decreased blood flow→→→ White blood cells fall out of axial stream into plasmatic zone 2. Rolling :- Is mediated by the action of E-selectins which bind endothelial cells loosely to leucocytes producing a characteristic rolling movement of leucocytes along the endothelial surface. 3. Adhesion:- Leucocytes adhere to the endothelial surface through the -8-  interaction of integines(leucocytes) and the immunoglobulin –family adhesion proteins (endothelium) 4. Transmigration (Diapedesis):-It is the movement of leucocytes across the endothelium.It is mediated by platelet-endothelial cell adhesion molecule- 1 (PECAM-1) expressed on both the endothelium and the leucocytes. II. Chemotaxis Definition: - Movement of leukocytes toward the inflammatory area along a chemical gradient Chemotactic agents for leukocytes include: - 1. Exogenous factors: - Products from bacteria - Toxins 2. Endogenous factors: - Cytokines, especially chemokine, lymphokines - Complement components especially C5a. - leucotriens B4 (LTB4). -9-  III. Phagocytosis Definition: - It is the ingestion and destruction of solid particles (tissue debris, living or dead bacteria and other foreign cells) by phagocytic cells mainly neutrophils and macrophages. Two main types of phagocytic cells 1- Polymorphonuclear neutrophils (PMNs) : Seen in early in acute inflammation (1-2 days), called microphages (phagocytosis of small particles) 2- Macrophages: Seen in late in acute inflammation (2-3 days) & in chronic inflammation phagocytosis of small& large particles Steps of Phagocytosis 1. Recognition and attachment 2. Engulfment 3. Degradation &killing 1. Recognition and attachment is facilitated by Opsonization which is the coating particles for recognition & attachment by phagocytic cells. The most important opsonins are IgG and C3b  IgG are bound to the phagocytic cell surface receptor Fc portion.  C3b bind to cellular receptors for C3b 2. Engulfment ingesting of the attached opsonized particle by pseudopodial extensions from the surface of the leucocytes, in this step result in fromation of phagosome which is a membrane-bound vesicle that encloses opsonized particle 3. Degradation &killing Phagosomes fuse with cytoplasmic lysosomes and form phagolysosomes then degradation &killing occurs either by -10- 1. Oxygen dependent mechanism the most important 2. Oxygen independent mechanism much less effective 1- Oxygen dependent mechanism (oxidative burst) Formation of phagolysosomes initiates rapid increase in oxygen consumption & activates 1. NADPH oxidase lead to production of the oxygen metabolites(hydrogen peroxide (H2O2) hydroxyl radical (HO).) in the phagosomal membrane 2. leucocyte enzyme myeloperoxidase Effect: - It oxidizes microbial proteins and disrupts its cell wall. 2- Oxygen independent mechanism The pH of the phagolysosome is low as that inhibit the growth of many types of microorganisms and activation of many proteins and enzymes include e.g. 1. Lysozyme 2. Lactoferrin 3. Major basic protein of eosinophils. 4. Other proteins as defensins and bactericidal permeability increasing protein. 5. Enzymes as glycosylases, phospholipases and nucleases -11- Chemical mediators of acute inflammation Definition:- Any substances that secreted and activated to help inflammatory process acts on blood vessels, inflammatory cells or other cells. Chemical mediators responsible for vascular and cellular events. Knowledge of those mediators is basis of anti-inflammatory drugs. Sources of chemical mediators 1- Exogenous Bacterial as E.coli Endotoxins 2- Endogenous  Cell -Derived chemical mediators produced locally by cells at the site of inflammation e.g. Leukocytes, Endothelial cell, Fibroblasts& Some mediators are derived from Necrotic cells...... etc (e.g Histamine)  Circulating plasma proteins “synthesized by liver”, found in inactive forms then activated (e.g complement system(Fragments of C3b and C5a) ) Biologic effects of mediators 1. Vascular phenomena: -12-   Vasodilatation → histamine, nitro oxide & prostaglandins  Increase vascular permeability → Histamine, sertonin & Bradykinins 2. Chemotaxis: →C5a, leukotriene B4 and lysosomal & bacterial products 3- Phagocytosis → C3b and Opsonins. 4. Pain →bradykinin and prostaglandins 5- Fever→ prostaglandins, IL6, TNF. 6- Tissue damage →lysosomal enzymes, oxygen free radicals, Nitric oxide The fate of acute inflammation 1. Resolution→→ tissue return to the normal status due to Minimal tissue damage e.g. lobar pneumonia.  Inflammatory fluid: - passes into lymphatic vessels.  Dead cells: - Phagocytosis of dead neutrophils and necrotic debris by macrophages  Repair by regeneration is the replacement of damaged cells by new cells of the same type. 2. Spread (Septicaemia, toxemia, lymphangitis, lymphadenitis Thrombophlebitis) 3. Fibrosis (Scarring) 4. Abscess Formation 5. Progression to Chronic Inflammation Types of Acute inflammation Acute inflammation is classified according to present or absent of pus into:- Suppurative/ Purulent acute inflammation. Non- Suppurative/ Non- Purulent acute inflammation. Pus is purulent thick, turbid yellowish inflammatory exudate -13-  Compositions of pus 1. Large number of neutrophils and pus cells 2. The liquefied necrotic material 3. bacteria 4. Fluid exudates A. Suppurative/ Purulent acute inflammation. I. Localized suppurative/ purulent acute inflammation 1- Abscess Definition:-acute localized suppurative inflammation with pus fromation Sites: - common in skin, subcutaneous tissue and may occurs internal organs as brain, lung, liver, kidney,……etc. -14- Cause: - Staphlococcus aureus secreted coagulase enzyme that lead localization Pathogenesis of abscess  The virulence of pyogenic organisms cause: 1) Marked tissue destruction 2) Attraction of large number of neutrophils. 3) Death of many neutrophils (pus cells)  release their lyzosomal enzymes  The Lyzosomal enzymes that release from pus cells lead to liquefaction of necrotic tissue and fibrin, result in pus formation (see before) Pathological Features - Early: Two zones necrotic tissue and inflammatory cells. - Later: Three zones a) A central necrotic core. b) A mid zone of pus. c) The peripheral zone: pyogenic membrane which is formed by fibrin and help in localize the infection. - Further enlargement Fate of abscess 1- Small abscess: Pus is absorbed, followed by healing. 2- Large abscess: absorption of pus is slow, a large abscess  pointing & rupture (spontaneous evacuation if not surgical drainage)  healing. -15- 3- Complications 1- Spread of infection: a) Direct enlarged in size. b) Lymphatic  lymphangitis and lymphadenitis. c) Blood spread may lead to Septicaemia, Pyaemia 2- Complications of evacuation and healing: a) Ulcer →→ is local discontinuity of the epithelial surface due to defect healing b) Sinus. →→is blind ended tract between abscess and epithelial surface due to chronic discharge to surface c) Fistula.→→ is a track connecting two epithelial lined surfaces d) Keloid e) Hemorrhage e.g. hemoptysis with lung abscess. f) Rupture: e.g. brain abscess. 3- Chronicity. Examples:- Chronic lung abscess. 4- Other complications: Compression effects: e.g. in case of brain abscess 2- Carbuncle Definition: - It is multiple communicating deep subcutaneous abscesses, opening on skin by multiple sinuses. Carbuncle is common in special patient→ diabetics (low immunity). Sites: - common in special sites in the back of the neck and scalp, where the skin and subcutaneous tissues are thick and tough due to dense fibrous septa dividing the -16- subcutaneous tissue into compartments. 3- Furuncle or boil Definition: - It is a small abscess related to hair follicles. Sites: - in any site covered by hairy skin. Boils are common in areas where shaving or otherwise removing hair, like the legs in women and the facial area in men II. Diffuse suppurative/ purulent acute inflammation Cellulitis Definition: - it is diffuse acute suppurative inflammation with pus formation. Cellulitis is common in special patient→ diabetics (low immunity). Cause: - Streptococcus hemolyticus  secreted enzymes as 1. Hyaluronidase (spread factor) 2. Streptokinase (fibrinolysin) which dissolve fibrin and facilitate the spread of infection. Sites: - Loose subcutaneous tissue & Areolar tissue (e.g. orbit, pelvis, perianal region & subcutaneous tissue of the limbs). -17-  Features Abscess Cellulitis Localized suppurative Type Diffuse suppurative inflammation inflammation Cause Staphlococcus aureus Streptococcus haemolyticus organisms secreted coagulase organisms secreted hyaluronidase Pathogenesis enzyme that lead to fibrin & streptokinase enzymes that deposition localization dissolve the fibrin Site Any tissue Loose connective tissue Thick, less red cells, few Thin, sanguineous, and extensive Pus necrotic tissue necrosis Spread Less More B. Non- suppurative/ Non- purulent acute inflammation. 