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Test bank for Basic Pathology 9th Edition by Vinay Kumar

Test bank for Basic Pathology 9th Edition by Vinay Kumar

Robbins Basic Pathology delivers the pathology knowledge you need, the way you need it, from the name you can trust! This medical textbook’s unbeatable author team helps you efficiently master the core concepts you need to know for your courses and USMLE exams.

Table of Content

Front Matter
Dedication
Contributors
Preface
Forty Years of Basic Pathology
Acknowledgments
Chapter 1 Cell Injury, Cell Death, and Adaptations
Introduction to Pathology
Overview of Cellular Responses to Stress and Noxious Stimuli
Figure 1–1 Stages in the cellular response to stress and injurious stimuli.
Figure 1–2 The relationship among normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation depicted here is hypertrophy, the type of reversible injury is ischemia, and the irreversible injury is ischemic coagulative necrosis. In the example of myocardial hypertrophy (lower left), the left ventricular wall is thicker than 2 cm (normal, 1–1.5 cm). Reversibly injured myocardium shows functional effects without any gross or light microscopic changes, or reversible changes like cellular swelling and fatty change (shown here). In the specimen showing necrosis (lower right) the transmural light area in the posterolateral left ventricle represents an acute myocardial infarction. All three transverse sections of myocardium have been stained with triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme loss after cell death.
Cellular Adaptations to Stress
Hypertrophy
Figure 1–3 Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (left) that was removed for postpartum bleeding. B, Small spindle-shaped uterine smooth muscle cells from a normal uterus. C, Large, plump hypertrophied smooth muscle cells from a gravid uterus; compare with B. (B and C, Same magnification.)
Hyperplasia
Figure 1–4 Atrophy as seen in the brain. A, Normal brain of a young adult. B, Atrophy of the brain in an 82-year-old man with atherosclerotic disease. Atrophy of the brain is due to aging and reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci. The meninges have been stripped from the bottom half of each specimen to reveal the surface of the brain.
Atrophy
Metaplasia
Figure 1–5 Metaplasia of normal columnar (left) to squamous epithelium (right) in a bronchus, shown schematically (A) and histologically (B).
Summary
Cellular Adaptations to Stress
Overview of Cell Injury and Cell Death
Figure 1–6 Cellular features of necrosis (left) and apoptosis (right).
Causes of Cell Injury
Table 1–1 Features of Necrosis and Apoptosis
Oxygen Deprivation
Chemical Agents
Infectious Agents
Immunologic Reactions
Genetic Factors
Nutritional Imbalances
Physical Agents
Aging
The Morphology of Cell and Tissue Injury
Figure 1–7 The relationship among cellular function, cell death, and the morphologic changes of cell injury. Note that cells may rapidly become nonfunctional after the onset of injury, although they are still viable, with potentially reversible damage; with a longer duration of injury, irreversible injury and cell death may result. Note also that cell death typically precedes ultrastructural, light microscopic, and grossly visible morphologic changes.
Reversible Injury
Figure 1–8 Morphologic changes in reversible and irreversible cell injury (necrosis). A, Normal kidney tubules with viable epithelial cells. B, Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. C, Necrotic (irreversible) injury of epithelial cells, with loss of nuclei and fragmentation of cells and leakage of contents.
Morphology
Necrosis
Morphology
Patterns of Tissue Necrosis
Figure 1–9 Coagulative necrosis. A, A wedge-shaped kidney infarct (yellow) with preservation of the outlines. B, Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I). The necrotic cells show preserved outlines with loss of nuclei, and an inflammatory infiltrate is present (difficult to discern at this magnification).
Figure 1–10 Liquefactive necrosis. An infarct in the brain showing dissolution of the tissue.
Figure 1–11 Caseous necrosis. Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white (cheesy) debris.
Figure 1–12 Fat necrosis in acute pancreatitis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery.
Figure 1–13 Fibrinoid necrosis in an artery in a patient with polyarteritis nodosa. The wall of the artery shows a circumferential bright pink area of necrosis with protein deposition and inflammation.
Morphology
Summary
Morphologic Alterations in Injured Cells and Tissues
Mechanisms of Cell Injury
Figure 1–14 The principal biochemical mechanisms and sites of damage in cell injury. ATP, adenosine triphospate; ROS, reactive oxygen species.
Depletion of ATP
Figure 1–15 The functional and morphologic consequences of depletion of intracellular adenosine triphosphate (ATP). ER, endoplasmic reticulum.
Mitochondrial Damage and Dysfunction
Influx of Calcium
Figure 1–16 Role of mitochondria in cell injury and death. Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis. This pathway of apoptosis is described in more detail later. ATP, adenosine triphosphate; ROS, reactive oxygen species.
Figure 1–17 Sources and consequences of increased cytosolic calcium in cell injury. ATP, adenosine triphosphate; ATPase, adenosine triphosphatase.
Figure 1–18 Pathways of production of reactive oxygen species. A, In all cells, superoxide (O2•) is generated during mitochondrial respiration by the electron transport chain and may be converted to H2O2 and the hydroxyl (•OH) free radical or to peroxynitrite (ONOO−). B, In leukocytes (mainly neutrophils and macrophages), the phagocyte oxidase enzyme in the phagosome membrane generates superoxide, which can be converted to other free radicals. Myeloperoxidase (MPO) in phagosomes also generates hypochlorite from reactive oxygen species (ROS). NO, nitric oxide; SOD, superoxide dismutase.
Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Figure 1–19 The generation, removal, and role of reactive oxygen species (ROS) in cell injury. The production of ROS is increased by many injurious stimuli. These free radicals are removed by spontaneous decay and by specialized enzymatic systems. Excessive production or inadequate removal leads to accumulation of free radicals in cells, which may damage lipids (by peroxidation), proteins, and deoxyribonucleic acid (DNA), resulting in cell injury.
Defects in Membrane Permeability
Figure 1–20 Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ typically are seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which often are produced on reperfusion of ischemic tissues, also cause membrane damage (not shown).
Damage to DNA and Proteins
Summary
Mechanisms of Cell Injury
Clinicopathologic Correlations: Examples of Cell Injury and Necrosis
Ischemic and Hypoxic Injury
Ischemia-Reperfusion Injury
Chemical (Toxic) Injury
Apoptosis
Causes of Apoptosis
Apoptosis in Physiologic Situations
Apoptosis in Pathologic Conditions
Figure 1–21 Morphologic appearance of apoptotic cells. Apoptotic cells (some indicated by arrows) in a normal crypt in the colonic epithelium are shown. (The preparative regimen for colonoscopy frequently induces apoptosis in epithelial cells, which explains the abundance of dead cells in this normal tissue.) Note the fragmented nuclei with condensed chromatin and the shrunken cell bodies, some with pieces falling off.
Morphology
Mechanisms of Apoptosis
The Mitochondrial (Intrinsic) Pathway of Apoptosis
The Death Receptor (Extrinsic) Pathway of Apoptosis
Activation and Function of Caspases
Figure 1–22 Mechanisms of apoptosis. The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of caspases. In the mitochondrial pathway, proteins of the Bcl-2 family, which regulate mitochondrial permeability, become imbalanced and leakage of various substances from mitochondria leads to caspase activation. In the death receptor pathway, signals from plasma membrane receptors lead to the assembly of adaptor proteins into a “death-inducing signaling complex,” which activates caspases, and the end result is the same.
Clearance of Apoptotic Cells
Examples of Apoptosis
Growth Factor Deprivation
DNA Damage
Figure 1–23 The mitochondrial pathway of apoptosis. The induction of apoptosis by the mitochondrial pathway is dependent on a balance between pro- and anti-apoptotic proteins of the Bcl family. The pro-apoptotic proteins include some (sensors) that sense DNA and protein damage and trigger apoptosis and others (effectors) that insert in the mitochondrial membrane and promote leakage of mitochondrial proteins. A, In a viable cell, anti-apoptotic members of the Bcl-2 family prevent leakage of mitochondrial proteins. B, Various injurious stimuli activate cytoplasmic sensors and lead to reduced production of these anti-apoptotic proteins and increased amounts of pro-apoptotic proteins, resulting in leakage of proteins that are normally sequestered within mitochondria. The mitochondrial proteins that leak out activate a series of caspases, first the initiators and then the executioners, and these enzymes cause fragmentation of the nucleus and ultimately the cell.
Table 1–2 Diseases Caused by Misfolding of Proteins
Accumulation of Misfolded Proteins: ER Stress
Apoptosis of Self-Reactive Lymphocytes
Figure 1–24 The unfolded protein response and ER stress. A, In healthy cells, newly synthesized proteins are folded with the help of chaperones and are then incorporated into the cell or secreted. B, Various external stresses or mutations induce a state called ER stress, in which the cell is unable to cope with the load of misfolded proteins. Accumulation of these proteins in the ER triggers the unfolded protein response, which tries to restore protein homeostasis; if this response is inadequate, the cell dies by apoptosis.
Cytotoxic T Lymphocyte–Mediated Apoptosis
Summary
Apoptosis
Autophagy
Figure 1–25 Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes (Atg genes), which initiate the formation of membrane-bound vesicles in which cellular organelles are sequestered. These vesicles fuse with lysosomes, in which the organelles are digested, and the products are used to provide nutrients for the cell. The same process can trigger apoptosis, by mechanisms that are not well defined.
Intracellular Accumulations
Fatty Change (Steatosis)
Cholesterol and Cholesteryl Esters
Proteins
Figure 1–26 Mechanisms of intracellular accumulation: (1) Abnormal metabolism, as in fatty change in the liver. (2) Mutations causing alterations in protein folding and transport, so that defective molecules accumulate intracellularly. (3) A deficiency of critical enzymes responsible for breaking down certain compounds, causing substrates to accumulate in lysosomes, as in lysosomal storage diseases. (4) An inability to degrade phagocytosed particles, as in carbon pigment accumulation.
Glycogen
Pigments
Figure 1–27 Lipofuscin granules in a cardiac myocyte. A, Light microscopy (deposits indicated by arrows). B, Electron microscopy. Note the perinuclear, intralysosomal location.
Pathologic Calcification
Dystrophic Calcification
Figure 1–28 Hemosiderin granules in liver cells. A, Hematoxylin-eosin–stained section showing golden-brown, finely granular pigment. B, Iron deposits revealed by a special staining process called the Prussian blue reaction.
