Pathoma 2021 PDF

https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma  C C S N S P 21 ED T ON N R,...

https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma  C C S N S P 21 ED T ON N R, I 2 21 https://t.me/USMLEPathoma https://t.me/USMLEPathoma  R E 1 11 1 1 1 1 1 1 1 https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Growth Adaptations, Cellular Injury, and Cell Death.............1 Inflammation, Inflammatory Disorders, and Wound Healing... 11 Principles of Neoplasia........................................ 23 Hemostasis and Related Disorders............................. 31 Red Blood Cell Disorders....................................... 41 White Blood Cell Disorders.................................... 53 Vascular Pathology............................................ 65 Cardiac Pathology............................................. 73 Respira espirator oryy Tr Trac actt Pathology................................... 85 Gastr astroin ointtestinal P Paathology.................................... 99 Exocrine Ex ocrine Pancr Pancreas eas,, Gallbladder Gallbladder,, and Liver Liver Pa Pathol...........115 115 Kidne idneyy and Urinary Urinary Trac actt Pa Pathology.......................... 125 Female Genital System and Gestational Pathology............ 137 Male Genital System Pathology............................... 151 Endocrine Pathology......................................... 159 Breast Pathology............................................. 175 Central Nervous System Pathology........................... 181 Musculoskeletal Pathology................................... 195 Skin Pathology............................................... 205 Index................................................................. 213 https://t.me/USMLEPathoma https://t.me/USMLEPathoma  1 https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Growth GrowthAdaptations, Adaptations,Cellular Cellular Injury, Injury,and CellDeath andCell Death 11 GROWTH ADAPTATIONS I. BASIC PRINCIPLES A. An organ is in homeostasis with the physiologic stress placed on it. B. An increase, decrease, or change in stress on an organ can result in growth adaptations. IL HYPERPLASIA AND HYPERTROPHY A. An increase in stress leads to an increase in organ size. 1. Occurs via an increase in the size (hypertrophy) and/or the number (hyperplasia) of cells B. Hypertrophy involves gene activation, protein synthesis, and production of organelles. C. Hyperplasia involves the production of new cells from stem cells. D. Hyperplasia and hypertrophy generally occur together (e.g., uterus during pregnancy). 1. Permanent tissues (e.g., cardiac muscle, skeletal muscle, and nerve), however, cannot make new cells and undergo hypertrophy only. 2. For example, cardiac myocytes undergo hypertrophy, not hyperplasia, in response to systemic hypertension (Fig. 1.1). E. Pathologic hyperplasia (e.g., endometrial hyperplasia) can progress to dysplasia and, eventually, cancer. 1. A notable exception is benign prostatic hyperplasia (BPH), which does not increase the risk for prostate cancer. III. ATROPHY A. A decrease in stress (e.g., decreased hormonal stimulation, disuse, or decreased nutrients/blood supply) leads to a decrease in organ size (atrophy). 1. Occurs via a decrease in the size and number of cells B. Decrease in cell number occurs via apoptosis. C. Decrease in cell size occurs via ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular components. 1. In ubiquitin-proteosome degradation, intermediate filaments of the cytoskeleton are "tagged" with ubiquitin and destroyed by proteosomes. 2. Autophagy of cellular components involves generation of autophagic vacuoles. These vacuoles fuse with lysosomes whose hydrolytic enzymes breakdown cellular components. IV. METAPLASIA A. A change in stress on an organ leads to a change in cell type (metaplasia). 1. Most commonly involves change of one type of surface epithelium (squamous, columnar, or urothelial) to another 2. Metaplastic cells are better able to handle the new stress. B. Barrett esophagus is a classic example. pathoma.com 1 https://t.me/USMLEPathoma https://t.me/USMLEPathoma  GGrowthAAdaptations, p Cellular Injury, and CellDDeath 1 I I I I I 1 1.. 1 1 1 I 1 pathoma.com 1 https://t.me/USMLEPathoma https://t.me/USMLEPathoma  2 FUNDAMENTALS OF PATHOLOGY 1. Esophagus is normally lined by nonkeratinizing squamous epithelium (suited to handle friction of a food bolus). 2. Acid reflux from the stomach causes metaplasia to nonciliated, mucin-producing columnar cells (better able to handle the stress of acid, Fig. 1.2). C. Metaplasia occurs via reprogramming of stem cells, which then produce the new cell type. 1. Metaplasia is reversible, in theory, with removal of the driving stressor. 2. For example, treatment of gastroesophageal reflux may reverse Barrett esophagus. D. Under persistent stress, metaplasia can progress to dysplasia and eventually result in cancer. 1. For example, Barrett esophagus may progress to adenocarcinoma of the esophagus. 2. A notable exception is apocrine metaplasia of breast, which carries no increased risk for cancer. E. Vitamin A deficiency can also result in metaplasia. 1. Vitamin A is necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye. 2. In vitamin A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium. This change is called keratomalacia (Fig. 1.3). F. Mesenchymal (connective) tissues can also undergo metaplasia. 1. A classic example is myositis ossificans in which connective tissue within muscle changes to bone during healing after trauma (Fig. 1.4). V. DYSPLASIA A. Disordered cellular growth B. Most often refers to proliferation of precancerous cells 1. For example, cervical intraepithelial neoplasia (CIN) represents dysplasia and is a precursor to cervical cancer. C. Often arises from longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus) D. Dysplasia is reversible, in theory, with alleviation of inciting stress. 1. If stress persists, dysplasia progresses to carcinoma (irreversible). VI. APLASIA AND HYPOPLASIA A. Aplasia is failure of cell production during embryogenesis (e.g., unilateral renal agenesis). B. Hypoplasia is a decrease in cell production during embryogenesis, resulting in a relatively small organ (e.g., streak ovary in Turner syndrome). Fig. 1.1 Left ventricular hypertrophy. (Courtesy of Fig.1.2 Barrett esophagus. Aliya Husain, MD) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Growth Adaptations, Cellular Injury, and Cell Death 3 CELLULAR INJURY I. BASIC PRINCIPLES A. Cellular injury occurs when a stress exceeds the cell's ability to adapt. B. The likelihood of injury depends on the type of stress, its severity, and the type of cell affected. 1. Neurons are highly susceptible to ischemic injury; whereas, skeletal muscle is relatively more resistant. 