1. Serous inflammation Characterized by: - excessive clear fluid poor in both inflammatory cells & fibrin. Examples:-  Skin blisters due to skin burns.  Epidermal vesicles due to herpes simplex viral infection.  Inflammation of serous membranes (pleura, pericardium and peritoneum) 2. Fibrinous inflammation Characterized by: - an inflammatory exudate rich in fibrin, with poor fluid. Examples:-  Lobar pneumonia  Inflammation of serous membranes. e.g. fibrinous pericarditis -18- 3. Serofibrinous inflammation Characterized by: - an inflammatory exudate rich in both fluid & fibrin Examples:-  Inflammation of serous membranes e.g. serofibrinous pericarditis Remark: Serous membranes may be affected by other types of inflammation (e.g. diffuse septic peritonitis). 4. Catarrhal inflammation Characterized by: - A mild form of acute inflammation of mucous membranes with excess mucus secretions Examples:- -  Catarrhal rhinitis (common cold)  Catarrhal appendicitis 5. Pseudomembranous /Membranous inflammation Characterized by: - A severe form of acute inflammation of mucous membranes with replacement of the normal mucous membrane by a false membrane. Pathogenesis:-  Caused by virulent bacteria  Bacteria secreting exotoxins lead to mucosal necrosis and marked inflammation  false membrane.  A false membrane composed of patches of necrotic tissue & fibrin. Examples:- -19-   Diphtheria Bacillary dysentery 6. Gangernous/ necrotizing inflammation. Characterized by: - A severe form of acute inflammation caused by virulent bacterial infections lead to ischemic necrosis associated by putrefaction. Examples:-  Cancrum oris.  Bed sores 7. Haemorrhagic inflammation Characterized by: - large numbers of RBCs in the inflammatory exudate due to destruction of the capillaries. Examples:-  Acute hemorrhagic pancreatitis 8. Allergic inflammation. Characterized by: - the presence of excessive serous fluid and many eosinophils in the inflammatory exudate. -20- Examples:-  Allergic rhinitis.  Allergic conjunctivitis. Chronic Inflammation Definition:- Inflammation of prolonged duration ―weeks to years ‖, in which inflammation, tissue destruction & healing occurs in same time. Causes ⚫ May follow acute inflammation due to failure of immunity ⚫ May start chronic by gradual onset (not preceded by acute inflammation) due to one or more of the following: 1. Infection with resistant organisms e.g. T.B. 2. Non-living irritants as foreign bodies e.g. talc or silicosis (inhalation of silica particles into lungs) 3. Development of autoimmunity e.g. rheumatoid arthritis. Types of chronic inflammation 1. Chronic Non-specific Inflammations: ⚫ Usually follow acute inflammation, e.g. chronic abscess. ⚫ Why termed "nonspecific’’? 1. All show the same microscopic features of chronic inflammation (chronic inflammatory cells, fibrosis….) 2. We can‗t identify the cause. 2. Chronic Specific Inflammations: ⚫ Usually start chronic. ⚫ Show microscopic features of chronic inflammation with additional features specific for each type as (bilharzia ova in cases of bilharziasis). ⚫ The majority of chronic specific inflammations occur in the form of -21-  granulomas. Granulomas/ granulomatous inflammation Definition: - A special form of chronic inflammation characterized by nodular collections of many macrophages with mixture of lymphocytes, plasma cells, giant cells. Characterized by: - ⚫ The macrophages have an important role in formation of granuloma. ⚫ The macrophages commonly change into  epithelioid cells (large pink, activated macrophages that look like epithelial cells) ⚫ Sometimes these epithelioid cells fuse together, forming giant cells, with multiple nuclei inside (multinucleated giant cells) ⚫ Some granulomas may exhibit central necrosis. ⚫ Old granulomas surrounded by fibrosis. Types of granulomas: 1. Infectious granulomas: Most of these granulomas are necrotizing. Examples:- T.B, Leprosy, Syphilis, Bilharziasis 2. Foreign body granulomas: Mostly non-necrotizing granulomas. Examples:- Silicosis & Surgical suture -22-  3. Granulomas of unkown aetiology: Mostly non-necrotizing granulomas. Examples:- Sarcoidosis& Crohn's disease. Acute Chronic Features Inflammation Inflammation Response Immediate reaction of Persisting reactions of tissue to tissue to injury injury Onset Rapid Slow Duration Short (hours to days) Longer (months to years) Immunity Innate Cell mediated Predominant cells Neutrophil `Lymphocytes and macrophages Main pathological Exudation of fluid and Proliferation of blood vessels event plasma proteins and fibrosis Tissue injury and Usually mild and self- Often severe and progressive fibrosis limited Vascular response Prominent Less prominent may be subtle Example Abscess T.B According to type of inflammation 1. Acute inflammatory cells ⚫ Neutrophils. Pyogenic. Dead neutrophils = pus cells. ⚫ Macrophages. They are derived from blood monocytes & tissue histiocytes ⚫ Possible variations e.g. ⚫ Eosinophils in allergic inflammation ⚫ Lymphocytes & plasma cells in viral infections ⚫ Few neutrophils in bacillary infections as Typhoid fever -23- 2. Chronic inflammatory cells ⚫ Lymphocytes. Plasma cells ⚫ Macrophages ⚫ Giant cells. They are most commonly seen in granulomas ⚫ Eosinophils in chroinc parasitic infection e.g bilharziasis General fate of inflammation -24-  Cell Injury Definition: - Cell injury is a sequence of events that occur if the limits of adaptive capability of cells to stimulus are exceeded or no adaptive response is possible. Key Concepts  Cellular hemostasis is maintaining a biological balance of several factors that make a cell healthy with perfect function.  Excess physiologic or pathologic stress may force the cell to a new steady state: Adaptation  Too much stress exceeds the cell‗s adaptive capacity: Injury  Cell injury is reversible up to a certain point  If the stimulus persists or is severe enough from the beginning, the cell reaches a point of no return and suffers irreversible cell injury and ultimately cell death.  The cellular response to injurious stimuli depends on type, duration& Severity of injury& the consequences depend on the type, status, adaptability, and genetic make-up of the injured cells. -25- Causes of cell injury 1. Oxygen deprivation (Hypoxia or ischemia) →→ is the most common causes 2. Infectious agents: viruses, bacteria, fungi, parasites. 3. Physical agents: - extremes of temperature, radiation and electric shock. 4. Chemical agents: poisons, air pollutants, insecticides, CO, asbestos, ethanol, therapeutics drugs. 5. Mechanical agent: trauma 6. Immunologic reactions: hypersensitivity. 7. Nutritional imbalances. Malnutrition, Diabetic Mellitus, Kwashiorkor, Marasmus, osteoporosis, deficiency Vitamin C 8. Genetic defect. Abnormalities to the genomes e.g. Down Syndrome 9. Aging →→Aged cells become less able to divide and multiply. Lose their ability to functions, or function abnormally. Remark:-  Hypoxia →→→Oxygen deficiency  Ischemia→→→Impaired blood supply (arterial or venous occlusion)  Infarction →→→Area of necrosis due to ischemia. Mechanisms of cell injury 1. Depletion of ATP 2. Disruption of ion transport/pumping 3. Mitochondrial damage 4. Influx of intracellular calcium and loss of calcium homeostasis 5. Accumulation of oxygen-derived free radical (Oxidative stress) 6. Defects in membrane permeability. 7. Defect in protein synthesis. -26-  8. Damage of genetic apparatus. All of these mechanisms lead to 1. Reversible Injury  Cell swelling due to defect in fluid & electrolyte homeostasis  Accumulation of substances in the cytoplasm or interstitial tissue.  The function of cells is impaired or lost Remark: Cellular accumulations are a sign of injury; also, their accumulation can cause cellular injury 2. Irreversible injury.  Two basic processes occur in necrosis due to severe or prolonged cell injury  Denaturation of protein  Enzymatic digestion of cell components.  