Metastatic Calcification
Morphology
Summary
Abnormal Intracellular Depositions and Calcifications
Cellular Aging
Figure 1–29 Mechanisms that cause and counteract cellular aging. DNA damage, replicative senescence, and decreased and misfolded proteins are among the best described mechanisms of cellular aging. Some environmental stresses, such as calorie restriction, counteract aging by activating various signaling pathways and transcription factors. IGF, insulin-like growth factor; TOR, target of rapamycin.
Figure 1–30 The role of telomeres and telomerase in replicative senescence of cells. Telomere length is plotted against the number of cell divisions. In most normal somatic cells there is no telomerase activity, and telomeres progressively shorten with increasing cell divisions until growth arrest, or senescence, occurs. Germ cells and stem cells both contain active telomerase, but only the germ cells have sufficient levels of the enzyme to stabilize telomere length completely. In cancer cells, telomerase is often reactivated.
Summary
Cellular Aging
Bibliography
Chapter 2 Inflammation and Repair
Overview of Inflammation and Tissue Repair
Figure 2–1 The components of acute and chronic inflammatory responses and their principal functions. The roles of these cells and molecules in inflammation are described in this chapter.
Table 2–1 Features of Acute and Chronic Inflammation
Summary
General Features of Inflammation
Acute Inflammation
Stimuli for Acute Inflammation
Figure 2–2 Vascular and cellular reactions of acute inflammation. The major local manifestations of acute inflammation, compared with normal, are (1) vascular dilation and increased blood flow (causing erythema and warmth), (2) extravasation of plasma fluid and proteins (edema), and (3) leukocyte (mainly neutrophil) emigration and accumulation.
Recognition of Microbes, Necrotic Cells, and Foreign Substances
Figure 2–3 Sensors of microbes and dead cells: Phagocytes, dendritic cells, and many types of epithelial cells express different classes of receptors that sense the presence of microbes and dead cells. A, Toll-like receptors (TLRs) located in the plasma membrane and endosomes and other cytoplasmic and plasma membrane receptors (members of families other than TLRs) recognize products of different classes of microbes. The proteins produced by TLR activation have numerous functions; only their role in inflammation is shown. B, The inflammasome is a protein complex that recognizes products of dead cells and some microbes and induces the secretion of biologically active interleukin-1 (IL-1). The inflammasome consists of a sensor protein (a leucine-rich protein called NLRP3), an adaptor, and the enzyme caspase-1, which is converted from an inactive to an active form. (Note that the inflammasome is distinct from phagolysosomes, which also are present in the cytoplasm but are vesicles that serve different functions in inflammation, as discussed later in the chapter.) CPP, calcium pyrophosphate; MSU, monosodium urate.
Vascular Changes
Figure 2–4 Formation of transudates and exudates. A, Normal hydrostatic pressure (blue arrows) is approximately 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is nearly equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil. B, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure. C, An exudate is formed in inflammation because vascular permeability increases as a result of the increase in interendothelial spaces.
Changes in Vascular Caliber and Flow
Increased Vascular Permeability
Responses of Lymphatic Vessels
Summary
Vascular Reactions in Acute Inflammation
Cellular Events: Leukocyte Recruitment and Activation
Leukocyte Recruitment
Margination and Rolling
Adhesion
Figure 2–5 Mechanisms of leukocyte migration through blood vessels. The leukocytes (neutrophils shown here) first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process: selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, intercellular adhesion molecule-1; IL-1, interleukin-1; PECAM-1, platelet endothelial cell adhesion molecule-1; TNF, tumor necrosis factor.
Table 2–2 Endothelial and Leukocyte Adhesion Molecules
Transmigration
Chemotaxis
Figure 2–6 Nature of leukocyte infiltrates in inflammatory reactions. The photomicrographs show an inflammatory reaction in the myocardium after ischemic necrosis (infarction). A, Early (neutrophilic) infiltrates and congested blood vessels. B, Later (mononuclear) cellular infiltrates. C, The approximate kinetics of edema and cellular infiltration. For sake of simplicity, edema is shown as an acute transient response, although secondary waves of delayed edema and neutrophil infiltration also can occur.
Summary
Leukocyte Recruitment to Sites of Inflammation
Leukocyte Activation
Phagocytosis
Figure 2–7 Leukocyte activation. Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that mediate the functions of the leukocytes. Only some receptors are depicted (see text for details). Lipopolysaccharide (LPS) first binds to a circulating LPS-binding protein (not shown). IFN-γ, interferon-γ.
Killing and Degradation of Phagocytosed Microbes
Figure 2–8 Phagocytosis. Phagocytosis of a particle (e.g., a bacterium) involves (1) attachment and binding of the particle to receptors on the leukocyte surface, (2) engulfment and fusion of the phagocytic vacuole with granules (lysosomes), and (3) destruction of the ingested particle. iNOS, inducible nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species.
Secretion of Microbicidal Substances
Neutrophil Extracellular Traps (NETs)
Leukocyte-Induced Tissue Injury
Figure 2–9 Neutrophil extracellular traps (NETs). A, Healthy neutrophils with nuclei stained red and cytoplasm green. B, Release of nuclear material from neutrophils (note that two have lost their nuclei), forming extracellular traps. C, An electron micrograph of bacteria (staphylococci) trapped in NETs.