2. Slowly developing ischemia (e.g., renal artery atherosclerosis) results in atrophy; whereas, acute ischemia (e.g., renal artery embolus) results in injury. C. Common causes of cellular injury include inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations. II. HYPOXIA A. Low oxygen delivery to tissue; important cause of cellular injury 1. Oxygen is the final electron acceptor in the electron transport chain of oxidative phosphorylation. 2. Decreased oxygen impairs oxidative phosphorylation, resulting in decreased ATP production. 3. Lack of ATP (essential energy source) leads to cellular injury. B. Causes of hypoxia include ischemia, hypoxemia, and decreased O2-carrying capacity of blood. C. Ischemia is decreased blood flow through an organ. Arises with 1. Decreased arterial perfusion (e.g., atherosclerosis) 2. Decreased venous drainage (e.g., Budd-Chiari syndrome) 3. Shock - generalized hypotension resulting in poor tissue perfusion D. Hypoxemia is a low partial pressure of oxygen in the blood (Pao2 < 60 mm Hg, Sao2 < 90%). Arises with 1. High altitude - Decreased barometric pressure results in decreased PAo2 2. Hypoventilation - Increased PAco2 results in decreased PAo2 3. Diffusion defect - PAo2 not able to push as much O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis) 4. V/Q mismatch - Blood bypasses oxygenated lung (circulation problem, e.g., right- to-left shunt), or oxygenated air cannot reach blood (ventilation problem, e.g., atelectasis). E. Decreased O2-carrying capacity arises with hemoglobin (Hb) loss or dysfunction. Examples include 1. Anemia (decrease in RBC mass)-Pao2 normal; Sao2 normal 2. Carbon monoxide poisoning Fig. 1.3 Keratomalacia. (Courtesy of Fig.1.4 Myositis Ossificans. (Reprinted with motherchildnutrition.org) permission from orthopaedia.com) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  4 FUNDAMENTALS OF PATHOLOGY i. CO binds hemoglobin more avidly than oxygen-Pao2 normal; Sao2 decreased ii. Exposures include smoke from fires and exhaust from cars or gas heaters. iii. Classic finding is cherry-red appearance of skin. iv. Early sign of exposure is headache; significant exposure leads to coma and death. 3. Methemoglobinemia i. Iron in heme is oxidized to Fe3+, which cannot bind oxygen-Pao2 normal; Sao2 decreased ii. Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns iii. Classic finding is cyanosis with chocolate-colored blood. iv. Treatment is intravenous methylene blue, which helps reduce Fe2+ back to Fe2+state. III. REVERSIBLE AND IRREVERSIBLE CELLULAR INJURY A. Hypoxia impairs oxidative phosphorylation resulting in decreased ATP. B. Low ATP disrupts key cellular functions including 1. Na+-K+pump, resulting in sodium and water buildup in the cell 2. Ca 2+pump, resulting in Ca2+ buildup in the cytosol of the cell 3. Aerobic glycolysis, resulting in a switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DNA. C. The initial phase of injury is reversible. The hallmark of reversible injury is cellular swelling. 1. Cytosol swelling results in loss of microvilli and membrane blebbing. 2. Swelling of the rough endoplasmic reticulum (RER) results in dissociation of ribosomes and decreased protein synthesis. D. Eventually, the damage becomes irreversible. The hallmark of irreversible injury is membrane damage. 1. Plasma membrane damage results in i. Cytosolic enzymes leaking into the serum (e.g., cardiac troponin) ii. Additional calcium entering into the cell 2. Mitochondrial membrane damage results in i. Loss of the electron transport chain (inner mitochondrial membrane) ii. Cytochrome c leaking into cytosol (activates apoptosis) 3. Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which, in turn, are activated by the high intracellular calcium. E. The end result of irreversible injury is cell death. Fig. 1.5 Coagulative necrosis of kidney. A, Gross appearance. B, Microscopic appearance. C, Normal kidney histology for comparison. (A, Courtesy of Aliya Husain, MD) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Growth Adaptations, Cellular Injury, and Cell Death 5 CELL DEATH I. BASIC PRINCIPLES A. The morphologic hallmark of cell death is loss of the nucleus, which occurs via nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis). B. The two mechanisms of cell death are necrosis and apoptosis. II. NECROSIS A. Death of large groups of cells followed by acute inflammation B. Due to some underlying pathologic process; never physiologic C. Divided into several types based on gross features III. GROSS PATTERNS OF NECROSIS A. Coagulative necrosis 1. Necrotic tissue that remains firm (Fig. 1.5A); cell shape and organ structure are preserved by coagulation of proteins, but the nucleus disappears (Fig. 1.5B). 2. Characteristic of ischemic infarction of any organ except the brain 3. Area of infarcted tissue is often wedge-shaped (pointing to focus of vascular occlusion) and pale. 4. Red infarction arises if blood re-enters a loosely organized tissue (e.g., pulmonary or testicular infarction, Fig. 1.6). B. Liquefactive necrosis 1. Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction. 2. Characteristic of i. Brain infarction - Proteolytic enzymes from microglial cells liquefy the brain. ii. Abscess - Proteolytic enzymes from neutrophils liquefy tissue. iii. Pancreatitis - Proteolytic enzymes from pancreas liquefy parenchyma. C. Gangrenous necrosis 1. Coagulative necrosis that resembles mummified tissue (dry gangrene, Fig. 1.7) 2. Characteristic of ischemia of lower limb and GI tract 3. If superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene). D. Caseous necrosis 1. Soft and friable necrotic tissue with "cottage cheese-like" appearance (Fig. 1.8) 2. Combination of coagulative and liquefactive necrosis 3. Characteristic of granulomatous inflammation due to tuberculous or fungal infection Fig. 1.6 Hemorrhagic infarction of testicle. Fig. 1.7 Dry gangrene. Fig. 1.8 Caseous necrosis of lung. (Courtesy ofYale (Courtesy of humpath.com) Rosen, MD) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  6 FUNDAMENTALS OF PATHOLOGY E. Fat necrosis 1. Necrotic adipose tissue with chalky-white appearance due to deposition of calcium (Fig. 1.9) 2. Characteristic of trauma to fat (e.g., breast) and pancreatitis-mediated damage of peripancreatic fat 3. Fatty acids released by trauma (e.g., to breast) or lipase (e.g., pancreatitis) join with calcium via a process called saponification. i. Saponification is an example of dystrophic calcification in which calcium deposits on dead tissues. In dystrophic calcification, the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate. ii. Metastatic calcification, as opposed to dystrophic calcification, occurs when high serum calcium or phosphate levels lead to calcium deposition in normal tissues (e.g., hyperparathyroidism leading to nephrocalcinosis). F. Fibrinoid necrosis 1. Necrotic damage to blood vessel wall 2. Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically (Fig. 1.10). 3. Characteristic of malignant hypertension and vasculitis IV.APOPTOSIS A. Energy (ATP)-dependent, genetically programmed cell death involving single cells or small groups of cells. Examples include 1. Endometrial shedding during menstrual cycle 2. Removal of cells during embryogenesis 3. CD8 + T cell-mediated killing of virally infected cells B. Morphology 1. Dying cell shrinks, leading cytoplasm to become more eosinophilic (pink, Fig. l.ll). 2. Nucleus condenses and fragments in an organized manner. 3. Apoptotic bodies fall from the cell and are removed by macrophages; apoptosis is not followed by inflammation. C. Apoptosis is mediated by caspases that activate proteases and endonucleases. 1. Proteases break down the cytoskeleton. 2. Endonucleases break down DNA. D. Caspases are activated by multiple pathways. 1. Intrinsic mitochondrial pathway i. Cellular injury, DNA damage, or decreased hormonal stimulation leads to inactivation of Bcl2. ii. Lack of Bcl2 allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases. Fig. 1.9 Fat necrosis of peri-pancreatic adipose Fig. 1.10 Fibrinoid necrosis of vessel. Fig.1.11 Apoptosis. tissue. (Courtesy of humpath.com) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Growth Adaptations, Cellular Injury, and Cell Death 7 2. Extrinsic receptor-ligand pathway i. FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases (e.g., negative selection of thymocytes in thymus). ii. Tumor necrosis factor (TNF) binds TNF receptor on the target cell, activating caspases. 3. Cytotoxic CD8+ T cell-mediated pathway i. Perforins secreted by CD8 + T cell create pores in membrane of target cell. ii. Granzyme from CD8 + T cell enters pores and activates caspases. iii. CD8 + T-cell killing of virally infected cells is an example. FREE RADICAL INJURY I. BASIC PRINCIPLES A. Free radicals are chemical species with an unpaired electron in their outer orbit. B. Physiologic generation of free radicals occurs during oxidative phosphorylation. 1. Cytochrome c oxidase (complex IV) transfers electrons to oxygen. 2. Partial reduction of O2 yields superoxide (O2ꜙ), hydrogen peroxide (H2O2 ), and hydroxyl radicals (˙OH ). C. Pathologic generation of free radicals arises with 1. Ionizing radiation - water hydrolyzed to hydroxyl free radical 2. Inflammation - NADPH oxidase generates superoxide ions during oxygen- dependent killing by neutrophils. 3. Metals (e.g., copper and iron)-Fe 2+ generates hydroxyl free radicals (Fenton reaction). 4. Drugs and chemicals - P450 system of liver metabolizes drugs (e.g., acetaminophen), generating free radicals. D. Free radicals cause cellular injury via peroxidation of lipids and oxidation of DNA and proteins; DNA damage is implicated in aging and oncogenesis. E. Elimination of free radicals occurs via multiple mechanisms. 1. Antioxidants (e.g., glutathione and vitamins A , C, and E) 2. Enzymes I) Superoxide dismutase (in mitochondria) - Superoxide (O2ꜙ) → H2O2 II) Glutathione peroxidase (in mitochondria) - 2GSH + free radical → GS-SG and H2O III) Catalase (in peroxisomes) - H 2O2 → O2ꜙ and H2O 3. Metal carrier proteins (e.g., transferrin and ceruloplasmin) II. EXAMPLES OF FREE RADICAL INJURY A. Carbon tetrachloride (CCl4) 1. Organic solvent used in the dry cleaning industry 2. Converted to CCl3 free radical by P450 system of hepatocytes 3. Results in cell injury with swelling of RER; consequently, ribosomes detach, impairing protein synthesis. 4. Decreased apolipoproteins lead to fatty change in the liver (Fig. 1.12). B. Reperfusion injury 1. Return of blood to ischemic tissue results in production of O2 -derived free radicals, which further damage tissue. 2. Leads to a continued rise in cardiac enzymes (e.g., troponin) after reperfusion of infarcted myocardial tissue https://t.me/USMLEPathoma https://t.me/USMLEPathoma  IK * * 8 FUNDAMENTALS OF PATHOLOGY AMYLOIDOSIS I. BASIC PRINCIPLES A. Amyloid is a misfolded protein that deposits in the extracellular space, thereby damaging tissues. B. Multiple proteins can deposit as amyloid. Shared features include 1. β- pleated sheet configuration 2. Congo red staining and apple-green birefringence when viewed microscopically under polarized light (Fig. 1.13) C. Deposition can be systemic or localized. II. SYSTEMIC AMYLOIDOSIS A. Amyloid deposition in multiple organs; divided into primary and secondary amyloidosis B. Primary amyloidosis is systemic deposition of AL amyloid, which is derived from immunoglobulin light chain. 1. Associated with plasma cell dyscrasias (e.g., multiple myeloma) C. Secondary amyloidosis is systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA). 1. SAA is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean fever (FMF). 2. FMF is due to a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin. i. Presents with episodes of fever and acute serosal inflammation (can mimic appendicitis, arthritis, or myocardial infarction) ii. High SAA during attacks deposits as AA amyloid in tissues. D. Clinical findings of systemic amyloidosis are diverse since almost any tissue can be involved. Classic findings include 1. Nephrotic syndrome; kidney is the most common organ involved. 2. Restrictive cardiomyopathy or arrhythmia 3. Tongue enlargement, malabsorption, and hepatosplenomegaly E. Diagnosis requires tissue biopsy. Abdominal fat pad and rectum are easily accessible biopsy targets. F. Damaged organs must be transplanted. Amyloid cannot be removed. III. LOCALIZED AMYLOIDOSIS A. Amyloid deposition usually localized to a single organ. B. Senile cardiac amyloidosis 1. Non-mutated serum transthyretin deposits in the heart. 2. Usually asymptomatic; present in 25% of individuals > 80 years of age C. Familial amyloid cardiomyopathy I 'V % I.- r Pi * r 4 »' *r&i* r> » * ' -3ft ; te?. w wk:< £. i. - * V \ VN * * H. w > II B 1 \ At? *i i Fig.1.12 Fatty change of liver. Fig. 1.13 Amyloid. A, Congo red. B, Apple-green birefringence. (Courtesy of Ed Uthman, MD) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Growth Adaptations, Cellular Injury, and Cell Death 9 1. Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy. 2. 5% of African Americans carry the mutated gene. D. Non-insulin-dependent diabetes mellitus (type II) 1. Amylin (derived from insulin) deposits in the islets of the pancreas. E. Alzheimer disease 1. Aβ amyloid (derived from β-amyloid precursor protein) deposits in the brain forming amyloid plaques. 