Activation of caspases cascade lead to damage of DNA is basic process in apoptosis. activation is done by  The extrinsic pathway—external ‗death receptors (e.g. TNF receptors)  The intrinsic pathway—proapoptotic molecules are released from mitochondria (e.g. BCL2) Remark: Caspases are normally inactive synthesized proteases. Types Of Cell Injury: 1- Reversible injury (Degeneration): caused by mild (non-lethal) injury→→ Intracellular accumulation of water, fat, Protein, cholesterol, glycogen, iron, calcium or pigments. -27- 2- Irreversible injury (Cell Death)  Necrosis  Apoptosis Morphological types of cell Injury 1. Cloudy swelling 2. Hydropic swelling 3. Hyaline 4. Mucoid degeneration 5. Amyloidosis 6. Pathological pigments 7. Pathological calcification 8. Necrosis 9. Apoptosis A-Reversible injury (Degeneration): 1- Intracellular accumulation - Metabolic imbalances in cells can lead to the intracellular accumulation of abnormal amounts of various substances that remains either transiently or permanently. - Cellular accumulations are a sign of injury; also, their accumulation can cause cellular injury - These accumulated substances included: -A- Normal cellular substances  Water  Lipid  Protein -28-   Glycogen B- Abnormal or exogenous substances Carbon, silica, asbestos, bacteria. 1. Intracellular accumulation of water a) Cloudy Swelling: Intracellular accumulation of small amount of water  cell swelling with eosinophilic granular cytoplasm. b) Hydropic Swelling (hydropic degeneration, ballooning degeneration). Intracellular accumulation of larger amounts of water  swollen cells pale, clear cytoplasmic vacuoles Examples:  Ballooning of renal tubules in cases of nephritis  Ballooning of liver cells in viral hepatitis. 2. Intracellular accumulation of lipids  Triglycerides  Cholesterol A- Steatosis (fatty change) Definition: intracellular accumulation of triglycerides within parenchymal cells Site: - Heart, kidney & other organs, but the most common in the liver (hepatic steatosis). Causes & Pathogenesis of: - 1- Fatty change of liver: - a) Hypoxia or bacterial toxins  ↓↓ enzymes of lipid metabolism. b) Excessive entry of free fatty acids into the liver (starvation, obesity& DM). -29-  c) Metabolic disease (Diabetes mellitus)  ↓↓ lipid metabolism. d) Impaired lipoprotein secretion from the liver (alcohol). e) Decreased apoprotein synthesis (protein malnutrition) f) Hepatotoxins as alcohol & Some liver cell diseases as HCV. 2- Fatty change of other organs due to hypoxic or toxic depression of lipid metabolism enzymes e.g. toxic diphtheritic myocarditis. Clinical Significance: - Fatty change may progress to cell necrosis  Diffuse fatty change of heart  heart failure  Fatty change of liver  progress to liver cirrhosis. Gross:- 1. Organ enlarged, soft greasy& rounded borders. Color is yellow; diffuse or patchy. -30-  1- Liver: the liver appears diffuse or patchy affect with nutmeg appearance. 2- Heart: diffuse or patchy tigeroid or tabby cat appearance Microscopic:- fat appears as small clear intracellular vacuoles or a single large vacuole push nucleus eccentric  signet ring appearance., Fat stained orange with Sudan III stain. B- Cholesterol and Cholesterol Esters - Atherosclerosis accumulation of cholesterol in macrophage (foam cell) and smooth muscle cells in the intima of aorta and arteries - Cholesterolosis accumulation of foam cells in the lamina propria of gallbladder 2- Extracellular accumulation include 1- Proteins  Amyloidosis is extracellular accumulation of abnormal folded protein due to defective intracellular transport and secretion of proteins lead to unfolded and misfolded protein →→→cell death. Amyloid protein appears as bright pink amorphous, homogenous, eosinophilic, material, staining red with Congo red stain. 3- Extracellular & intracellular accumulation. 1- Mucoid Degeneration Accumulation of excessive amount of mucin in unusual location, it is called mucoid/mucinous degeneration e.g. Cancer with high degree of mucous degree are called mucinous carcinoma. Extracellular accumulation of mucin is called myxomatous degeneration. -31- 2- Pathological Pigments A- Endogenous: - synthesized within the body itself as:- a. Lipofuscin pigment is worn and tear pigment with aging is sign of free radical injury and lipid peroxidation. Lipofuscin pigment deposit mainly in heart, liver….etc. In tissue sections it appears as a yellow-brown, finely granular cytoplasmic, often perinuclear, pigment. b. Melanin an endogenous, non-hemoglobin-derived, brown black pigment formed by melanocytes in skin mucous membranes &iris. c. Hemosiderin (iron) is a hemoglobin-derived, golden yellow-to brown and granular. Systemic overload of iron hemosiderin may be deposited in many organs and tissues, a condition called hemosiderosis  patients with congestive heart failure→→ Lung  In patients with hemochromatosis→→Liver, heart, pancreas  Hemolytic anemias, in which abnormal quantities of iron are released from erythrocytes.  Repeated blood. Remark: iron stained by the Prussian blue (seen as blue granules) to differentiated from melanin pigment d. Bilirubin usually due to i. Too much produced (e.g., hemolysis) ii. Not processed (e.g., cirrhosis) iii. Outflow blocked (e.g. gall bladder stones). -32-  iv. B- Exogenous coming from outside the body a. Anthracosis inhalation of carbon particles engulfed by macrophages. This pigment blacken the tissues of the lungs e.g. cigarette smoking , coal workers, air pollutant of urban life. b. Tattooing is a form of localized, exogenous skin pigment is phagocytosed by dermal macrophages. 3- Pathological Calcification Definition: - Abnormal intracellular or extracellular depositions of calcium salts. Gross: - calcification appears as fine, white granules or clumps, often felt as gritty deposits. Microscopic: - Calcium salts have a basophilic, amorphous granular, sometimes clumped appearance; outer layers may create lamellated configurations, called -33- psammoma bodies as seen in some types of papillary cancers e.g papillary thyroid carcinoma. Types of pathological calcification Dystrophic calcification Patients have a normal serum calcium level & absences of any defect of calcium metabolism Dystrophic calcification affects previously damaged & dead tissue as  Areas of necrosis coagulative, caseous, fat, or liquefactive.  The atheroma of advanced atherosclerosis  Aging or damaged heart valves.  Sometimes a tuberculous lymph node is virtually converted to stone.  Others, old thrombus, hematoma. Metastatic calcification Patients have a hypercalcemia with disturbance of calciummetabolism  Causes: Hyperparathyroidism, bony metastases Calcification affects normal tissue and previously damaged tissue. Metastatic calcification may occur widely throughout the body but mainly affected kidney, systemic arteries, pulmonary veins &lung. Remark: Pathological Calcification is the only one in substance accumulationswhich is irreversible. -34-  Dystrophic Metastatic Features calcification calcification Reflect deranged of calcium Pathogenesis Sign of cell injury metabolism site Dead or damage tissue Normal tissue Serum calcium Normal High Calcium metabolism Normal Abnormal Patient with Example Wall of chronic abscess hyperparathyroidism B) Irreversible injury (Cell Death) 1- Necrosis Definition: Death of a group of cells within a living body caused by an irritant. Causes: causes of cell injury but severe or prolonged Gross: Opaque yellow swollen area surrounding showed inflammation. Microscopic: 1- Cellular Changes: a) Nuclear Changes: Due to enzymatic digestion. ⚫ Pyknosis: The nucleus →small and dark. ⚫ Karyorrhexis: Nuclear fragmentation. ⚫ Karyolysis: dissolved nucleus b) Cytoplasmic Changes: Cytoplasm is eosinophilic due to loss of cytoplasmic RNA (basophilic) and glycogen (granular) with indistinct cell membranes. -35-  2- Architectural Changes: 2 possibilities: a) Necrotic tissue rapidly structureless due to cell lysis by lysosomal enzymes from (dead cells ± inflammatory cells). b) Necrotic cells preserve the architectural outlines of original tissue despite loss of the nuclei. ghosts of cells due to protein denaturation (mainly in ischemia necrosis). Then lysis later  structureless. Fate of necrotic tissue: 1- Inflammation due to release of chemical mediators. 2- Healing: mainly by fibrosis 3- Dystrophic calcification may occur. Types Of Necrosis 1. Coagulative necrosis 2. Liquifactive necrosis 3. Caseous necrosis 4. Fat necrosis (enzymatic & traumatic) 5. Gangrenous necrosis 6. Fibrinoid necrosis 1- Coagulative Necrosis: Seen in: - infarction of all organs except CNS. Pathogenesis: - Cell‗s basic outline is preserved for few days due to denaturation of cell proteins (coagulation); necrotic tissue showed ghosts of cells. Finally, necrotic tissue becomes structureless. Gross:- Opaque yellow swollen soft friable tissue Microscopic:- Necrotic tissue homogeneous, glassy eosinophilic appearance, surrounding viable tissue showed acute inflammation. -36-  Fate:- Healing by fibrosis ± dystrophic calcification. 2- Liquefactive Necrosis:  Seen in: - infarcts of CNS, pyogenic abscess (pus) & amoebiasis.  