Summary
Leukocyte Effector Mechanisms
Defects in Leukocyte Function
Table 2–3 Clinical Examples of Leukocyte-Induced Injury
Table 2–4 Defects in Leukocyte Functions
Outcomes of Acute Inflammation
Figure 2–10 Outcomes of acute inflammation: resolution, healing by scarring (fibrosis), or chronic inflammation (see text).
Summary
Sequence of Events in Acute Inflammation
Morphologic Patterns of Acute Inflammation
Figure 2–11 Serous inflammation. Low-power view of a cross-section of a skin blister showing the epidermis separated from the dermis by a focal collection of serous effusion.
Figure 2–12 Fibrinous pericarditis. A, Deposits of fibrin on the pericardium. B, A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P).
Figure 2–13 Purulent inflammation with abscess formation. A, Multiple bacterial abscesses in the lung (arrows) in a case of bronchopneumonia. B, The abscess contains neutrophils and cellular debris and is surrounded by congested blood vessels.
Figure 2–14 Ulcer. A, A chronic duodenal ulcer. B, Low-power cross-section of a duodenal ulcer crater with an acute inflammatory exudate in the base.
Morphology
Chemical Mediators and Regulators of Inflammation
Figure 2–15 Mediators of inflammation. The principal cell-derived and plasma protein mediators are shown. EC, endothelial cells.
Table 2–5 Actions of the Principal Mediators of Inflammation
Cell-Derived Mediators
Vasoactive Amines
Arachidonic Acid Metabolites: Prostaglandins, Leukotrienes, and Lipoxins
Anti-inflammatory Drugs That Block Prostaglandin Production
Figure 2–16 Production of arachidonic acid metabolites and their roles in inflammation. Note the enzymatic activities whose inhibition through pharmacologic intervention blocks major pathways (denoted with a red X). COX-1, COX-2, cyclooxygenases 1 and 2; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.
Table 2–6 Principal Inflammatory Actions of Arachidonic Acid Metabolites (Eicosanoids)
Platelet-Activating Factor
Cytokines
Tumor Necrosis Factor and Interleukin-1
Chemokines
Figure 2–17 The roles of cytokines in acute inflammation. The cytokines TNF, IL-1, and IL-6 are key mediators of leukocyte recruitment in local inflammatory responses and also play important roles in the systemic reactions of inflammation.
Reactive Oxygen Species
Nitric Oxide
Lysosomal Enzymes of Leukocytes
Neuropeptides
Summary
Major Cell-Derived Mediators of Inflammation
Plasma Protein–Derived Mediators
Complement
Figure 2–18 The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC).
Figure 2–19 Interrelationships among the four plasma mediator systems triggered by activation of factor XII (Hageman factor). See text for details.
Coagulation and Kinin Systems
Table 2–7 Role of Mediators in Different Reactions of Inflammation
Summary
Plasma Protein–Derived Mediators of Inflammation
Anti-inflammatory Mechanisms
Chronic Inflammation
Figure 2–20 A, Chronic inflammation in the lung, showing the characteristic histologic features: collection of chronic inflammatory cells (asterisk); destruction of parenchyma, in which normal alveoli are replaced by spaces lined by cuboidal epithelium (arrowheads); and replacement by connective tissue, resulting in fibrosis (arrows). B, By contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.
Chronic Inflammatory Cells and Mediators
Macrophages
Figure 2–21 Pathways of macrophage activation. Different stimuli activate monocytes/macrophages to develop into functionally distinct populations. Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-γ, and are microbicidal and involved in potentially harmful inflammation. Alternatively activated macrophages are induced by IL-4 and IL-13, produced by TH2 cells (a helper T cell subset) and other leukocytes, and are important in tissue repair and fibrosis. IFN-γ, interferon-γ; IL-4, IL-13, interkeukin-4, -13.
Lymphocytes
Other Cells
Figure 2–22 Macrophage–lymphocyte interactions in chronic inflammation. Activated lymphocytes and macrophages stimulate each other, and both cell types release inflammatory mediators that affect other cells. IFN-γ, interferon-γ; IL-1, interleukin-1; TNF, tumor necrosis factor.
Granulomatous Inflammation
Figure 2–23 A typical granuloma resulting from infection with Mycobacterium tuberculosis showing central area of caseous necrosis, activated epithelioid macrophages, giant cells, and a peripheral accumulation of lymphocytes.
Table 2–8 Examples of Diseases with Granulomatous Inflammation
Morphology
Summary
Features of Chronic Inflammation
Systemic Effects of Inflammation
Summary
Systemic Effects of Inflammation
Overview of Tissue Repair
Figure 2–24 Mechanisms of tissue repair: regeneration and scar formation. After mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration, but after more severe injury with damage to the connective tissue, repair is by scar formation.
Cell and Tissue Regeneration
The Control of Cell Proliferation
Proliferative Capacities of Tissues
Figure 2–25 Mechanisms regulating cell populations. Cell numbers can be altered by increased or decreased rates of stem cell input, cell death by apoptosis, or changes in the rates of proliferation or differentiation.
Stem Cells
Figure 2–26 The production of induced pluripotent stem cells (iPS cells). Genes that confer stem cell properties are introduced into a patient’s differentiated cells, giving rise to stem cells, which can be induced to differentiate into various lineages.