2. Gene for β-APP is present on chromosome 21. Most individuals with Down syndrome (trisomy 21) develop Alzheimer disease by the age of 40 (early-onset). F. Dialysis-associated amyloidosis 1. β2-microglobulin deposits in joints. G. Medullary carcinoma of the thyroid 1. Calcitonin (produced by tumor cells) deposits within the tumor ('tumor cells in an amyloid background'). I REMINDER Thank you for choosing Pathoma for your studies. We strive to provide the highest quality educational materials while keeping affordability in mind. A tremendous amount of time and effort has gone into developing these materials, so we appreciate your legitimate use of this program. It speaks to your integrity as a future physician and the high ethical standards that we all set forth for ourselves when taking the Hippocratic oath. Unauthorized use of Patho ma materials is contrary to the ethical standards of a training physician and is a violation of copyright. Pathoma videos are updated on a regular basis and the most current version, as well as a complete list of errata, can be accessed through your account at Pathoma.com. Sincerely, Dr. Sattar, MD https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Inflammation, Inflammatory Disorders, 1 and Wound Healing INTRODUCTION I. INFLAMMATION A. Allows inflammatory cells, plasma proteins (e.g., complement), and fluid to exit blood vessels and enter the interstitial space B. Divided into acute and chronic inflammation ACUTE INFLAMMATION I. BASIC PRINCIPLES A. Characterized by the presence of edema and neutrophils in tissue (Fig. 2.lA) B. Arises in response to infection (to eliminate pathogen) or tissue necrosis (to clear necrotic debris) C. Immediate response with limited specificity (innate immunity) IL MEDIATORS OF ACUTE INFLAMMATION A. Toll-like receptors (TLRs) 1. Present on cells of the innate immune system (e.g., macrophages and dendritic cells) 2. Activated by pathogen-associated molecular patterns (PAMPs) that are commonly shared by microbes i. CD14 (a co-receptor for TLR4) on macrophages recognizes lipopoly- saccharide (a PAMP) on the outer membrane of gram-negative bacteria. 3. TLR activation results in upregulation of NF-κB, a nuclear transcription factor that activates immune response genes leading toproduction of multiple immune mediators. 4. TLRs are also present on cells of adaptive immunity (e.g., lymphocytes) and, hence, play an important role in mediating chronic inflammation. B. Arachidonic acid (AA) metabolites 1. AA is released from the phospholipid cell membrane by phospholipase A2 and then acted upon by cyclooxygenase or 5-lipoxygenase. i. Cyclooxygenase produces prostaglandins (PG). a. PGI 2, PGD 2, and PGE2 mediate vasodilation and increased vascular permeability. b. PGE2 also mediates pain and fever. ii. 5-lipoxygenase produces leukotrienes (LT). a. LTB 4 attracts and activates neutrophils. b. LTC 4, LTD 4, and LTE 4 (slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm, and increased vascular permeability. C. Mast cells 1. Widely distributed throughout connective tissue 2. Activated by (1) tissue trauma, (2) complement proteins C3a and C5a, or (3) cross-linking of cell-surface IgE by antigen pathoma.com 11 https://t.me/USMLEPathoma https://t.me/USMLEPathoma  12 FUNDAMENTALS OF PATHOLOGY Immediate response involves release of preformed histamine granules, which i. mediate vasodilation of arterioles and increased vascular permeability. ii. Delayed response involves production of arachidonic acid metabolites, particularly leukotrienes. D. Complement 1. Proinflammatory serum proteins that "complement" inflammation 2. Circulate as inactive precursors; activation occurs via i. Classical pathway - C1 binds IgG or IgM that is bound to antigen. ii. Alternative pathway - Microbial products directly activate complement. iii. Mannose-binding lectin (MBL) pathway - MBL binds to mannose on microorganisms and activates complement. 3. All pathways result in production of C3 convertase (mediates C3 →C3a and C3b), which, in turn, produces C5 convertase (mediates C5 → C5a and C5b). C5b complexes with C6-C9 to form the membrane attack complex (MAC). i. C3a and C5a (anaphylatoxins) - trigger mast cell degranulation, resulting in histamine-mediated vasodilation and increased vascular permeability ii. C5a - chemotactic for neutrophils iii. C3b - opsonin for phagocytosis iv. MAC - lyses microbes by creating a hole in the cell membrane E. Hageman factor (Factor XII) 1. Inactive proinflammatory protein produced in liver 2. Activated upon exposure to subendothelial or tissue collagen; in turn, activates i. Coagulation and fibrinolytic systems ii. Complement iii. Kinin system - Kinin cleaves high-molecular-weight kininogen (HMWK) to bradykinin, which mediates vasodilation and increased vascular permeability (similar to histamine), as well as pain. III. CARDINAL SIGNS OF INFLAMMATION A. Redness (rubor) and warmth (calor) 1. Due to vasodilation, which results in increased blood flow 2. Occurs via relaxation of arteriolar smooth muscle; key mediators are histamine, prostaglandins, and bradykinin. B. Swelling (tumor) 1. Due to leakage of fluid from postcapillary venules into the interstitial space (exudate) 2. Key mediators are (1) histamine, which causes endothelial cell contraction and (2) tissue damage, resulting in endothelial cell disruption. C. Pain (dolor) 1. Bradykinin and PGE2 sensitize sensory nerve endings. 4' , * 1 L > mwwf fV - y; v j& ' '* , v r , » »4 t. /4 i. : ,4 ~( W / ^ *« 4 » 4 * f *. « ikfmmj * - % 7 '. % # , '.ifc i * 1% iS * * -^ 4* #* * '. y v - # # t Fig. 2.1 Inflammation. A, Acute inflammation with neutrophils. B, Chronic inflammation with lymphocytes and plasma cells. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Inflammation, Inflammatory Disorders, and Wound Healing 13 D. Fever 1. Pyrogens (e.g., LPS from bacteria) cause macrophages to release IL-1 and TNF, which increase cyclooxygenase activity in perivascular cells of the hypothalamus. 2. Increased PGE2 raises temperature set point. IV. NEUTROPHIL ARRIVAL AND FUNCTION A. Step 1 - Margination 1. Vasodilation slows blood flow in postcapillary venules. 2. Cells marginate from center of flow to the periphery. B. Step 2 - Rolling 1. Selectin "speed bumps" are upregulated on endothelial cells. i. P-selectin release from Weibel-Palade bodies is mediated by histamine. ii. E-selectin is induced by TNF and IL-1. 2. Selectins bind sialyl Lewis X on leukocytes. 3. Interaction results in rolling of leukocytes along vessel wall. C. Step 3 - Adhesion 1. Cellular adhesion molecules (ICAM and VCAM) are upregulated on endothelium by TNF and IL-1. 2. Integrins are upregulated on leukocytes by C5a and LTB4 3. Interaction between CAMs and integrins results in firm adhesion of leukocytes to the vessel wall. 4. Leukocyte adhesion deficiency is most commonly due to an autosomal recessive defect of integrins (CD18 subunit). i. Clinical features include delayed separation of the umbilical cord, increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes), and recurrent bacterial infections that lack pus formation. D. Step 4 - Transmigration and Chemotaxis 1. Leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants (chemotaxis). 