Pathogenesis: - Usually due to predominant of enzymatic dissolution of necrotic cells (usually due to release of proteolytic enzymes from neutrophils) over protein denaturation.  Fate: - Necrotic tissue→→completely liquefied → turbid fluid→→Absorbed→→space healed by fibrosis ± dystrophic calcification. 3- Gangrenous Necrosis: usually coagulative or liquefactive followed by putrefaction by saprophytes bacteria. 4- Caseous Necrosis:  Seen in: - mycobacterial infection (tuberculosis)  Gross :- yellowish white & "cheesy" like necrotic material.  Pathogenesis:- -37-  1. Necrosis starts as ischemic coagulative necrosis. 2. Hypersensitivity to tuberculous antigens release of proteolytic enzymes  partial liquefaction of the coagulated necrotic cells  cell fragmentation. 3. Tubercle bacilli are rich in fats that liberated from dead bacteria adds to the cheesy appearance.  Microscopic: - granular eosinophilic structureless (fragmented necrotic cells). 5- Fat Necrosis a) Enzymatic Fat Necrosis: ⚫ Seen in :- Acute Hemorrhagic Pancreatitis ⚫ Pathogenesis : inflammation →escape of lipase and protease enzymes  necrosis surrounding peritoneal fat cells. ⚫ Grossly: chalky white hard patches, because necrotic fat cells →fatty acids + calcium = calcium soaps. ⚫ Microscopic:- necrotic fat cells, surrounded by chronic inflammatory cells and fibrosis, with calcification. -38-  b) Traumatic Fat Necrosis:  Seen in: It is common in the female breast and subcutaneous fat & usually caused by trauma  Pathogenesis: Rupture of fat cells->auto-digestion and release of fatty acids, which combine with calcium.  Gross: Hard chalky white mass. This mass clinically mistaken for breast tumor. Microscopic: - same as enzymatic fat necrosis. 6- Fibrinoid Necrosis: Seen in: - the walls of blood vessels in vasculitise.g. autoimmune collagen diseases (as rheumatic fever, rheumatoid arthritis, lupus erythematosus…etc), that lead to immune mediated vascular damage Pathogenesis: - autoantibodies against collagen of blood vessel  lead to fragmentation of collagen into fine particles resembling fibrin. Microscopic: - Glassy, eosinophilic fibrin-like material is deposited within the vascular walls. Remark: It is not true necrosis since it does not affect living cells. 2- Apoptosis (programmed cell death) ⚫ Definition: death of individual cells surrounded by viable cells ⚫ When a cell dies by activation of an internally suicide program. It is an active process—energy dependent ⚫ Does not elicit inflammatory response Types Of Apoptosis -39-  Physiologic ⚫ During embryogenesis e.g. Removal of interdigital webs of toes and fingers. ⚫ Hormone-dependent e.g. involution of organs as thymus gland in the adult, endometrial cells loss during menstruation Pathologic ⚫ Irradiated tissues ⚫ Cell death induced by cytotoxic t-lymphocytes ⚫ Viral infections e.g. Viral hepatitis ⚫ Cell death in tumors Morphology of Apoptosis  Cell shrinkage with increased cytoplasmic density  Chromosome condensation  Formation of cytoplasmic blebs and apoptotic bodies  Phagocytosis of apoptotic cells or cell bodies by adjacent healthy cells -40- Features Necrosis Apoptosis Groups of cells, disrupting tissue Single cells within living Affect structure tissues A passive process—not energy- Active process—energy- Process dependent dependent Induce a significant Inflammation No inflammatory response inflammatory response Cell size Enlarged Reduced Pyknosis / karyorrhexis / Nucleus Fragmented karyolysis Plasma Disrupted Intact membrane Cellular Enzymatic digested Intact contents May be pathologic or Types Always pathologic physiologic -41-  Repair Repair/Healing Definition: - Replacement of damaged tissue by new healthy one. Damage → Inflammation→ removing of dead tissue & Replacement by new healthy one Types of repair 1. Regeneration Replacement of dead tissue by same type of tissue.Seen with mild and superficial injury 2. Fibrosis/ Scar (Fibrosis= Gliosis in CNS) Replacement of dead tissue by connective tissue. Seen with severe injury Tissues of the body divided into three types according to Proliferative Capacities : 1) Continuously dividing(labile) tissues 2) Stable tissues 3) Permanent tissues 1) Labile cells / Tissue  cells are continuously proliferating & continuously dying  can easily regenerate after injury  contain a pool of stem cells (self-renewal and differentiation) -42-  Examples:- -  Skin epidermis  GIT epithelium  Bone marrow cells Stem cells  Self-renewal capacity  Asymmetric replication  Capacity to develop into multiple differentiations  Extensive proliferative potential Types of stem cells  Embryonic stem cells: Pluripotent cells that can give rise to all tissues ofthe body  Adult stem cells: (tissue stem cells) Examples:- -  Hematopoietic stem cells →→→ Bone marrow  Stem cells in base of crypts→→→ Intestine  Stem cells in Hair follicle bulge →→→ Skin 2) Stable cells (quiescent cells)  Cells have limited ability to proliferate  Normally in G1 stage, but can proliferate in response to injury Examples: -  Parenchyma of most solid tissue (Liver, kidney, and glands), peripheral nerves  Endothelial cell, fibroblast and Smooth muscles. -43-  3- Permanent cell: Non-dividing, non-proliferated in postnatal life Normally in G0 stage, never proliferate Response to injury always by fibrosis (scar) Examples: -  Cardiac muscle  Skeletal muscle  Neurons (CNS) Factors affecting efficiency & type of repair A. General factors 1. Age 2. Nutritional Deficiency 3. Drugs 4. Endocrine diseases 5. General heath (Infection /tumor) B. Local factors 1. Severity of tissue damage  With mild to moderate injury (e.g. hepatitis A infection) →→ cells damage with survival of supporting tissue (reticular tissue)  regeneration Normal Liver  With severe injury (e.g. hepatitis C infection) →→ gross tissue damage including supporting tissue → post necrotic scaring (fibrosis)Liver cirrhosis. -44-  2. Blood supply 3. Persistent infection or foreign body present. 4. Ability of tissue to proliferate (type of injured cells) C. Factors affecting mechanism of repair 1. Growth factors. 2. Cell to cell interactions 3. Cell to matrix interactions Growth factors &Cytokins Definition: - Proteins that affect cell growth by affect proliferation, cell migration, differentiation, tissue remodeling &angiogenesis Sources: - Damage tissue cells, inflammatory cells& endothelial cells Examples: -  Epidermal growth factor (EGF),  Hepatocyte growth factor (HGF),  Fibroblast growth factor (FGF),  Transforming growth factor alpha or betal (TGF-a, -b), vascular endothelial growth factor (VEGF)  Platelets derived growth factor (PDGF)  Cytokins e.g TNF, IL-1 & interferon. -45-  Types of repair 1- Healing by regeneration Definition: - Proliferation of cells to replace the damaged components by same type of cells and return to a normal state Occurs in All the time in labile tissues Limited form in stable tissues according to severity of injury Examples: - 1. Healing of epidermis 2. Healing of mucous membrane 3. Healing of liver cells 4. Healing of bone fractures 5. Healing of Peripheral nerve 2- Healing By Fibrosis Definition: - Replace the damaged components by scar formation due to deposition of connective (fibrous) tissue Occurs in With severe injury of all types of tissues All the time in permanent cells Examples: - 1. Healing of myocardial infarction. 2. Healing of CNS infarction or brain abscess 3. Severe destruction of connective tissue frame work (as in liver cirrhosis) 4. With extensive cell injury e.g. necrosis 5. In chronic inflammation 6. Wound healing (primary and second intension) -46- Pathogenesis: - Steps in repair by fibrosis 1. Inflammatory response Neutrophils and macrophages Remove damaged and dead tissue 2. Formation of new blood vessels (Angiogenesis) 3. Migration and proliferation of fibroblasts ( Fibrogenesis) 4. Formation of granulation tissue 5. Maturation to permanent scar 6. Tissue remodeling 7. Wound contraction & strength 2- Angiogenesis Definition: - Formation of new blood vessels by action of growth factors include VEGF, PDGF, FGF &TGF – beta. Source:- 1. Proliferation from endothelial precursor cells. 2. Budding from pre-existing vessels The main steps in angiogenesis from pre-existing vessels are 1. Vasodilation due to nitric oxide& VEGF. 2. Increased vascular permeability of pre-existing vessel due to VEGF. 3. Proteolytic degradation of vessel basement membranes. 