Summary
Cell Proliferation, the Cell Cycle, and Stem Cells
Growth Factors
Signaling Mechanisms of Growth Factor Receptors
Table 2–9 Growth Factors Involved in Regeneration and Repair
Table 2–10 Principal Signaling Pathways Used by Cell Surface Receptors
Summary
Growth Factors, Receptors, and Signal Transduction
Role of the Extracellular Matrix in Tissue Repair
Figure 2–27 The major components of the extracellular matrix (ECM), including collagens, proteoglycans, and adhesive glycoproteins. Note that although there is some overlap in their constituents, basement membrane and interstitial ECM differ in general composition and architecture. Both epithelial and mesenchymal cells (e.g., fibroblasts) interact with ECM through integrins. For simplification, many ECM components have been left out (e.g., elastin, fibrillin, hyaluronan, syndecan).
Components of the Extracellular Matrix
Collagen
Elastin
Proteoglycans and Hyaluronan
Adhesive Glycoproteins and Adhesion Receptors
Functions of the Extracellular Matrix
Summary
Extracellular Matrix and Tissue Repair
Role of Regeneration in Tissue Repair
Figure 2–28 Regeneration of the liver. Computed tomography scans show a donor liver in living-donor liver transplantation. A, The donor liver before the operation. Note the right lobe (outline), which will be resected and used as a transplant. B, Scan of the same liver 1 week after resection of the right lobe; note the enlargement of the left lobe (outline) without regrowth of the right lobe.
Scar Formation
Steps in Scar Formation
Figure 2–29 Steps in repair by scar formation. Injury to a tissue that has limited regenerative capacity first induces inflammation, which clears dead cells and microbes, if any. This is followed by formation of vascularized granulation tissue and then deposition of ECM to form the scar. ECM, extracellular matrix.
Figure 2–30 A, Granulation tissue showing numerous blood vessels, edema, and a loose ECM containing occasional inflammatory cells. Collagen is stained blue by the trichrome stain; minimal mature collagen can be seen at this point. B, Trichrome stain of mature scar, showing dense collagen with only scattered vascular channels. ECM, extracellular matrix.
Angiogenesis
Figure 2–31 Mechanism of angiogenesis. In tissue repair, angiogenesis occurs mainly by growth factor–driven outgrowth of residual endothelium, sprouting of new vessels, and recruitment of pericytes to form new vessels.
Growth Factors Involved in Angiogenesis
Activation of Fibroblasts and Deposition of Connective Tissue
Growth Factors Involved in ECM Deposition and Scar Formation
Remodeling of Connective Tissue
Summary
Repair by Scar Formation
Factors That Influence Tissue Repair
Figure 2–32 Keloid. A, Excess collagen deposition in the skin forming a raised scar known as a keloid. B, Thick connective tissue deposition in the dermis.
Selected Clinical Examples of Tissue Repair and Fibrosis
Figure 2–33 Steps in wound healing by first intention (left) and second intention (right). In the latter case, note the large amount of granulation tissue and wound contraction.
Healing of Skin Wounds
Healing by First Intention
Figure 2–34 Healing of skin ulcers. A, Pressure ulcer of the skin, commonly found in diabetic patients. B, A skin ulcer with a large gap between the edges of the lesion. C, A thin layer of epidermal re-epithelialization, and extensive granulation tissue formation in the dermis. D, Continuing re-epithelialization of the epidermis and wound contraction.
Healing by Second Intention
Wound Strength
Fibrosis in Parenchymal Organs
Summary
Cutaneous Wound Healing and Pathologic Aspects of Repair
Bibliography
Chapter 3 Hemodynamic Disorders, Thromboembolism, and Shock
Hyperemia and Congestion
Morphology
Figure 3–1 Liver with chronic passive congestion and hemorrhagic necrosis. A, In this autopsy specimen, central areas are red and slightly depressed compared with the surrounding tan viable parenchyma, creating “nutmeg liver” (so called because it resembles the cut surface of a nutmeg). B, Microscopic preparation shows centrilobular hepatic necrosis with hemorrhage and scattered inflammatory cells.
Table 3–1 Pathophysiologic Causes of Edema
Edema
Figure 3–2 Factors influencing fluid movement across capillary walls. Capillary hydrostatic and osmotic forces are normally balanced so there is little net movement of fluid into the interstitium. However, increased hydrostatic pressure or diminished plasma osmotic pressure leads to extravascular fluid accumulation (edema). Tissue lymphatics drain much of the excess fluid back to the circulation by way of the thoracic duct; however, if the capacity for lymphatic drainage is exceeded, tissue edema results.
Increased Hydrostatic Pressure
Reduced Plasma Osmotic Pressure
Lymphatic Obstruction
Sodium and Water Retention
Figure 3–3 Pathways leading to systemic edema due to heart failure, renal failure, or reduced plasma osmotic pressure.
Morphology
Clinical Correlation
Summary
Edema
Hemorrhage
Figure 3–4 A, Punctate petechial hemorrhages of the colonic mucosa, a consequence of thrombocytopenia. B, Fatal intracerebral hemorrhage.