2. Neutrophils are attracted by bacterial products, IL-8, C5a, and LTB4. E. Step 5 - Phagocytosis 1. Consumption of pathogens or necrotic tissue; phagocytosis is enhanced by opsonins (IgG and C3b). 2. Pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes. 3. Chediak-Higashi syndrome is a protein trafficking defect (autosomal recessive) characterized by impaired phagolysosome formation. Clinical features include i. Increased risk of pyogenic infections ii. Neutropenia (due to intramedullary death of neutrophils) iii. Giant granules in leukocytes (due to fusion of granules arising from the Golgi apparatus) iv. Defective primary hemostasis (due to abnormal dense granules in platelets) v. Albinism vi. Peripheral neuropathy F. Step 6 - Destruction of phagocytosed material 1. O2-dependent killing is the most effective mechanism. 2. HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes. i. O2 is converted to O 2 ꜙ by NADPH oxidase (oxidative burst). ii. O2ꜙ is converted to H2O2 by superoxide dismutase (SOD). iii. H2O2 is converted to HOCl (bleach) by myeloperoxidase (MPO). https://t.me/USMLEPathoma https://t.me/USMLEPathoma  14 FUNDAMENTALS OF PATHOLOGY « 3. Chronic granulomatous disease (CGD) is characterized by poor O2-dependent killing. i. Due to NADPH oxidase defect (X-linked or autosomal recessive) ii. Leads to recurrent infection and granuloma formation with catalase-positive organisms, particularly Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus iii. Nitroblue tetrazolium test is used to screen for CGD. Leukocytes are incubated with NBT dye, which turns blue if NADPH oxidase can convert O2 to O2ꜙ, but remains colorless if NADPH oxidase is defective. 4. MPO deficiency results in defective conversion of H2O2 to HOCl. i. Increased risk for Candida infections; however, most patients are asymptomatic. ii. NBT is normal; respiratory burst (O2 to H2O2) is intact. 5. O2-independent killing is less effective than O2 -dependent killing and occurs via enzymes present in leukocyte secondary granules (e.g., lysozyme in macrophages and major basic protein in eosinophils). G. Step 7 - Resolution 1. Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus. V. MACROPHAGES A. Macrophages predominate after neutrophils and peak 2-3 days after inflammation begins. 1. Derived from monocytes in blood B. Arrive in tissue via the margination, rolling, adhesion, and transmigration sequence C. Ingest organisms via phagocytosis (augmented by opsonins) and destroy phagocytosed material using enzymes (e.g., lysozyme) in secondary granules (O 2- independent killing) D. Manage the next step of the inflammatory process. Outcomes include 1. Resolution and healing - Anti-inflammatory cytokines (e.g., IL-10 and TGF- β) are produced by macrophages. 2. Continued acute inflammation - marked by persistent pus formation; IL-8 from macrophages recruits additional neutrophils. 3. Abscess - acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines. 4. Chronic inflammation - Macrophages present antigen to activate CD4+ helper T cells, which secrete cytokines that promote chronic inflammation. CHRONIC INFLAMMATION I. BASIC PRINCIPLES A. Characterized by the presence of lymphocytes and plasma cells in tissue (Fig. 2.lB) B. Delayed response, but more specific (adaptive immunity) than acute inflammation C. Stimuli include (1) persistent infection (most common cause); (2) infection with viruses, mycobacteria, parasites, and fungi; (3) autoimmune disease; (4) foreign material; and (5) some cancers. II. T LYMPHOCYTES A. Produced in bone marrow as progenitor T cells B. Further develop in the thymus where the T-cell receptor (TCR) undergoes rearrangement and progenitor cells become CD4 + helper T cells or CD8 + cytotoxic T cells 1. T cells use TCR complex (TCR and CD3) for antigen surveillance. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Inflammation, Inflammatory Disorders, and Wound Healing 15 2. TCR complex recognizes antigen presented on MHC molecules. i. CD4+ T cells - MHC class II ii. CD8+ T cells - MHC class I 3. Activation of T cells requires (1) binding of antigen/MHC complex and (2) an additional 2nd signal. C. CD4 + helper T-cell activation 1. Extracellular antigen (e.g., foreign protein) is phagocytosed, processed, and presented on MHC class II, which is expressed by antigen presenting cells (APCs). 2. B7 on APC binds CD28 on CD4 + helper T cells providing 2nd activation signal. 3. Activated CD4 + helper T cells secrete cytokines that "help" inflammation and are divided into two subsets. i. TH1 subset secretes IFN-γ (activates macrophage, promotes B-cell class switching from IgM to IgG, promotes TH1phenotype and inhibits TH2 phenotype). ii. T H 2 subset secretes IL-4 (facilitates B-cell class switching to IgE), IL-5 (eosinophil chemotaxis and activation, and class switching to IgA), and IL-13 (function similar to IL-4). D. CD8 + cytotoxic T-cell activation 1. Intracellular antigen (derived from proteins in the cytoplasm) is processed and presented on MHC class I, which is expressed by all nucleated cells and platelets. 2. IL-2 from CD4 + TH1 cell provides 2nd activation signal. 3. Cytotoxic T cells are activated for killing. 4. Killing occurs via i. Secretion of perforin and granzyme; perforin creates pores that allow granzyme to enter the target cell, activating apoptosis. ii. Expression of FasL, which binds Fas on target cells, activating apoptosis III. B LYMPHOCYTES A. Immature B cells are produced in the bone marrow and undergo immunoglobulin rearrangements to become naïve B cells that express surface IgM and IgD. B. B-cell activation occurs via 1. Antigen binding by surface IgM or IgD; results in maturation to IgM- or IgD- secreting plasma cells 2. B-cell antigen presentation to CD4+ helper T cells via MHC class IL i. CD40 receptor on B cell binds CD40L on helper T cell, providing 2nd activation signal. ii. Helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching, hypermutation, and maturation to plasma cells). IV. GRANULOMATOUS INFLAMMATION A. Subtype of chronic inflammation B. Characterized by granuloma, which is a collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm), usually surrounded by giant cells and a rim of lymphocytes C. Divided into noncaseating and caseating subtypes 1. Noncaseating granulomas lack central necrosis (Fig. 2.2A). Common etiologies include reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, and cat scratch disease. 2. Caseating granulomas exhibit central necrosis and are characteristic of tuberculosis and fungal infections (Fig. 2.2B). D. Steps involved in granuloma formation https://t.me/USMLEPathoma https://t.me/USMLEPathoma  y * T ' a s * 16 * FUNDAMENTALS * / OF PATHOLOGY 1. Macrophages process and present antigen via MHC class II to CD4 + helper T cells. 