L2,3,4 Cell Injuries PDF

# Introduction to Pathology ## Presented by: - Dr. Eiman Adel Hasby - Prof., Pathology Department - IT-Unit Director - Tanta Faculty of Medicine, Egypt - Associate Trainer in TICFDL, Tanta University - Assistant to Ministry of Health Undersecretary at Directorate of Health Affairs in Gharbia, Egypt...

# Introduction to Pathology ## Presented by: - Dr. Eiman Adel Hasby - Prof., Pathology Department - IT-Unit Director - Tanta Faculty of Medicine, Egypt - Associate Trainer in TICFDL, Tanta University - Assistant to Ministry of Health Undersecretary at Directorate of Health Affairs in Gharbia, Egypt ## Lecture Frame - Introduction to Pathology - Principles: - Meaning of "Pathology" - Definition of "Disease" - Aspects of Studying a disease ## What is Pathology? - Scientific study of the disease ## What is Disease? - Any disturbance of the structure and/or function of an organ or tissue. ## Common Terms in Pathology - Patient - Lesions - Characteristic Changes in tissues and cells produced by disease - Morphology - Size - Shape - Color - Consistency - Weight - Borders - Cut Section - Causal Factors - Etiology of Disease - "Why" of Disease - Mechanism - Pathogenesis of Disease - "How" of Disease - Functional Implications - Symptoms - Signs - Clinical Significance - What is wrong (diagnosis) - What is going to happen (prognosis) - What can be done about it (treatment) - What should be done to avoid complications and spread (prevention) ## Etiology vs Pathogenesis vs Disease | Category | Definition | |---|---| | Etiology | Why does disease occur? | | Pathogenesis | How does disease occur? | | Disease | What is the disease? | ## Aspects of Studying Diseases - Definition - Aetiology - Predisposing/Risk factors - Exciting factors - Pathogenesis - Pathological Picture - Gross - Microscopic (histopathology) - Prognosis - Complications ## Historical Background - Father of Medicine: Hippocrates - "Wherever the art of medicine is loved, there is also a love of humanity” - Father of Modern Medicine: Sir William Osler - "The good physician treats the disease; the great physician treats the patient who has the disease." - “Medicine is a science of uncertainty and an art of probability” - Father of Pathology: Rudolf Virchow - "Medical education does not exist to provide student with a way of making a living, but to ensure the health of the community." ## Historical Background - Images - A timeline shows medical history of the last century, beginning with the Rod of Asclepius and moving to the double helix of DNA. - A visual representation shows a statue of Hippocrates with the caption,"The Father of Medicine in the Internet age" ## Cellular Injury - Part I - Presented by: - Dr. Eiman Adel Hasby - Prof., Pathology Department - IT-Unit Director - Tanta Faculty of Medicine, Egypt - Associate Trainer in TICFDL, Tanta University ## Learning Objectives - Explain causes of cellular injury - Demonstrate understanding of cellular changes during injury and cell death - Describe cellular alterations during injury ## Lecture Frame: Cell Injury - Causes of cellular injury - Depends on the state of the cell and the type of insult - Response to an insult - adaptation - reversible injury - irreversible injury with cell death - Vulnerable sites - Intracellular sites and systems - Important changes - Grossly - Microscopically - Cellular Adaptive responses to injury ## Definition of Cell Injury - Metabolic & morphologic changes in a tissue when it is exposed to an injurious agent ## Causes of Cellular Injury 1. Hypoxia/ Ischemia 2. Immunologic dysfunction 3. Pathogens (viruses, bacteria, parasites and fungi) 4. Physical forms of injury (heat/cold/radiation/trauma) 5. Congenital disorders 6. Chemical injury (acids/alkali/toxins) 7. Nutritional or vitamin imbalance - Inadequate calorie/protein intake - Excess caloric intake - Vitamin deficiencies ## Normal Cell to Cell Injury and Death - Stress/Increased demand can lead to adaptation - Injurious stimulus and failure to adapt can lead to cell injury and cell death ## Cellular Changes During Injury - Homeostatic cell - Metabolic Changes - Ischemia, Toxins, etc. - Reversible vs Irreversible Changes - Point of no return - Apoptosis and Necrosis ## Factors Affecting Response to Cell Injury - **Response Depends On Stimulus:** - Type - Severity - Duration - **Consequence Depends On Cell:** - Type - State - Adaptability ## Important Mechanisms of Cell Injury - Critical intracellular targets susceptible to injury - DNA - Production of ATP via aerobic respiration - Cell membranes - Protein synthesis ## Mechanisms of Cell Injury - Image - This image shows the different ways that cell injury can occur. Mitochondria damage can cause ATP depletion, entry of calcium, and the formation of Reactive oxygen species (ROS). Membrane damage can cause the loss of cellular components, the leakage of pro-apoptotic proteins and the activation of pro-apoptotic proteins. The activation of caspase can lead to the leakage of mitochondrial proteins and the activation of pro-apoptotic proteins. DNA damage can occur due to ROS or the activation of caspase and can lead to multiple downstream effects. ## Mechanisms of Cell Injury - Myocardial Ischemia - Decreased Oxidative Phosphorylation (Decreased ATP) - Na+ K+ ATPase pump failure - Influx of Na+ and Efflux of K+ lead to increased cell swelling - Endoplasmic reticulum swelling and loss of microvilli - Membrane blebs - Ribosomal Detachment - Severe Membrane Damage - Influx of Ca2+ - Cytoplasm enzyme leak out of cell - Troponin 1 (Troponin I) ## Morphologic Alterations in Cell Injury A graph is shown with the following columns: - Reversible cell injury - Irreversible cell injury - Ultrastructural changes - Light microscopic changes - Gross morphologic changes The graph shows the effect of injury on cell function over time. The impact of injury on cell function is dependent on the duration of injury. - Reversible cell injury can lead to a decrease in cell function. With time, cell function can return to normal. - Irreversible cell injury can lead to a significant decrease in cell function and may lead to cell death. ## Morphologic Changes in Cell Injury - An image shows three cells: normal cells; cells with reversible injury; and cells with irreversible injury. - An image shows progression of Cell injury to Apoptosis and Necrosis ## Classification of Morphologic Forms of Cell Injury | Mechanism of Cell Injury | Nomenclature | |---|---| | Reversible Cell Injury | Retrogressive Changes (older term: Degenerations) | | Irreversible Cell Injury | Cell Death: Necrosis | | Programmed Cell Death | Apoptosis | | Deranged Cell Metabolism | Intracellular Accumulation of Lipid, Protein, Carbohydrate | | After-effects of Necrosis | Gangrene, Pathologic Calcification | ## Clinical Application - The loss of membrane integrity (cell death) allows intracellular enzymes to leak out, which can then be measured in the blood. - Detection of these proteins in the circulation serves as a clinical marker of cell death and organ injury. ## Clinically Important Examples - Myocardial Injury - Troponin (most specific) - CPKMB - Lactate Dehydrogenase (LDH) - Hepatitis - Transaminases - Pancreatitis - Amylase - Lipase - Biliary Tract Obstruction - Alkaline Phosphatase ## Intracellular Accumulations - Normal cellular constituent accumulated in excess: - Water - Fat - CHO (Mucin) - Protein ## Abnormal Substance - Either: - Exogenous - mineral or product of infectious agents - Endogenous - product of abnormal synthesis or metabolism - Examples - Purine metabolism (gout) - Calcification (Dystrophic and metastatic) ## Intracellular Accumulations - Pigment - Exogenous - melanin - Endogenous - Melanin - Hemotogenous - lipochrome ## Exogenous Pigment - Image of a tattoo - Image of a person's eye that shows that Argyria ## Exogenous Pigment - Anthracosis - A microscopic image shows the lung with abundant black carbon pigment in the septal walls and around the bronchiole. - Distended respiratory bronchioles - Dust-laden macrophages - Dilated alveoli ## Endogenous Pigment - 1-Melanin Pigment - Endogenous, non-hemoglobin-derived, brown-black pigment formed in melanocytes - Tyrosine - Tyrosinase - Melanin ## Normal Melanin - Skin - Suprarenal glands - Eye: Retina & Choroid ## Melanogenesis - This image shows a diagram of melanogenesis. The melanocyte starts with tyrosine and then converts it into melanin through a series of steps. ## Pathological Melanin Pigmentation - Overproduction of melanin - Addison's disease - chronic adrenal insufficiency; over pigmentation of exposed areas of the skin (face &hands) and mucus membranes of mouth & gums - Chloasma - brown patches of the skin during pregnancy or due to ovarian disturbance. - Pigmented