Hemostasis and Thrombosis
Normal Hemostasis
Endothelium
Antithrombotic Properties of Normal Endothelium
Inhibitory Effects on Platelets
Figure 3–5 Normal hemostasis. A, After vascular injury, local neurohumoral factors induce a transient vasoconstriction. B, Platelets bind via glycoprotein 1b (GpIb) receptors to von Willebrand factor (vWF) on exposed extracellular matrix (ECM) and are activated, undergoing a shape change and granule release. Released adenosine diphosphate (ADP) and thromboxane A2 (TxA2) induce additional platelet aggregation through binding of platelet GpIIb-IIIa receptors to fibrinogen. This platelet aggregate fills the vascular defect, forming the primary hemostatic plug. C, Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, “cementing” the platelets into a definitive secondary hemostatic plug that is larger and more stable than the primary plug and contains entrapped red cells and leukocytes. D, Counterregulatory mechanisms, such as release of t-PA (tissue plasminogen activator, a fibrinolytic product) and thrombomodulin (interfering with the coagulation cascade), limit the hemostatic process to the site of injury.
Inhibitory Effects on Coagulation Factors
Fibrinolysis
Prothrombotic Properties of Injured or Activated Endothelium
Activation of Platelets
Activation of Clotting Factors
Antifibrinolytic Effects
Figure 3–6 Anticoagulant properties of normal endothelium (left) and procoagulant properties of injured or activated endothelium (right). NO, nitric oxide; PGI2, prostaglandin I2 (prostacyclin); t-PA, tissue plasminogen activator; vWF, von Willebrand factor. Thrombin receptors are also called protease-activated receptors (PARs).
Summary
Endothelial Cells and Coagulation
Platelets
Figure 3–7 Platelet adhesion and aggregation. Von Willebrand factor functions as an adhesion bridge between subendothelial collagen and the glycoprotein Ib (GpIb) platelet receptor. Platelet aggregation is accomplished by fibrinogen binding to platelet GpIIb-IIIa receptors on different platelets. Congenital deficiencies in the various receptors or bridging molecules lead to the diseases indicated in the colored boxes. ADP, adenosine diphosphate.
Platelet Adhesion
Platelet Activation
Platelet Aggregation
Platelet-Endothelial Interactions
Summary
Platelet Adhesion, Activation, and Aggregation
Coagulation Cascade
Figure 3–8 The coagulation cascade. Factor IX can be activated by either factor XIa or factor VIIa: In laboratory tests, activation is predominantly dependent on factor XIa, whereas in vivo, factor VIIa appears to be the predominant activator of factor IX. Factors in red boxes represent inactive molecules; activated factors, indicated with a lowercase a, are in green boxes. Note that thrombin (factor IIa) (in light blue boxes) contributes to coagulation through multiple positive feedback loops. The red X’s denote points at which tissue factor pathway inhibitor (TFPI) inhibits activation of factor X and factor IX by factor VIIa. HMWK, high-molecular-weight kininogen; PL, phospholipid.
Figure 3–9 Sequential conversion of factor X to factor Xa by way of the extrinsic pathway, followed by conversion of factor II (prothrombin) to factor IIa (thrombin). The initial reaction complex consists of a protease (factor VIIa), a substrate (factor X), and a reaction accelerator (tissue factor) assembled on a platelet phospholipid surface. Calcium ions hold the assembled components together and are essential for the reaction. Activated factor Xa then becomes the protease component of the next complex in the cascade, converting prothrombin to thrombin (factor IIa) in the presence of a different reaction accelerator, factor Va.
Figure 3–10 Role of thrombin in hemostasis and cellular activation. Thrombin generates fibrin by cleaving fibrinogen, activates factor XIII (which is responsible for cross-linking fibrin into an insoluble clot), and also activates several other coagulation factors, thereby amplifying the coagulation cascade (Fig. 3–8). Through protease-activated receptors (PARs), thrombin activates (1) platelet aggregation and TxA2 secretion; (2) endothelium, which responds by generating leukocyte adhesion molecules and a variety of fibrinolytic (t-PA), vasoactive (NO, PGI2), or cytokine (PDGF) mediators; and (3) leukocytes, increasing their adhesion to activated endothelium. ECM, extracellular matrix; NO, nitric oxide; PDGF, platelet-derived growth factor; PGI2, prostaglandin I2 (prostacyclin); TxA2, thromboxane A2; t-PA, tissue type plasminogen activator. See Figure 3–6 for anticoagulant activities mediated by thrombin via thrombomodulin.
Figure 3–11 The fibrinolytic system, illustrating various plasminogen activators and inhibitors (see text).
Summary
Coagulation Factors
Thrombosis
Endothelial Injury
Figure 3–12 Virchow’s triad in thrombosis. Endothelial integrity is the most important factor. Abnormalities of procoagulants or anticoagulants can tip the balance in favor of thrombosis. Abnormal blood flow (stasis or turbulence) can lead to hypercoagulability directly and also indirectly through endothelial dysfunction.
Abnormal Blood Flow
Hypercoagulability
Table 3–2 Hypercoagulable States
Figure 3–13 Mural thrombi. A, Thrombus in the left and right ventricular apices, overlying white fibrous scar. B, Laminated thrombus in a dilated abdominal aortic aneurysm. Numerous friable mural thrombi are also superimposed on advanced atherosclerotic lesions of the more proximal aorta (left side of photograph).
Morphology
Fate of the Thrombus
Figure 3–14 Low-power view of a thrombosed artery stained for elastic tissue. The original lumen is delineated by the internal elastic lamina (arrows) and is totally filled with organized thrombus.