4. Migration of endothelial cells from original capillary towards the area of injury 5. Proliferation of endothelial cells 6. Formation of mature blood vessels. -47-  3- Fibrogenesis Definition: - Migration and proliferation of fibroblasts to the site of damage by action of growth factors include PDGF, FGF, TGF – beta & cytokines e.g. TNF, IL-1 Function of fibroblasts: - collagen deposition early fibroblasts deposit collagen type III then I. 4- Granulation tissue formation Definition: - Highly vascularized edematous connective tissue. Gross: - pink granular soft and fleshy Microscopic: - Granulation tissue composed of 1. Newly formed capillaries. 2. Proliferating fibroblasts. 3. Inflammatory cells. 4. Edematous stroma. 5- Maturation of granulation tissue  permanent scar  Synthesis of Extracellular matrix (ECM) proteins by action of Growth factors include PDGF, FGF, TGF & IL-1.  More collagen type I deposition.  Capillary resorption by macrophages. -48-   Formation of a pale, avascular scar. 6- Tissue remodeling  Degradation of excess collagen and other ECM proteins by a family of matrix metalloproteinases (MMPs) & TIMs (Tissue inhibitors of metalloproteinases) inhibit their action.  Lead to the formation of an avascular firm white scar tissue. 7- Wound contraction & strength  Fibroblasts transformed to Myofibroblasts lead to contract the scar & minimize the scar (decreased in size).  Increase collagen deposition led to strength the wound. Types of Skin Wound Healing 1- First intention healing (primary union) Small wounds that easily close edges Epithelial regeneration predominates over fibrosis Small amount of granulation tissue &Little fibrosis Healing is fast, with minimal scarring/infection Examples: - ⚫ Paper cuts ⚫ Surgical incisions Mechanism of first intention: - By 24 hours Clot forms the wound covered by scab -49-  Neutrophils come in Epithelium begins to regenerate By 3-7 days Macrophages come in Granulation tissue. Collagen deposition Epithelium increases in thickness Weeks later Granulation tissue gone Collagen is remodeled Epidermis full& mature (but without dermal appendages) Finally, scar forms. Scar is avascular fibrous tissue and covered by thin layer of epidermis. It has no skin appendages (hair follicles sebaceous and sweat glands) 2- Second intention healing( Second union) Larger wounds that have large gap due to (extensive loss of tissue, necrosis& infection) Fibrosis predominates over epithelial regeneration Large amount of granulation tissue & fibrosis Healing is slower, and more scarring/ infection Examples:- - 1. Infarction& abscess 2. Infected surgical wound 3. Large burns and ulcers 4. Extraction sockets Mechanism of Second intention:- Similar mechanism to first intention with some differences -50-   More inflammation  More granulation tissue  Wound contraction Features Primary wound healing Secondary wound healing Wound Small size, small gap & Large size, large gap & Clean Unclean Tissue loss No Yes Chance of Infection Low High Healing Fast Slow Margins Surgically clean Irregular Healing Scanty granulation tissue Granulation tissue fill the gap Scar tissue Scanty Abundant Outcome wounds Nearly linear scar Contracted irregular wound Complication Less common More common Complications of Wound Healing 1. Delayed wound healing 2. Cosmetic Deformities 3. Function loss e.g. contracture is exaggeration in the process of contraction of the wound (severe burn around a joint) 4. Keloid: excess scar tissue due to overdone repair covered by stretched epidermis. 5. Chronic Ulcer, Sinus, Fistula. 6. Implantation epidermoid cyst result of the growth of epidermal cells within a focal area of the dermis 7. Rarely carcinoma (Marjolin’s ulcer) -51-  Factors delayed wound healing 1. Infection is the most important cause of delay in healing; it prolongs the inflammation phase of the process increases the local tissue injury. 2. Poor nutrition effects on wound healing (Vitamin C is essential for collagen) 3. Glucocorticoids inhibit inflammation with decreased wound strength and less fibrosis. 4. Poor blood supply due to diabetes or atherosclerosis. 5. Diabetes mellitus: Increases tendency to infection, so delays repair 6. Foreign bodies left in the wound. 7. Chronic inflammation leads to excess fibrosis as in cirrhosis. Healing of injury bone Definition: - Bone healing is complex and sequential stages that occur to restore injured bone to normal state Types of bone healing 1. Healing by callus formation (indirect, secondary) 2. Healing by direct union (primary) Stages of bone healing A. Healing by callus formation 1. Hematoma formation→ Occurs immediately 2. Inflammation and cellular proliferation 8hrs to 1-2weeks -52-   Migration of inflammatory cells (macrophages, neutrophils, platelets)  Proliferation and differentiation of mesenchymal stem cells→ into chondroblast & osteoblast  migration of osteoclasts → remove dead bone  Neovascularization  The end of this stage→ the result is formation of granulation tissue (Called procallus/ soft callus) 3. Callus formation A. formation of provisional callus 2-3wks to 4-8wks  Chondroblast→ cartilage islands deposition  Osteoblast→ Osteoid tissue deposition consists of bone matrix and collagen matrix then undergoing calcification by alkaline phosphatase activity→ osseous tissue (non-lamellar(woven) bone  Provisional callus consists of cartilage, osteoid tissue & woven bone B. Formation of permanent callus Weeks to 2-3months  Cartilage is disintegrating  Non-lamellar (woven) bone removes by osteoclast and replace by lamellar(compact) bone 4. Remodelling 2months to years  Guided by mechanical stress exposure along line of weight bearing  Osteoclasts are responsible -53-   Bone marrow regenerates inside the medullary canal. B. Healing by direct union 1. Contact Healing Direct contact between the fracture ends allows healing to be with lamellar bone immediately 2. Gap Healing Gaps less than 200-500 microns are primarily filled with woven bone that is subsequently remodeled into lamellar bone Remark: - Larger gaps are healed by indirect bone healing. Complications of healing of injury bone ⚫ Malunion/fibrous union  Usually when immobilization is not done  False joints may also form (Pseudoarthrosis) -54- ⚫ Delayed union Delayed union due to many systemic and local factors as malnutrition, DM, drugs – (NSAIDs, steroids, cytotoxic), tobacco use, vitamin deficiency, type of fracture, irradiated bone, type of bone ⚫ Non-union→ In the presence of soft tissue between the fracture ends ⚫ Infection ⚫ Post-traumatic arthritis ⚫ Growth abnormalities →specially fracture near joints or at growth plate site. -55-  Infectious diseases 1- Bacterial Infections  Routes of infection: 1. Exogenous by inhalation, ingestion or local contact with skin or mucous membranes, blood or blood product transfusion 2. Endogenous from bacteria normally present in the body as intestinal E. coli, oral streptococcus viridans and respiratory pneumococci. Infection occurs if immunity is lowered.  Effects of bacterial infection: 1. Cell injury: Necrosis and degeneration. 2. Inflammation: acute, subacute or chronic. 3. Development of immunity and/ or hypersensitivity. 4. Blood invasion with bacteria and/or bacterial products leading to a) Bacteremia. b) Toxemia c) Septicemia d) Pyaemia Bacteremia Definition: This is transient invasion of blood with bacteria without significant toxaemia. examples:  After tooth extraction (Streptococcus viridans bacteria).  A septic focus as tonsillitis & sinusitis. Effects:  In most cases, no harmful effects.  Uncommonly, causing lesions. Specially with a predisposing factor, e.g. Streptococcus viridans that reach the blood after tooth extraction can cause subacute infective endocarditis on top of rheumatic valvulitis. Toxaemia Definition: the circulation of bacterial toxins in the blood harmful effects may association with septicemia and pyaemia. These toxins may be endotoxins (released only from dead bacteria) or exotoxins (released from alive bacteria) -56- Types: 1. According to onset: 1. Acute toxemia as in acute abscess& diphtheria, cholera 2. Chronic toxemia as in chronic abscess & tuberculosis 2. According to type of bacterial toxins: 1. Endotoxic toxemia: as E coli& typhoid infections 2. Exotoxic toxemia: as cholera and diphtheria. Septicaemia Definition: A fatal condition, large numbers of virulent bacteria circulate and multiply in blood accompanied by severe toxaemia. Etiology:  Causative bacteria Strept hemolyticus (most common cause of septicemia), staphylococci & gonococci.  Predisposing factor: Low immunity as diabetics  Source of infection: as complication of many conditions as puerperal sepsis, acute osteomyelitis &post-operative infections Pyaemia Definition: It is fatal condition, development of multiple small abscesses (pyaemic abscesses) in one or more organs due to the circulation of septic emboli derived from septic thrombi. Pathogenesis of pyaemia.  