tumors - melanomas - Melanosis coli - patchy blackish colored areas of mucosa of the large gut in chronic intestinal obstruction. - Diminution or absence of melanin - 1- Albinism - congenital absence of melanin from the skin → waxy color, white hair and red iris. - 2- Leukoderma - localized whitish patches of the skin - 3-Vitiligo ## Haematogenous Pigments - Hemosiderin: - Hemoglobin-derived, iron-containing, golden yellow-to-brown, granular or crystalline pigment - Stored in cells - Bilirubin - Normal major pigment found in bile - Derived from hemoglobin - Contains no iron - Parasitic Pigments - Malarial infection - Hematozoidin - Bilharizial pigment ## Haemochromatosis/Hemosiderosis - Pathologic deposition of hemosiderin in tissues - **Primary (bronzed diabetes)** - Rare - Hereditary autosomal recessive - Primarily affects males - Due to an inborn error of iron metabolism with excess iron absorption from the duodenum - Pathologic features: - Liver cell necrosis -> pigment cirrhosis - Pancreas -> atrophy & necrosis of islets of Langerhans -> diabetes mellitus - Skin -> bronzed coloration - **Secondary** - **Localized hemosiderosis** - Seen around of areas of hemorrhage as brownish pigment - Usually taken up by histiocytes - **Generalized hemosiderosis** - Rapid blood transfusion - Haemolytic anemia - Prolonged administration of iron - Excess hemosiderin is deposits in cells of the reticuloendothelial system, liver cells, and renal tubules. ## Prussian Blue Reaction - A microscopic image shows a section that has been stained with Prussian blue. This technique is used to detect iron deposits in tissues. Hemosiderin is the pigment that stains blue with this technique. ## Haemochromatosis - Localized - Local tissue - Macrophages - Fibroblasts - Endothelial and alveolar cells - Examples - Hemorrhage in tissues - Black eye - Brown induration of the lung - Infarction - Generalized (systemic) - Parenchymal Deposits - Liver - Pancreas - Kidney - Heart - Skin - RE Cell Deposits - Liver - Spleen - Bone marrow - Examples - Acquired Hemosiderosis - Chronic hemolytic disorders - Blood transfusion - Parenteral administration of iron - Hereditary (Idiopathic) Hemochromatosis - Increased absorption - Genetic defect - Excessive dietary intake (African Iron Overload) ## Hyperbilirubinemia - Increased bilirubin in the blood occurs in cases of jaundice - Yellowish coloration of: - Mucous membranes - Skin - Sclera - soft palate - Internal organs - Causes of Jaundice - 1- Overproduction of bilirubin due to haemolysis of RBCs (haemolytic jaundice) - 2- Obstruction of the flow of bile (obstructive jaundice) - 3- Inability of the liver cells to excrete all the bilirubin brought to them (hepatocellular jaundice) ## Lipofuscin (lipochrome)- Wear and tear/Aging Pigment - Insoluble pigment composed of polymers of lipids and phospholipids complexed with protein - Derived through lipid peroxidation of polyunsaturated lipids of subcellular membranes - Not injurious to the cell or its functions - Tell-tale sign of free radical injury and lipid peroxidation - Yellow-brown, finely granular intracytoplasmic, often perinuclear pigment seen in cells undergoing slow, regressive changes - Particularly prominent in liver and heart of: - Aging patients - Patients with severe malnourishment and cancer cachexia - Electron Microscopy: - Highly electron dense - Membranous structures in their midst - Perinuclear location ## Brown Atrophy of the Heart - It is a pathological condition seen in: - old persons - Marked loss of weight e.g. late stages of malignant tumours, starvation & severe malnutrition. - **Gross Picture:** - Heart becomes reduced in size and weight. - Myocardium of the ventricles is thin, atrophied and the muscle is brownish in color. - Coronaries are tortuous. - Pericardial fat is diminished and gelatinous in appearance. - **Microscopic Picture:** - Myocardial muscle fibres are thin and atrophied with yellowish crystals of lipochrome on both sides of the nuclei. ## Pathologic Calcification - Definition: Abnormal deposition of calcium salts in tissues other than bone and teeth - The calcium salts are deposited as calcium phosphate. - Normal blood calcium level (9-11 mg/dl) ## Dystrophic Calcification - Deposition of calcium salts in dead or degenerating tissues - Occurs: - Despite normal serum levels of calcium - In the absence of derangements