Clinical Correlation
Venous Thrombosis (Phlebothrombosis)
Summary
Thrombosis
Disseminated Intravascular Coagulation
Embolism
Pulmonary Thromboembolism
Figure 3–15 Embolus derived from a lower-extremity deep venous thrombus lodged in a pulmonary artery branch.
Systemic Thromboembolism
Fat Embolism
Amniotic Fluid Embolism
Figure 3–16 Unusual types of emboli. A, Bone marrow embolus. The embolus is composed of hematopoietic marrow and marrow fat cells (clear spaces) attached to a thrombus. B, Amniotic fluid emboli. Two small pulmonary arterioles are packed with laminated swirls of fetal squamous cells. The surrounding lung is edematous and congested.
Air Embolism
Summary
Embolism
Infarction
Figure 3–17 Red and white infarcts. A, Hemorrhagic, roughly wedge-shaped pulmonary infarct (red infarct). B, Sharply demarcated pale infarct in the spleen (white infarct).
Figure 3–18 Remote kidney infarct, now replaced by a large fibrotic scar.
Morphology
Factors That Influence Infarct Development
Summary
Infarction
Shock
Table 3–3 Three Major Types of Shock
Pathogenesis of Septic Shock
Figure 3–19 Major pathogenic pathways in septic shock. Microbial products activate endothelial cells and cellular and humoral elements of the innate immune system, initiating a cascade of events that lead to end-stage multiorgan failure. Additional details are given in the text. DIC, disseminated intravascular coagulation; HMGB1, high-mobility group box 1 protein; NO, nitric oxide; PAF, platelet-activating factor; PAI-1, plasminogen activator inhibitor-1; PAMP, pathogen-associated molecular pattern; STNFR, soluble tumor necrosis factor receptor; TF, tissue factor; TFPI, tissue factor pathway inhibitor.
Stages of Shock
Morphology
Clinical Course
Summary
Shock
Bibliography
Chapter 4 Diseases of the Immune System
Innate and Adaptive Immunity
Figure 4–1 The principal mechanisms of innate immunity and adaptive immunity. NK, natural killer.
Cells and Tissues of the Immune System
Lymphocytes
T Lymphocytes
Figure 4–2 Lymphocyte antigen receptors. A, The T cell receptor (TCR) complex and other molecules involved in T cell activation. The TCRα and TCRβ chains recognize antigen (in the form of peptide–MHC complexes expressed on antigen-presenting cells), and the linked CD3 complex initiates activating signals. CD4 and CD28 are also involved in T cell activation. (Note that some T cells express CD8 and not CD4; these molecules serve analogous roles.) B, The B cell receptor complex is composed of membrane IgM (or IgD, not shown) and the associated signaling proteins Igα and Igβ. CD21 is a receptor for a complement component that promotes B cell activation. Ig, immunoglobulin; MHC, major histocompatibilty complex.
Major Histocompatibility Complex Molecules: The Peptide Display System of Adaptive Immunity
Figure 4–3 The human leukocyte antigen (HLA) complex and the structure of HLA molecules. A, The location of genes in the HLA complex. The sizes and distances between genes are not to scale. The class II region also contains genes that encode several proteins involved in antigen processing (not shown). B, Schematic diagrams and crystal structures of class I and class II HLA molecules. LT, lymphotoxin; TNF, tumor necrosis factor.
B Lymphocytes
Natural Killer Cells
Antigen-Presenting Cells
Dendritic Cells
Other Antigen-Presenting Cells
Effector Cells
Lymphoid Tissues
Summary
Cells and Tissues of the Immune System
Overview of Normal Immune Responses
The Early Innate Immune Response to Microbes
The Capture and Display of Microbial Antigens
Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of Cell-Associated Microbes
Figure 4–4 Cell-mediated immunity. Naive T cells recognize MHC-associated peptide antigens displayed on dendritic cells in lymph nodes. The T cells are activated to proliferate (under the influence of the cytokine IL-2) and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity. Effector CD4+ T cells of the TH1 subset recognize the antigens of microbes ingested by phagocytes and activate the phagocytes to kill the microbes; TH17 effector cells enhance leukocyte recruitment and stimulate inflammation; TH2 cells activate eosinophils. CD8+ CTLs kill infected cells harboring microbes in the cytoplasm. Some activated T cells differentiate into long-lived memory cells. APC, antigen-presenting cell; CTLs, cytotoxic T lymphocytes.
Cytokines: Messenger Molecules of the Immune System
Figure 4–5 Subsets of CD4+ effector T cells. In response to stimuli (mainly cytokines) present at the time of antigen recognition, naive CD4+ helper T cells may differentiate into populations of effector cells that produce distinct sets of cytokines and perform different functions. The types of immune reactions elicited by each subset, and its role in host defense and immunological diseases, are summarized. Two other populations of CD4+ T cells, regulatory cells and follicular helper cells, are not shown.
Effector Functions of T Lymphocytes
Humoral Immunity: Activation of B Lymphocytes and Elimination of Extracellular Microbes
Figure 4–6 Humoral immunity. Naive B lymphocytes recognize antigens, and under the influence of helper T cells and other stimuli (not shown), the B cells are activated to proliferate and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy chain class switching and affinity maturation, and some become long-lived memory cells. Antibodies of different heavy chain isotypes (classes) perform different effector functions, shown on the right.