Starts by septic thrombus (contain bacteria, usually Staphylococcus aureus) formed most commonly in veins.  Septic thrombus → fragmentation  multiple septic emboli→circulate in the blood, impacted in the small blood vessels of organs peripherally→ form Multiple small abscesses (pyaemic abscesses) will develop near impacted emboli. Types of pyaemia: 1. Pulmonary pyaemia 2. Portal pyaemia 3. Systemic pyaemia. -57-  1- Tuberculosis Definition: - Chronic infectious granulomatous inflammation caused by Mycobacterium tuberculosis( rod shaped Acid fast bacilli ) There are two species: 1. Human tubercle bacilli. 2. Bovine tubercle bacilli. Predisposing factor:  Race: black >white  Patient: - low socioeconomic status, low immune patients (diabetes mellitus, cirrhosis, malnutrition and cancer)  Age:- Extremes of ages due to imperfect immune responses  Diagnosis Clinically by radiography, culture, or Zeihl Neelsen stain for acid fastbacilli,) &pathological by FNAC, or excisional biopsy Mode of Transmition In Primary tuberculosis: it is the first time to TB bacilli enter the body reach to primary site as lung, intestine, tonsils, or skin by 1. Inhalation leads to pulmonary tuberculosis  infective coughed Or sneezed droplets in the air by a patient with open T.B,  or contaminated dust 2. Ingestion or Swallowing leads to TB of tonsils or intestine infected milk (from diseased cows) or contaminated dust 3. Inoculation through skin is extremely rare. In Secondary tuberculosis: organism reach organ through :- 1. Exogenous→ Re-infection for the second time occurs as in primary TB either by Inhalation or Ingestion or Inoculation 2. Endogenous from reactivation of lesion containing the living TB bacilli Sites of secondary tuberculosis :- Many organs of body as kidney, liver, vertebrae (pott’s disease) female & male genital tracts ………etc. Pathogenesis of T.B: -58-  In Primary infection: 1. Macrophages: engulf bacilli. These macrophages swollen & pink in color resembling the epithelial cells, called “epithelioid cells” Some epithelioid cells fuse together forming giant cells called “Langhan’s Giant cells”. 2. Then. The macrophages are unable to kill the bacilli that multiply& lyse the host cells. 3. After few weeks: - sensitized T-lymphocytes accumulation around epithelioid cells release Lymphokines which are responsible for:-  First, they activate macrophages to kill intracellular mycobacteria. →→ →→immunity.  Second lyses infected macrophages and kill bacilli results in the formation of caseating granuloma. →→→→→ acquired hypersensitivity (delayed hypersensitivity type IV). -59- Types of T.B. Secondary Tuberculosis Primary Tuberculosis Reinfection type Infection of sensitized patient due to re- Infection for the first time. infection or reactivation In Egypt it mainly affects children. In Egypt it mainly affects adults. Spread is more common. Spread is less common Type IV hypersensitivity less Type IV hypersensitivity more developed developed so Tissue destruction is less so Tissue destruction is more marked. marked. Sites any organs of body included Sites :- primary sites primary sites Primary Tuberculosis (Childhood Type) Primary tuberculosis complex: - Tubercle bacilli will exist in three sites: 1. Somewhere in the infected primary sites (primary tuberculous focus) 2. In the draining lymphatics (tuberculous lymphangitis). 3. In the draining lymph nodes (tuberculous lymphadenitis). Primary Pulmonary Tuberculosis 1. Ghon's Focus: Small yellow subpleural granuloma in mid lung field. 2. Tuberculous lymphadenitis in the hilum is a small yellow granuloma in a hilar lymph node next to a bronchus 3. Tuberculous Lymphadenitis Microscopic picture:- Granulomas in T B are called tubercles caseating granuloma , composed of central caseous necrosis surrounded by epitheloid cells , Langhan‘s giant cells& lymphocytes. Old granuloma surrounded by fibrosis Others sites of common tuberculosis infection 1- primary Intestinal infection, the primary focus lesion is common in the illocaecal region. 2- Lymph nodes T.B mainly affected cervical L.Ns groups. -60- Complications of tuberculosis: 1. Spread 2. Hemorrhage 3. Organ destruction and severe fibrosis 4. Recurrence (re-activation) 2- Syphilis Definition: Chronic infectious granulomatous inflammation caused by bacterial called Treponema Pallidum. Mode of Infection& types: organism can be transmitted in one of 2 ways: 1. Acquired Syphilis:  Venereal Type (most common). transmitted by sexual contact.  Non-venereal type: Touching syphilitic lesions or blood transfusion from syphilitic donor. 2. Congenital Syphilis: Transplacental transmission from syphilitic mother to her fetus lead to abortion, stillbirth or delivery of baby with syphilitic lesions 2- Fungal Infections Predisposing factors :- Low immunity e.g. Corticosteroid administration, prolonged broad spectrum antibiotic therapy, immunosuppressive therapy or others states of immunocompromising as diabetes and AIDS defects in neutrophillic and macrophage functions Fungal infections are divided into 1. Superficial fungal infections e.g. Tinea & Some cases of Candidiasis 2. Deep Fungal Infections cause systemic disease e.g. candidiasis Candidiasis (Moniliasis) Definition: Infection with the fungus called "Candida albicans". This fungus is a normal commensal of oral cavity, GIT, vagina and skin.t becomes pathogenic in the low immunity conditions. Pathology: There are several patterns: -61- 1- Superficial Candidiasis: Most common. Usually due to prolonged antibiotic use. Manifestations:  oral Thrush& Vaginal lesions: White oral mucosal patches  Cutaneous eczematous lesion: macerations of interdigital skin. 2- Invasive candidiasis: It is often fatal. Seen in Immunosuppression. Many organs may be involved with micro abscesses as brain, liver, kidney. Osteomyelitis Definition: - is inflammation of bone and bone marrow Classification 1) According to the duration of inflammation. Acute (6 weeks) 2) According to Etiology of osteomyelitis 1- Bacterial (most common)  A)Acute suppurative osteomylitis  Acute hematogenous osteomyelitis  Acute non- hematogenous osteomyelitis  B) Chronic osteomyelitis  Specific →→ T.B or sypilitic osteomyelitis  Non-specific →→ chronic suppurative osteomyelitis 2- Non- bacterial  Viral osteomyelitis  Radiation osteomyelitis 3) The mode of infection the organisms reach bone through 1. Hematogenous route→→ more common, from septic focus elsewhere in body 2. Non hematogenous route →→ from adjacent septic focus (ostitis media sinusitis), open fractures) Acute Suppurative Osteomyelitis General features  Age: common in Infancy and childhood, affect also adults.  Sex: Males predominate 4:1 -62-   Location: Metaphysis of long bone in children epiphyseal in adults.  Predisposing factors: - Poor nutrition, low immunity, preexisting septic focus. Etiology: - Staphylococcus aureus is common organism, other as Strep. pyogenes E.Coli, T.B & syphilis Clinical Features: -  Severe pain.  Swelling due to Distension of periosteum with pus & inflammatory edema of surrounding soft tissue.  Redness.  Hotness  Loss of function Pathogenesis 1. Bacteria reach the bone through hematogenous or direct route 2. Infection → medullary inflammation exudate formation →↑↑ intramedullary pressure→→Compression/ Thrombosis of vessels →→necrosis of bone + pus formation 3. ↑Sequestrum →is necrotic bone, separated from surrounding vital bone by osteoclast activity surrounded by pus 4. ↑↑intramedullary pressure→→Suppurative inflammation extend through the cortical bone to involve the periosteum→→Elevation of periosteum from the underling cortical bone by pus lead to subperiosteal abscess formation. That disruption of blood supply to cortical bone, predispose to further bone necrosis Complications: - 1. Spread: -  Direct spread →→ arthiritis , myositis  Blood spread →→ septicemia, toxemia, pyemia 2. Chronic osteomyelitis→→ due to Inadequate treatment 3. Pathological fracture →→ due to bone weakness as result of extensive bone destruction 4. Growth arrest (deformity) →→ due to destroy growth plate. 5. Epithelialization of sinuses may lead to developedsquamous cells carcinoma in chronic cases. -63- Treatment of osteomyelitis: - 1. Surgical treatment 2. Antibiotic therapy 3. General treatment: nutritional therapy or general supportive treatment by intaking enough caloric, protein, vitamin etc 4. Immobilization 5. Reconstruction 6. Correct host immunity e.g. control blood sugar level in diabetic patient, treatment of chronic disease. -64-  Disorders of Immunity Key Concepts Functions of immune system 1. To provide defense of human body from: -  Any infection.  