in calcium metabolism - Areas of necrosis or degeneration -> large amounts of alkaline phosphatase -> deposition of calcium salts - Examples: - Necrosis: - Tuberculous Caseation - Fat necrosis in acute hemorrhagic pancreatitis - In the wall of: - Blood vessels in atherosclerosis and atheroma - Chronic abscess - Old scar - In degeneration of: - Tumors e.g. leiomyoma & meningioma - Thyroid nodular goiter - Dead: - Bilharzial ova - Hydatid cysts - Fetus (Lithopedion) ## Metastatic Calcification - Deposition of calcium salts in otherwise normal tissues - Results from hypercalcemia secondary to some disturbance in calcium metabolism - Examples - Hyperparathyroidism - Increased mobilization of calcium from the bone - Hypervitaminosis D - Increased absorption of calcium from the gastrointestinal tract - Chronic renal disease with phosphate retention leading to secondary hyperparathyroidism - Destructive bone diseases ## Examples of Dystrophic Calcification - A microscopic image of caseous necrosis in a tuberculous lymph node shows basophilic granular deposits with healed granulomas surrounding them. - A microscopic image of a degenerated tunica media in a muscular artery shows calcified deposits. ## Examples of Metastatic Calcification - A microscopic image of a nephron shows calcification in tubular basement membrane. ## Differences Between Dystrophic and Metastatic Calcification | Feature | Dystrophic Calcification | Metastatic Calcification | |---|---|---| | Definition | Deposits of calcium salts in dead and degenerated tissues | Deposits of calcium salts in normal tissues | | Calcium Metabolism | Normal | Deranged | | Serum Calcium Level | Normal | Hypercalcemia | | Reversibility | Generally irreversible | Reversible upon correction of metabolic disorder | | Causes | Necrosis (caseous, liquefactive, fat), infarcts, thrombi, hematomas, dead parasites, old scars, atheromas, Mönckeberg’s sclerosis, certain tumors, cysts, calcinosis cutis | Hyperparathyroidism (due to adenoma, hyperplasia, CRF), bony destructive lesions (e.g. myeloma, metastatic carcinoma), prolonged immobilization, hypervitaminosis D, milk-alkali syndrome, hypercalcemia of infancy | | Pathogenesis | Increased binding of phosphates with necrotic and degenerative tissue, which in turn binds to calcium forming calcium phosphate precipitates | Increased precipitates of calcium phosphate due to hypercalcemia at certain sites e.g. in lungs, stomach, blood vessels and cornea | ## Calcinosis and Pathologic Ossification - **Calcinosis:** - A disorder of unknown cause characterized by abnormal deposition of calcium salts in the skin and subcutaneous tissues forming tumor-like swellings. - **Pathologic ossification:** - Formation of bone structure in extra-osseous sites. - May be preceded by calcification. - Sites: Arteries, cardiac valves, organizing hematomas, pleural scars and in muscles after trauma as myositis ossificans. ## References: - Vinay Kumar, Abul K. Abbas, Nelson Fausto, Jon C. Aster. Eighth edition - Kumar, Cotran & Robbins, Basic Pathology. Saunders publisher, 10th ed., 2017 - Mohan H., Mohan P., Mohan T & mohan S. (Eds.). (2018) Text book of pathology 8th edition - Kaplan Medical, USMLE STEP 1 LECTURE NOTES, PATHOLOGY 2017 - https://webpath.med.utah.edu/LABS/LABMENU.html - http://www.medscap.com/pathologyhome # Cellular Pathology - Presented by: - Dr. Eiman Adel Hasby - Prof., Pathology Department - IT-Unit Director - Tanta Faculty of Medicine, Egypt - Associate Trainer in TICFDL, Tanta University ## Agenda - Pigmentation - Calcification ## Disturbance of Pigment Metabolism - Pigments are substances whose intrinsic color makes them recognizable in living tissue. - Either: - Synthesized within the body itself (endogenous pigments) - Introduced into the body (exogenous pigments) - They may be: - Inert and ignored by the body, lie on or within tissue - Act on the body as foreign or poisonous substances, eliciting an inflammatory reaction ## Pigments - **Exogenous** - Cosmotic (tattooing) - Iatrogenic - Amalgam - Argyria - Carotene - Tetracycline - Occupational - Anthracosis - Plumpism - **Endogenous** - Melanin - Hemotogenous - Lipochrome ## Exogenous Pigment - Tattoo - This image shows a tattoo on a person's arm. ## Exogenous Pigment - Argyria - This image shows an eye that has been affected by Argyria. The condition is caused by the deposition of