2. Interaction leads macrophages to secrete IL-12, inducing CD4 + helper T cells to differentiate into T H1 subtype. 3. TH1cells secrete IFN-γ, which converts macrophages to epithelioid histiocytes and giant cells. PRIMARY IMMUNODEFICIENCY I. DIGEORGE SYNDROME A. Developmental failure of the third and fourth pharyngeal pouches 1. Due to 22q11 microdeletion B. Presents with T-cell deficiency (lack of thymus); hypocalcemia (lack of parathyroids); and abnormalities of heart, great vessels, and face II. SEVERE COMBINED IMMUNODEFICIENCY (SCID) A. Defective cell-mediated and humoral immunity B. Etiologies include 1. Cytokine receptor defects - Cytokine signaling is necessary for proliferation and maturation of B and T cells. 2. Adenosine deaminase (ADA) deficiency - ADA is necessary to deaminate adenosine and deoxyadenosine for excretion as waste products; buildup of adenosine and deoxyadenosine is toxic to lymphocytes. 3. MHC class II deficiency - MHC class II is necessary for CD4 + helper T cell activation and cytokine production. C. Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines D. Treatment is sterile isolation ('bubble baby') and stem cell transplantation. Ill. X-LINKED AGAMMAGLOBULINEMIA A. Complete lack of immunoglobulin due to disordered B-cell maturation 1. Pre- and pro-B cells cannot mature. B. Due to mutated Bruton tyrosine kinase; X-linked C. Presents after 6 months of life with recurrent bacterial, enterovirus (e.g., polio and coxsackievirus), and Giardia lamblia infections; maternal antibodies present during the first 6 months of life are protective. D. Live vaccines (e.g., polio) must be avoided. IV. COMMON VARIABLE IMMUNODEFICIENCY (CVID) A. Low immunoglobulin due to B-cell or helper T-cell defects Fig. 2.2 Granuloma. A, Noncaseating. B, Caseating. Fig. 2.3 Angioedema. (Courtesy of James Heilman, MD, Wikipedia) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Inflammation, Inflammatory Disorders, and Wound Healing 17 B. Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood C. Increased risk for autoimmune disease and lymphoma V. IgA DEFICIENCY A. Low serum and mucosal IgA; most common immunoglobulin deficiency B. Increased risk for mucosal infection, especially viral; however, most patients are asymptomatic. VI. HYPER-IgM SYNDROME A. Characterized by elevated IgM B. Due to mutated CD40L (on helper T cells) or CD40 receptor (on B cells) 1. Second signal cannot be delivered to helper T cells during B-cell activation. 2. Consequently, cytokines necessary for immunoglobulin class switching are not produced. C. Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor opsonization), especially at mucosal sites. VII. WISKOTT-ALDRICH SYNDROME A. Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity); bleeding is a major cause of death B. Due to mutation in the WASP gene; X-linked VIII. COMPLEMENT DEFICIENCIES A. C5-C9 deficiencies-increased risk for Neisseria infection (N gonorrhoeae and N meningitidis) B. Cl inhibitor deficiency-results in hereditary angioedema, which is characterized by edema of the skin (especially periorbital, Fig. 2.3) and mucosal surfaces AUTOIMMUNE DISORDERS I. BASIC PRINCIPLES A. Characterized by immune-mediated damage of self tissues 1. US prevalence is 1%-2%. B. Involves loss of self-tolerance 1. Self-reactive lymphocytes are regularly generated but develop central (thymus and bone marrow) or peripheral tolerance. 2. Central tolerance in thymus leads to T-cell (thymocyte) apoptosis or generation of regulatory T cells. i. AIRE mutations result in autoimmune polyendocrine syndrome. 3. Central tolerance in bone marrow leads to receptor editing or B-cell apoptosis. 4. Peripheral tolerance leads to anergy or apoptosis of T and B cells. i. Fas apoptosis pathway mutations result in autoimmune lymphoproliferative syndrome (ALPS). 5. Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-β ). i. CD25 polymorphisms are associated with autoimmunity (MS and type 1DM). ii. FOXP3 mutations lead to IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked). C. More common in women; classically affects women of childbearing age 1. Estrogen may reduce apoptosis of self-reactive B cells. D. Etiology is likely an environmental trigger in genetically-susceptible individuals. 1. Increased incidence in twins https://t.me/USMLEPathoma https://t.me/USMLEPathoma  18 FUNDAMENTALS OF PATHOLOGY 2. Association with certain HLA types (e.g., HLA-B27) and PTPN22 polymorphisms 3. Environmental triggers lead to bystander activation or molecular mimicry. E. Autoimmune disorders are clinically progressive with relapses and remissions and often show overlapping features; partially explained by epitope spreading II. SYSTEMIC LUPUS ERYTHEMATOSUS A. Chronic, systemic autoimmune disease 1. Flares and remissions are common. B. Classically arises in middle-aged females, especially African American and Hispanic women 1. May also arise in children and older adults (less dramatic gender bias) C. Antigen-antibody complexes damage multiple tissues (type III HSR). 1. Poorly-cleared apoptotic debris (e.g., from UV damage) activates self-reactive lymphocytes, which then produce antibodies to host nuclear antigens. 2. Antigen-antibody complexes are generated at low levels and taken up by dendritic cells. 3. DNA antigens activate TLRs, amplifying immune response (IFN-α). 4. Antigen-antibody complexes are subsequently generated at higher levels and deposit in multiple tissues causing disease. 5. Deficiency of early complement proteins (C1q, C4, and C2) is associated with SLE. D. Almost any tissue can be involved. Classic findings include 1. Fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon 2. Malar 'butterfly' rash (Fig. 2.4A) or discoid rash (Fig. 2.4B), especially upon exposure to sunlight 3. Oral or nasopharyngeal ulcers (usually painless) 4. Arthritis (usually involving ≥ 2 joints) 5. Serositis (pleuritis and pericarditis) 6. Psychosis or seizures 7. Renal damage i. Diffuse proliferative glomerulonephritis is the most common and most severe form of injury. ii. Other patterns of injury (e.g., membranous glomerulonephritis) also occur. 8. Anemia, thrombocytopenia, or leukopenia (type II HSR) 9. Libman-Sacks endocarditis 10. Antinuclear antibody (ANA; sensitive, but not specific) 11. Anti-dsDNA or anti-Sm antibodies (highly specific) E. Antiphospholipid antibody is associated with SLE (one-third of patients). 1. Autoantibody directed against proteins bound to phospholipids Fig. 2.4A Malar 'butterfly' rash, SLE. Fig. 2.48 Discoid rash, SLE. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Inflammation, Inflammatory Disorders, and Wound Healing 19 2. Important antiphospholipid antibodies include anticardiolipin (false-positive VDRL and RPR syphilis screening tests), anti-β2-glycoprotein I, and lupus anticoagulant (falsely-elevated PTT). F. Antiphospholipid antibody syndrome is characterized by hypercoagulable state due to antiphospholipid antibodies (especially lupus anticoagulant). 1. Results in arterial and venous thrombosis including deep venous, hepatic vein, placental (recurrent pregnancy loss), and cerebral (stroke) thrombosis 2. Requires lifelong anticoagulation 3. Associated with SLE; however, more commonly occurs as a primary disorder G. Antihistone antibody is characteristic of drug-induced lupus. 1. Procainamide, hydralazine, and isoniazid are common causes. 2. ANA is positive by definition. 3. CNS and renal involvement are rare. 4. Removal of drug usually results in remission. H. First-line treatment includes avoiding exposure to direct sunlight and glucocorticoids for flares; other immunosuppressive agents are useful in severe or refractory disease. I. 5-year survival is > 90%; renal failure, infection, and accelerated coronary atherosclerosis (occurs late) are common causes of death. III. SJÖGREN SYNDROME A. Autoimmune destruction of lacrimal and salivary glands 1. Lymphocyte-mediated damage (type IV HSR) with fibrosis B. Classically presents as dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and recurrent dental caries in an older woman (50-60 years)-"Can't chew a cracker, dirt in my eyes" 1. May progress to ulceration of corneal epithelium and oral mucosa C. Can be primary (sicca syndrome) or associated with another autoimmune disorder, especially rheumatoid arthritis 1. Rheumatoid factor is often present even when rheumatoid arthritis is absent. D. Characterized by ANA and anti-ribonucleoprotein antibodies (anti-SSA/Ro and anti-SSB/La) 1. Anti-SSA and anti-SSB are associated with extraglandular manifestations (e.g., neuropathy). 2. Pregnant women with anti-SSA are at risk for delivering babies with neonatal lupus and congenital heart block. 3. Anti-SSA and anti-SSB are also seen in a subset of patients with SLE (screen pregnant patients) E. Lymphocytic sialadenitis on lip biopsy (minor salivary glands) is an additional diagnostic criterion (Fig. 2.4C). F. Increased risk for B-cell (marginal zone) lymphoma, which presents as unilateral enlargement of the parotid gland late in disease course IV. SYSTEMIC SCLEROSIS (SCLERODERMA) A. Autoimmune disorder characterized by sclerosis of skin and visceral organs 1. Classically presents in middle-aged females (30-50 years) B. Fibroblast activation leads to deposition of collagen. 1. Autoimmune damage to mesenchyme is possible initiating event. 2. Endothelial dysfunction leads to inflammation (increased adhesion molecules), vasoconstriction (increased endothelin and decreased NO), and secretion of growth factors (TGF-β and PDGF). 3. Fibrosis, initially perivascular, progresses and causes organ damage. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  20 FUNDAMENTALS OF PATHOLOGY C. Limited type-Skin involvement is limited (hands and face) with late visceral involvement. 1. Prototype is CREST syndrome: Calcinosis/anti-Centromere antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly (Fig. 2.4D), and Telangiectasias of the skin. D. Diffuse type-Skin involvement is diffuse with early visceral involvement. 1. Any organ can be involved. 2. Commonly involved organs include i. Vessels (Raynaud phenomenon) ii. GI tract (esophageal dysmotility and reflux) iii. Lungs (interstitial fibrosis and pulmonary hypertension) iv. Kidneys (scleroderma renal crisis) 3. Highly associated with antibodies to DNA topoisomerase I (anti-Scl-70). V. MIXED CONNECTIVE TISSUE DISEASE A. Autoimmune-mediated tissue damage with mixed features of SLE, systemic sclerosis, and polymyositis B. Characterized by ANA along with serum antibodies to U1 ribonucleoprotein WOUND HEALING I. BASIC PRINCIPLES A. Healing is initiated when inflammation begins. B. Occurs via a combination of regeneration and repair II. REGENERATION A. Replacement of damaged tissue with native tissue; dependent on regenerative capacity of tissue B. Tissues are divided into three types based on regenerative capacity: labile, stable, and permanent. C. Labile tissues possess stem cells that continuously cycle to regenerate the tissue. 1. Small and large bowel (stem cells in mucosal crypts, Fig. 2.5) 2. Skin (stem cells in basal layer, Fig. 2.6) 3. Bone marrow (hematopoietic stem cells) D. Stable tissues are comprised of cells that are quiescent (G 0) , but can reenter the cell cycle to regenerate tissue when necessary. 1. Classic example is regeneration of liver by compensatory hyperplasia after partial resection. Each hepatocyte produces additional cells and then reenters quiescence. Fig. 2.4C Lymphocytic sialadenitis, Sjögren Fig. 2.4D Sclerodactyly, scleroderma. Fig. 2.5 Intestinal crypts. syndrome. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Inflammation, Inflammation Inflammatory , Inflammatory Disorders, Disorders and Wound , and Wound Healing Healing 21 E. Permanent tissues lack significant regenerative potential (e.g., myocardium, skeletal muscle, and neurons). III. REPAIR A. Replacement of damaged tissue with fibrous scar B. Occurs when regenerative stem cells are lost (e.g., deep skin cut) or when a tissue lacks regenerative capacity (e.g., healing after a myocardial infarction, Fig. 2.7) C. Granulation tissue formation is the initial phase of repair (Fig. 2.8). 1. Consists of fibroblasts (deposit type III collagen), capillaries (provide nutrients), and myofibroblasts (contract wound) D. Eventually results in scar formation, in which type III collagen is replaced with type I collagen 1. Type III collagen is pliable and present in granulation tissue, embryonic tissue, uterus, and keloids. 2. Type I collagen has high tensile strength and is present in skin, bone, tendons, and most organs. 3. Collagenase removes type III collagen and requires zinc as a cofactor. IV. MECHANISMS OF TISSUE REGENERATION AND REPAIR A. Mediated by paracrine signaling via growth factors (e.g., macrophages secrete growth factors that target fibroblasts) B. Interaction of growth factors with receptors (e.g., epidermal growth factor with growth factor receptor) results in gene expression and cellular growth. C. Examples of mediators include 1. TGF-α - epithelial and fibroblast growth factor 2. TGF-β - important fibroblast growth factor; also inhibits inflammation 3. Platelet-derived growth factor - growth factor for endothelium, smooth muscle, and fibroblasts 4. Fibroblast growth factor - important for angiogenesis; also mediates skeletal development 5. Vascular endothelial growth factor (VEGF) - important for angiogenesis V. NORMAL AND ABERRANT WOUND HEALING A. Cutaneous healing occurs via primary or secondary intention. 