Cells-mutants.  Tumor cells.  Transplanted cells.  Any substances which are recognized by immune system as foreign. Organs of immune system:  Central organs: bone marrow and thymus. They response for central tolerance where during immune system developing self-reactive immune cells are destroy or inactivated by central organs.  Peripheral organs: lymphatic nodules, spleen, mucosa- associated lymphoid tissue. Immune mechanisms 1. Innate immunity (natural or native) is the first line of defense, present before infection, providing protection against inhaled microbes 2. Adaptive (Acquired) immunity there is two main types: 1. Cell-mediated (or cellular) immunity.  It is responsible for defense against intracellular microbes.  It is mediated by T lymphocytes.  Performed by: - NK(natural killer) cells - macrophages - basophiles, neutrophils.  The result is formation of chronic inflammatory cells infiltrates and granulomas. -65-  2. Humoral immunity  It protects against extra- cellular microbes and their toxins.  It is mediated by B lymphocytes and their secreted products.  Performed by: - B-lymphocytes, that transformed into plasmocytes and produce IgM, G, & activated complex of complement (C3 and C5).  The result is phagocytosis of bacteria &neutralizations of exotoxins. Disorders of immunity are lesions related to the immune system Seen in the following forms: 1. Immune- mediated injury (hypersensitivity reactions/ allergy) 2. Autoimmune diseases 3. Immunodeficiency diseases “congenital or acquired”. 4. Amyloidosis 5. Tumors of the lymphatic system. -66-  Hypersensitivity Definition: - Exaggerated immune response against living irritants (bacteria, virus. etc) or non- living irritants (such as food proteins, dust, pollens, drugs…etc) leading to tissue destruction Classified into  Based on the immune mechanisms of tissue injury: Type I, Type II, Type III and Type IV.  Based on duration to developed into 1. Immediate Hypersensitivity →→→are types I, II & III which mediated by serum antibodies and rapidly develop. 2. Delayed Hypersensitivity →→→ is type IV is mediated by sensitized T – lymphocytes (cell-mediated) and the reaction develops in a longer time. Type I Hypersensitivity (Anaphylaxis; Anaphylactic Reaction) Pathogenesis: - anaphylactic reaction develops into 2 steps.  First time stimulation of formation of specific antibodies (IgE), that bound to mast cells& induce mast cell proliferation →→ No harmful effect, but the individual become sensitized to this antigen.  Second time cell degranulation lead to liberation of histamine and other chemical mediators→→→Cellular damage with severe inflammatory reaction  Phases of type I hypersensitivity - Initial (rapid) response: within 5-30 min after re-exposure with resolution within 30 min, mediated by vasoactive amines and other primary mediators release from mast cells -67-  - Second (delayed) phase: 2-8 hours later, lasts for days and characterized by an intense infiltration by inflammatory cells mainly eosinophils and tissue damage. It is mediated by secondary mast cell mediators. Pathologic lesions: vascular dilation, edema, smooth muscle contraction& excess mucus production Clinical Manifestations  Systemic anaphylaxis: Typically follows administration of allergen as: penicillin allergy  Respiratory distress (difficulty in breathing)  Diarrhea  Urticaria  Shock (Anaphylactic shock)  Local anaphylaxis (Atopy):  It has hereditary predisposition.  It differs from systemic anaphylaxis in that IgE production is localized in certain -68-  tissue.  Examples: Hay Fever, allergic rhinitis, bronchial asthma, allergic conjunctivitis. Food allergies Remark: - Anaphylaxis (systemic type I hypersensitivity reaction) represents a medical emergency, is potentially life-threatening, and is effectively treated with I.M. adrenaline. Type II Hypersensitivity (Cytotoxic Hypersensitivity): Pathogenesis: - This type is tissue or organ specific  Some of self-reactive T or B cells were escape from central tolerance→→→ then attack healthy tissue  Self-reactive B cells become activated produce IgM and (mainly) IgG that attached to antigens on surface of host cells.  There are two types of antigens; intrinsic normally present on surface of host cells or extrinsic antigens from infections or some medication(a hapten)  The antigen is bind with Antibodies IgM and IgG lead to:-  Complement Dependent Reaction →Complement activation→ the target cell undergo lysis e.g. Incompatible blood transfusion, Rh incompatibility (erythroblastosis fetalis), Goodpasture‗s syndrome autoimmune hemolytic anemia , and thrombocytopenia.  Antibody- Dependent Cell- Mediated Cytotoxicity → Target cells are lysed by non- sensitized cells[ NK cells, monocytes, and granulocytes] e.g. Some types of rejection of transplanted organs  Or Antibody- mediated cellular dysfunction e.g. Myasthenia gravis, Grave's disease. -69- TYPE III Hypersensitivity (Immune Complex Reaction): Pathogenesis: - The antibodies IgM and IgG bind with soluble antigens produce antigen- antibody immune complexes →→ are deposited in vascular basement membrane →Complement activation lead to lysis and destruction of basement membrane →→ inflammation and tissue damage→→ →Acute Necrotizing Vasculitis (fibrinoid necrosis) Immune complexes can be deposited: 1- Generalized, if immune complexes are formed in the blood circulation and are deposited in many organs e.g. SLE, Rheumatoid arthritis& serum sickness. 2- Or Localized in particular organs (Arthus reaction type), such as: - kidneys (glomerulonephritis), - joints (arthritis), - small blood vessels of the skin if the complexes are formed and deposited locally→→ e.g. repeated subcutaneous injection of antigens (e.g. insulin) producing local vasculitis, necrosis and oedema. -70- Type IV Hypersensitivity (T-cell mediated cytotoxicity) Pathogenesis: -  The antigen is a part of a microorganism: bacteria as tuberculosis, virus, fungus or parasite that phagocytized by a macrophage and presented to T cells.  exposure →→ Sensitized T lymphocytes release cytokines of several types, of lymphocytes& basophils then inhibiting their migration from the area & other cytokines cause tissue damage (necrosis). Examples:  Caseous necrosis in tuberculosis and tuberculin skin test.  Cell-mediated graft rejection.  Contact dermatitis.  Some autoimmune diseases. -71-  Autoimmunity Definition: - Loss of tolerance, where some of the normal tissue components are considered Autoimmunity can be organ-specific (Hashimoto‗s thyroiditis) or non-organ specific (Systemic Lupus Erythematous(SLE)), depending on the distribution of the autoantigen & the type of autoantibody formation. Pathogenesis of autoimmune diseases  Genetic factors  Immunological factors  Altered tissue antigenicity  Cross reaction Remark: - In many autoimmune diseases, there is overlap between different types of hypersensitivity reaction. -72-  Immunodeficiency Diseases Definition: - Deficient immune response (immunodeficiency) involving B or T lymphocytes, macrophages, complement. Types of immunodeficiency diseases o Congenital: as: X-linked agammaglobulinemia of Bruton, congenital thymus hypoplasia (DiGeorge syndrome), isolated IgA deficiency. o Acquired: AIDS, drug-induced immunodeficiency (e.g. immuran) & diabetes mellitus. -73-  Cellular adaptation and disturbance of cell growth Definition: - Reversible changes in cells in response to changes in their environment When cells exposure to stress →→→ Cellular adaptation or cell injury (reversible or irreversible) Stress may be:-  Physiologic needs - Increased/decreased workload e.g. skeletal muscle and body building - Increased/decreased stimulation e.g. estrogen/prolactin stimulation of breast (lactation) & ↑estrogenic of uterus in pregnancy  Pathologic injury - Increased/decreased workload e.g cardiac muscle in hypertension, skeletal muscle disuse (limb immobilization) - Increased/decreased stimulation e.g denervation of muscle in poliomyelitis Types: 1. Atrophy. 2. Hypertrophy. 3. Hyperplasia. 