silver in the tissues. ## Endogenous Pigment - **Melanin** - Endogenous, non-hemoglobin-derived, brown-black pigment formed in melanocytes when Tyrosine interacts with Tyrosinase - Normally found in: - Skin - Suprarenal glands - Eye: Retina & Choroid - **Hemotogenous** - Hemosiderin and Bilirubin ## Pathological Melanin Pigmentation - Overproduction of melanin - Addison's disease - Chronic adrenal insufficiency; over pigmentation of exposed areas of the skin (face &hands) and mucus membranes of mouth & gums - Chloasma - Brown patches of the skin during pregnancy or due to ovarian disturbance - Pigmented tumors - Melanomas - Melanosis coli - Patchy blackish colored areas of mucosa of the large gut in chronic intestinal obstruction. - Diminution or absence of melanin - 1- Albinism - Congenital absence of melanin from the skin → waxy color, white hair and red iris. - 2- Leukoderma - Localized whitish patches of the skin. - 3-Vitiligo ## Examples of Melanin Conditions - A microscopic image shows a compound naevus, which has been stained with hematoxylin and eosin. The image shows clusters of benign naevus cells in the dermis as well as in the lower epidermis. These cells contain coarse, granular, brown-black melanin pigment. - Images of albinism, vitiligo and leukoderma ## Hemotogenous Pigments - Hemosiderin: - Hemoglobin-derived, iron-containing golden yellow-to-brown pigment - Granular or crystalline - Stored in cells - Bilirubin - Normal major pigment found in bile - Derived from hemoglobin - Contains no iron - Parasitic Pigments - Malarial infection (hematozoidin) - Bilharizial pigment ## Haemochromatosis/Hemosiderosis - A condition that results in the accumulation of iron in the tissues. - **Primary (bronzed diabetes)** - Rare - Hereditary autosomal recessive - Primarily affects males - Due to an inborn error of iron metabolism with excess iron absorption from the duodenum - Pathologic features: - Liver cell necrosis -> pigment cirrhosis - Pancreas -> atrophy & necrosis of islets of Langerhans -> diabetes mellitus - Skin -> bronzed coloration - **Secondary** - **Localized hemosiderosis** - Seen around of areas of hemorrhage as brownish pigment - Usually taken up by histiocytes - **Generalized hemosiderosis** - Rapid blood transfusion - Haemolytic anemia - Prolonged administration of iron - Excess hemosidrin is deposits in cells of the reticuloendothelial system, liver cells, and renal tubules. ## Prussian Blue Reaction - A microscopic image shows a section that has been stained with Prussian blue. This technique is used to detect iron deposits in tissues. Hemosiderin is the pigment that stains blue with this technique. ## Haemochromatosis - Images - Liver cell necrosis - A picture shows a liver section that shows the difference between normal and liver with brown color . - Macrophages with Hemosiderin - A microscopic image shows Prussian blue reaction to stain hemosiderin in a macrophage. ## Haemochromatosis - Effects - Images with captions show the effects of localized and generalized hemosiderosis. ## Hyperbilirubinemia - Increased bilirubin in the blood occurs in cases of jaundice - Yellowish coloration of: - Mucous membranes - Skin - Sclera - Soft palate - Internal organs - Causes of Jaundice - 1- Overproduction of bilirubin due to haemolysis of RBCs (haemolytic jaundice) - 2- Obstruction of the flow of bile (obstructive jaundice) - 3- Inability of the liver cells to excrete all the bilirubin brought to them (hepatocellular jaundice) ## Lipofuscin (lipochrome)- Wear-and-tear/Aging Pigment - Insoluble pigment composed of polymers of lipids and phospholipids complexed with protein - Derived through lipid peroxidation of polyunsaturated lipids of subcellular membranes - Not injurious to the cell or its functions - Tell-tale sign of free radical injury and lipid peroxidation - Yellow-brown, finely granular intracytoplasmic, often perinuclear pigment seen in cells undergoing slow, regressive changes - Particularly prominent in liver and heart of: - Aging patients - Patients with severe malnourishment and cancer cachexia - Electron Microscopy: - Highly electron dense - Membranous structures in their midst - Perinuclear location ## Brown Atrophy of the Heart - It is a pathological condition seen in: - old persons - Marked loss of weight e.g. late stages of malignant tumours, starvation & severe malnutrition. - **Gross