1. Primary intention-Wound edges are brought together (e.g., suturing of a surgical incision); leads to minimal scar formation 2. Secondary intention-Edges are not approximated. Granulation tissue fills the defect; myofibroblasts then contract the wound, forming a scar. B. Delayed wound healing occurs in 1. Infection (most common cause; S aureus is the most common offender) Fig. 2.6 Basal layer of skin. Fig. 2.7 Myocardial scarring. (Courtesy of Fig. 2.8 Granulation tissue. Aliya Husain.MD) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  22 FUNDAMENTALS OF PATHOLOGY 2. Vitamin C, copper, or zinc deficiency i. Vitamin C is an important cofactor in the hydroxylation of proline and lysine procollagen residues; hydroxylation is necessary for eventual collagen cross-linking. ii. Copper is a cofactor for lysyl oxidase, which cross-links lysine and hydroxylysine to form stable collagen. iii. Zinc is a cofactor for collagenase, which replaces the type III collagen of granulation tissue with stronger type I collagen. 3. Other causes include foreign body, ischemia, diabetes, and malnutrition. C. Dehiscence is rupture of a wound; most commonly seen after abdominal surgery D. Hypertrophic scar is excess production of scar tissue that is localized to the wound (Fig. 2.9). E. Keloid is excess production of scar tissue that is out of proportion to the wound (Fig. 2.10). 1. Characterized by excess type III collagen 2. Genetic predisposition (more common in African Americans) 3. Classically affects earlobes, face, and upper extremities Fig. 2.9 Hypertrophic scar. (Reprinted with Fig. 2.10 Keloid. permission, http://emedicine.medscape.com/ article/1128404-overview) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Principles of Neoplasia 3 NEOPLASIA I. BASIC PRINCIPLES A. Neoplasia is new tissue growth that is unregulated, irreversible, and monoclonal; these features distinguish it from hyperplasia and repair. B. Monoclonal means that the neoplastic cells are derived from a single mother cell. C. Clonality was historically determined by glucose-6-phosphate dehydrogenase (G6PD) enzyme isoforms. 1. Multiple isoforms (e.g., G6PDA, G6PDB, and G6PDC) exist; only one isoform is inherited from each parent. 2. In females, one isoform is randomly inactivated in each cell by lyonization (G6PD is present on the X chromosome). 3. Normal ratio of active isoforms in cells of any tissue is 1:1 (e.g., 50% of cells have G6PDA, and 50% of cells have G6PDB). 4. 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells). 5. Only one isoform is present in neoplasia, which is monoclonal. 6. Clonality can also be determined by androgen receptor isoforms, which are also present on the X chromosome. D. Clonality of B lymphocytes is determined by immunoglobulin (Ig) light chain phenotype. 1. Ig is comprised of heavy and light chains. 2. Each B cell expresses light chain that is either kappa or lambda. 3. Normal kappa to lambda light chain ratio is 3:1. 4. This ratio is maintained in hyperplasia, which is polyclonal. 5. Ratio increases to > 6:1 or is inverted (e.g., kappa to lambda ratio = 1:3) in lymphoma, which is monoclonal. E. Neoplastic tumors are benign or malignant. 1. Benign tumors remain localized and do not metastasize. 2. Malignant tumors (cancer) invade locally and have the potential to metastasize. F. Tumor nomenclature is based on lineage of differentiation (type of tissue produced) and whether the tumor is benign or malignant (Table 3.1). Table 3.1: Examples of Tumor Nomenclature LINEAGE OF MALIGNANT BENIGN DIFFERENTIATION (CANCER) Epithelium Adenoma Adenocarcinoma Papilloma Papillary carcinoma Mesenchyme Lipoma Liposarcoma Lymphocyte (Does not exist) Lymphoma/Leukemia Melanocyte Nevus (mole) Melanoma pathoma.com 23 https://t.me/USMLEPathoma https://t.me/USMLEPathoma  24 ' i FUNDAMENTALS OF PATHOLOGY II. EPIDEMIOLOGY A. Cancer is the 2nd leading cause of death in both adults and children. 1. The leading causes of death in adults are (1) cardiovascular disease, (2) cancer, and (3) chronic respiratory disease. 2. The leading causes of death in children are (1) accidents, (2) cancer, and (3) congenital defects. B. The most common cancers by incidence in adults are (1) breast/prostate, (2) lung, and (3) colorectal. C. The most common causes of cancer mortality in adults are (1) lung, (2) breast/ prostate, and (3) colorectal. III. ROLE OF SCREENING A. Cancer begins as a single mutated cell. B. Approximately 30 divisions occur before the earliest clinical symptoms arise. C. Each division (doubling time) results in increased mutations. 1. Cancers that do not produce symptoms until late in disease will have undergone additional divisions and, hence, additional mutations. 2. Cancers that are detected late tend to have a poor prognosis. 3. Screening seeks to catch dysplasia (precancerous change) before it becomes carcinoma or carcinoma before clinical symptoms arise; efficacy of screening, however, requires a decrease in cancer-specific mortality. D. Common screening methods include 1. Pap smear - detects cervical dysplasia (CIN) before it becomes carcinoma 2. Mammography - detects in situ breast cancer (e.g., DCIS) before it invades or invasive carcinoma before it becomes clinically palpable 3. Prostate specific antigen (PSA) and digital rectal exam - detects prostate carcinoma before it spreads 4. Hemoccult test (for occult blood in stool) and colonoscopy - detect colonic adenoma before it becomes colonic carcinoma or carcinoma before it spreads CARCINOGENESIS I. BASIC PRINCIPLES A. Cancer formation is initiated by damage to DNA of stem cells. The damage overcomes DNA repair mechanisms, but is not lethal. 1. Carcinogens are agents that damage DNA, increasing the risk for cancer. Important carcinogens include chemicals, oncogenic viruses, and radiation (Table 3.2). B. DNA mutations eventually disrupt key regulatory systems, allowing for tumor promotion (growth) and progression (spread). 1. Disrupted systems include proto-oncogenes, tumor suppressor genes, and regulators of apoptosis. II. ONCOGENES A. Proto-oncogenes are essential for cell growth and differentiation; mutations of proto-oncogenes form oncogenes that lead to unregulated cellular growth. B. Categories of oncogenes include growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators (Table 3.3). 1. Growth factors induce cellular growth (e.g., PDGFB in astrocytoma). 2. Growth factor receptors mediate signals from growth factors (e.g., ERBB2 [HER2/neu] in breast cancer). 3. Signal transducers relay receptor activation to the nucleus (e.g., ras). https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Principles of Neoplasia 25 Table 3.2: Important Carcinogens and Associated Cancers CARCINOGENIC AGENT ASSOCIATED CANCER COMMENTS CHEMICALS Hepatocellular carcinoma Derived from Aspergillus, wh