4. Metaplasia Effect of adaptation  helpful: increase organ size so it can function better  More harm than good. Example: increased organ size requires more blood supply. If that is not available, organ becomes ischemic 1- Atrophy Definition: - Atrophy is a decrease in the size of cells lead to decreased size of the organ. Pathogenesis: -  Reduction in intracellular organelles Decreased number of mitochondria, myofilaments, ER by proteolysis.The atrophic cell shows autophagic vacuoles (Residual bodies) (i.e. lipofuscin  brown atrophy)  Diminished function but not dead Types of atrophy: - 1. Physiological atrophy Senile atrophy With old age , may be due to ↓↓ endocrine stimulation(e.g. atrophy of gonads after menopause ) & arteriosclerosis (brain atrophy) -74-  Atrophy of thymus gland after puberty 2. Pathological atrophy 1. Disuse atrophy prolonged decrease function e.g. fracture limb→ immobilization 2. Starvation atrophy depletion of carbohydrate, fat& protein e.g. Undernutrition 3. Ischemic atrophy gradual decrease blood supply e.g. atherosclerosis 4. Endocrine atrophy loss of endocrine regulatory mechanism e.g. hypopituitarism 5. Pressure atrophy- Erosion of spine caused by prolonged pressure by aneurysm or benign tumor 6. Neuropathic atrophy interruption of nerve supply e.g. poliomyelitis 7. Idiopathic atrophy no apparent causes of atrophy e.g. myopathies, testicular atrophy. 2- Hypertrophy Definition:- is increase in the size of cells with increase in the size and weight of organ. Pathogenesis:-  Increased in workload / hormonal stimulation →leads to increased synthesis of protein & intracellular organelles which leads to increased cell size. - Not due to swelling of cells. - No new cells proliferations - May occur with hyperplasia e.g. uterus in pregnancy Types of hypertrophy:- 1. Physiological hypertrophy:  Smooth muscles hypertrophy of uterus in pregnancy.  Enlargement of heart & skeletal muscles in athletes 2. Pathological hypertrophy:  Hypertrophy of cardiac muscle in patients With systemic hypertension that characterized by increased thickness of cardiac walls and increased weight of the heart  Compensatory hypertrophy seen after unilateral nephrectomy. 3- Hyperplasia Definition: - is an increase in the number of cells. lead to an increase in the size of the organ. Pathogenesis:-  Excessive hormone/growth factors stimulation [due to excess hormone, cell injury -75-  &viral infection..... etc] of target tissue leads to hyperplasia.  May occur with hypertrophy e.g. uterus in pregnancy Types of hyperplasia 1. Physiological hyperplasia  Hormonal hyperplasia of the breast during pregnancy &lactation 2. Pathologic hyperplasia  Compensatory hyperplasia ⚫ Hyperplasia of bone marrow after bleeding ⚫ Regeneration of liver after partial hepatectomy  Hormonal hyperplasia. ⚫ Endometrial hyperplasia→→ with excess estrogen ⚫ Benign prostatic hyperplasia →→ with excess androgens ⚫ Connective tissue cells in wound healing →→ with excess growth factors production. 4- Metaplasia Definition: - is reversible replacement of one adult differentiated (mature) cell type by another differentiated one in same category. Pathogenesis:-  Chronic irritation e.g. in trachea & bronchi of smoker →→ Reprogramming mediated by signals from cytokines, growth factor. reprogramming occurs in 1. Stem cells present in normal tissues 2. undifferentiated mesenchymal cells in connective tissue  May be some loss of function or predispose to malignancy Types of metaplasia. 1. Epithelium metaplasia 1. Squamous metaplasia  Columnar to squamous epithelium (most common epithelial -type of metaplasia due to chronic irritation e.g. In trachea and bronchi of smokers, cervix with HPV infection  Transitional epithelium to squamous epithelium due to chronic irritation e.g. in bilharziasis of urinary bladder. 2. Glandular( intestinal) metaplasia of squamous epithelium of esophagus to intestinal mucosa called Barrette‘s esophagitis with GERD (hyperacidity) 2. Mesenchymal metaplasia 1. Osseous metaplasia:- replacement of fibrous tissue to bone at sites of -76-  healing wound after injury ( post-traumatic myositis ossificans). Dysplasia Definition:- Disordered cellular proliferation characterized by loss in uniformity & arrangement of cells often affect epithelium& usually accompanied with metaplasia & hyperplasia e.g. atypical hyperplasia. Pathogenesis:-  Often cause by chronic irritation or prolonged inflammation.  On removal of simulus, the changes may disappear special in mild dysplasia.  In majority of cases dysplasia progresses into carcinoma insitu or invasive cancer.  Dysplasia is mainly seen in:  Urinary bladder in bilharziasis,  Cervix in chronic HPV cervicitis  bronchi in chronic heavy smoking,  Oral mucosa by the effect of sharp tooth Microscopic changes: - Dysplastic epithelial cells changes including 1. Increased number of layers of epithelial cells (cellular proliferation). 2. Disorderly arranged cells (Loss of polarity). 3. changes in size and shape of cells and their nuclei (Cellular & nuclear pleomorphism). 4. Increased nucleocytoplasmic ratio (↑↑N/C ratio). 5. Nuclear hyperchromatism. 6. Increased mitotic activity (No abnormal mitosis). 7. Prominent nucleoli Grades of dysplasia: 1. Grade I (mild dysplasia): involving lower third of the epithelium 2. Grade II (moderate dysplasia): involving lower two third of epithelium 3. Grade III (severe dysplasia): involving more than two third and it may involve full thickness of epithelium (carcinoma in situ). -77-  Carcinoma in situ Definition: It is an intraepithelial carcinoma or preinvasive carcinoma, represent a severe form of epithelial atypia without invasion of the basement membrane Pathological Features: 1- It is difficult to detect GROSSLY. 2- It may cause a thick indurated patch. It is a microscopic change characterized by: 1-Diffuse cellular atypia involving the whole thickness of the affected epithelium. The cells are pleomorphic with dark nuclei and numerous mitosis i.e. cytological malignant. Their architectural orientation is disturbed. 2-No invasion of basement membrane. Common sites of CIS: Mammary gland, bladder, cervix , endometrium , GIT , and skin. Fate: Progression to invasive carcinoma after variable times (usually years). -78-  Neoplasia Definition: - An abnormal mass of tissue, due to exceeds, autonomous and purposeless cell proliferations. The growth continuous even after the cessation of the stimuli which induced it Neo + plasia  new + growth. Clinically tumor = neoplasm, cancer = malignant tumor. General features of neoplasia 1- Tumor proliferation is uncontrolled &irreversible. 2- Tumors can be arise from any cells, even from permanent cells and has no useful function 3- Any neoplasm has two basic components: ⚫ parenchyma: - formed of neoplastic cells with abnormal DNA ⚫ The supportive tissue: - with normal DNA, formed of non-neoplastic stroma and vessels →→done by host as result of substance released by tumor cells as angiogensis factors. Differences between Hyperplasia and Neoplasia Hyperplasia Neoplasia Stimuli Present May be present Reversibility Reversible Irreversible. - polyclonal -usually, monoclonal Proliferation - Diffuse proliferation not form -Localized /focal proliferation mass form a mass Proliferated cells are like Proliferated cells are abnormal Cells normal cells cells (as in malignant tumor) May be useful as compensatory Effect Harmful hyperplasia. Classification& nomenclature of neoplasms A- According to their behavior 1. Benign neoplasms. Suffix ―…..oma‖ as lipoma 2. Malignant neoplasms. Malignant epithelial tumor----------- called carcinoma Malignant mesenchymal tumor ------ called sarcoma 3. Locally malignant neoplasms or locally aggressive tumors, characterized by:  Slow rate of growth than frank malignant tumors. -79-   Local invasion tumor.  No distant spread (no metastases)  Low grade tumor.  Much better Prognosis than malignant tumors.  Local recurrence after surgical excision is common  They may rarely change into frank malignant tumors that metastasize Locally malignant tumors include: - 1. Basal Cell Carcinoma. arising from basal layer of epidermis of skin 2. Giant Cell Tumor (Osteoclastoma). arise from osteoclast cells. 3. Chordoma. arise from cellular remnants of the notochord 4. Adamantinoma/ Ameloblastoma arise from of odontogenic epithelium. 5. Carcinoid Tumor. arising from the enterochromaffin cells disseminated throughout the GIT, lung and other tissue as ovary 6. Craniopharyngioma, tumor of central nervous system, usually in sellar and suprasellar areas. B- According to tissue of origin 1. Epithelial tumors e.g. Adenoma/adenocarcinoma (tumor forming glands), Papilloma (tumor with finger like projections) & Polyp (tumor that projects above surface epithelium) 2. Mesenchymal tumors e.g. fibroma/fibrosarcoma 3. Others. Lymphoma, malignant melanoma. ⚫ Misnomers ⚫ Hepatoma: malignant liver tumor ⚫ Melanoma: malignant skin tumor from melanocytes ⚫ Seminoma: malignant tumor of testes. ⚫ Lymphoma: malignant tumor of lymphocytes ⚫ Leukemia: WBCs malignant tumor of haemopoietic stem cells. Nomenclature: exceptions ⚫ Teratoma – Tumor of Germ cell – formed of multiple tissuesarise from germ cells (usually gonads). May be Benign