Picture:** - Heart becomes reduced in size and weight. - Myocardium of the ventricles is thin, atrophied and the muscle is brownish in color. - Coronaries are tortuous. - Pericardial fat is diminished and gelatinous in appearance. - **Microscopic Picture:** - Myocardial muscle fibres are thin and atrophied with yellowish crystals of lipochrome on both sides of the nuclei. ## Brown Atrophy of the Heart - Images - A microscopic slide shows the heart muscle with brownish color due to accumulation of lipofuscin pigment within the myocardial muscle. - A microscopic image shows perinuclear lipofuscin granules in the cytoplasm of the myocardial fibers, especially around the nuclei. ## Pathologic Calcification - Definition: Abnormal deposition of calcium salts in tissues other than bone and teeth - The calcium salts are deposited as calcium phosphate. - Normal blood calcium level (9-11 mg/dl) ## Dystrophic Calcification - Deposition of calcium salts in dead or degenerating tissues - Occurs: - Despite normal serum levels of calcium - In the absence of derangements in calcium metabolism - Areas of necrosis or degeneration -> large amounts of alkaline phosphatase -> deposition of calcium salts - Examples: - Necrosis: - Tuberculous Caseation - Fat necrosis in acute hemorrhagic pancreatitis - In the wall of: - Blood vessels in atherosclerosis and atheroma - Chronic abscess - Old scar - In degeneration of: - Tumors e.g. leiomyoma & meningioma - Thyroid nodular goiter - Dead: - Bilharzial ova - Hydatid cysts - Fetus (Lithopedion) ## Metastatic Calcification - Deposition of calcium salts in otherwise normal tissues - Results from hypercalcemia secondary to some disturbance in calcium metabolism - Examples - Hyperparathyroidism - Increased mobilization of calcium from the bone - Hypervitaminosis D - Increased absorption of calcium from the gastrointestinal tract - Chronic renal disease with phosphate retention leading to secondary hyperparathyroidism - Destructive bone diseases ## Examples of Dystrophic Calcification - A microscopic image of caseous necrosis in a tuberculous lymph node shows basophilic granular deposits with healed granulomas surrounding them. - A microscopic image of a degenerated tunica media in a muscular artery shows calcified deposits. ## Examples of Metastatic Calcification - A microscopic image of a nephron shows calcification in tubular basement membrane. ## Differences Between Dystrophic and Metastatic Calcification | Feature | Dystrophic Calcification | Metastatic Calcification | |---|---|---| | Definition | Deposits of calcium salts in dead and degenerated tissues | Deposits of calcium salts in normal tissues | | Calcium Metabolism | Normal | Deranged | | Serum Calcium Level | Normal | Hypercalcemia | | Reversibility | Generally irreversible | Reversible upon correction of metabolic disorder | | Causes | Necrosis (caseous, liquefactive, fat), infarcts, thrombi, hematomas, dead parasites, old scars, atheromas, Mönckeberg’s sclerosis, certain tumors, cysts, calcinosis cutis | Hyperparathyroidism (due to adenoma, hyperplasia, CRF), bony destructive lesions (e.g. myeloma, metastatic carcinoma), prolonged immobilization, hypervitaminosis D, milk-alkali syndrome, hypercalcemia of infancy | | Pathogenesis | Increased binding of phosphates with necrotic and degenerative tissue, which in turn binds to calcium forming calcium phosphate precipitates | Increased precipitates of calcium phosphate due to hypercalcemia at certain sites e.g. in lungs, stomach, blood vessels and cornea | ## Calcinosis and Pathologic Ossification - **Calcinosis:** - A disorder of unknown cause characterized by abnormal deposition of calcium salts in the skin and subcutaneous tissues forming tumor-like swellings. - **Pathologic ossification:** - Formation of bone structure in extra-osseous sites. - May be preceded by calcification. - Sites: Arteries, cardiac valves, organizing hematomas, pleural scars and in muscles after trauma as myositis ossificans. ## References: - Vinay Kumar, Abul K. Abbas, Nelson Fausto, Jon C. Aster. Eighth edition - Kumar, Cotran & Robbins, Basic Pathology. Saunders publisher, 10th ed., 2017 - Mohan H., Mohan P., Mohan T & mohan S. (Eds.). (2018) Text book of pathology 8th edition - Kaplan Medical, USMLE STEP 1 LECTURE NOTES, PATHOLOGY 2017 - https://webpath.med.utah.edu/LABS/LABMENU.html - http://www.medscap.com/pathologyhome