Decline of Immune Responses and Immunologic Memory
Summary
Overview of Normal Immune Responses
Hypersensitivity Reactions: Mechanisms of Immune-Mediated Injury
Causes of Hypersensitivity Reactions
Table 4–1 Mechanisms of Hypersensitivity Reactions
Types of Hypersensitivity Reactions
Immediate (Type I) Hypersensitivity
Sequence of Events in Immediate Hypersensitivity Reactions
Figure 4–7 Sequence of events in immediate (type I) hypersensitivity. Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates TH2 responses and IgE production. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate hypersensitivity.
Figure 4–8 Mast cell mediators. Upon activation, mast cells release various classes of mediators that are responsible for the immediate and late-phase reactions. ECF, eosinophil chemotactic factor; NCF, neutrophil chemotactic factor (neither of these has been biochemically defined); PAF, platelet-activating factor.
Table 4–2 Summary of the Action of Mast Cell Mediators in Immediate (Type I) Hypersensitivity
Clinical and Pathologic Manifestations
Figure 4–9 Immediate hypersensitivity. A, Kinetics of the immediate and late-phase reactions. The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in a previously sensitized person), and the late-phase reaction develops 2 to 24 hours later. B–C, Morphology: The immediate reaction (B) is characterized by vasodilation, congestion, and edema, and the late-phase reaction (C) is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells.
Table 4–3 Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)
Summary
Immediate (Type I) Hypersensitivity
Antibody-Mediated Diseases (Type II Hypersensitivity)
Mechanisms of Antibody-Mediated Diseases
Figure 4–10 Mechanisms of antibody-mediated injury. A, Opsonization of cells by antibodies and complement components, and ingestion of opsonized cells by phagocytes. B, Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. C, Antireceptor antibodies disturb the normal function of receptors. In these examples, antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease, and acetylcholine (ACh) receptor antibodies impair neuromuscular transmission in myasthenia gravis.
Immune Complex Diseases (Type III Hypersensitivity)
Table 4–4 Examples of Immune Complex–Mediated Diseases
Systemic Immune Complex Disease
Figure 4–11 Immune complex disease: The sequential phases in the induction of systemic immune complex–mediated diseases (type III hypersensitivity).
Morphology
Local Immune Complex Disease
Summary
Pathogenesis of Diseases Caused by Antibodies and Immune Complexes
T Cell–Mediated (Type IV) Hypersensitivity
Table 4–5 T Cell–Mediated Diseases*
Inflammatory Reactions Elicited by CD4+ T Cells
Figure 4–12 Mechanisms of T cell–mediated (type IV) hypersensitivity reactions. A, In cytokine-mediated inflammatory reactions, CD4+ T cells respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. B, In some diseases, CD8+ CTLs directly kill tissue cells. APC, antigen-presenting cell; CTLs, cytotoxic T lymphocytes.
Delayed-Type Hypersensitivity
T Cell–Mediated Cytotoxicity
Figure 4–13 Delayed-type hypersensitivity reaction in the skin. A, Perivascular accumulation (“cuffing”) of mononuclear inflammatory cells (lymphocytes and macrophages), with associated dermal edema and fibrin deposition. B, Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that marks positively with anti-CD4 antibodies.
Summary
Mechanisms of T Cell–Mediated Hypersensitivity Reactions
Autoimmune Diseases
Figure 4–14 Granulomatous inflammation. A, A section of a lymph node shows several granulomas, each made up of an aggregate of epithelioid cells and surrounded by lymphocytes. The granuloma in the center shows several multinucleate giant cells. B, The events that give rise to the formation of granulomas in type IV hypersensitivity reactions. Note the role played by T cell–derived cytokines.
Table 4–6 Autoimmune Diseases
Immunologic Tolerance
Figure 4–15 Immunologic self-tolerance: The principal mechanisms of central and peripheral self-tolerance in T and B cells.
Mechanisms of Autoimmunity
Genetic Factors in Autoimmunity
Table 4–7 Association of Human Leukocyte Antigen (HLA) Alleles with Autoimmune Diseases
Figure 4–16 Pathogenesis of autoimmunity. Autoimmunity arises from the inheritance of susceptibility genes that may interfere with self-tolerance, in association with environmental triggers (infection, tissue injury, inflammation) that alter the display of self antigens, promote lymphocyte entry into tissues, and enhance the activation of self-reactive lymphocytes.
Role of Infections and Tissue Injury
Table 4–8 Selected Non–Human Leukocyte Antigen (HLA) Genes Associated with Autoimmune Diseases
Summary
Immunologic Tolerance and Autoimmunity
Systemic Lupus Erythematosus
Table 4–9 1997 Revised Criteria for Classification of Systemic Lupus Erythematosus*
Figure 4–17 Model for the pathogenesis of systemic lupus erythematosus. Genetic susceptibility and exposure result in failure of self-tolerance and persistence of nuclear antigens. Autoantibodies serve to internalize nuclear components, which engage TLRs and stimulate IFN production. IFN may stimulate B and T cell responses to the nuclear antigens. IFN, interferon; IgG, immunoglobulin G; MHC, major histocompatibility complex; TLRs, Toll-like receptors; UV, ultraviolet.
Pathogenesis
Genetic Factors
Environmental Factors
Immunologic Abnormalities in SLE
Spectrum of Autoantibodies in SLE
Table 4–10 Selected Autoantibodies Associated with Presumed Autoimmune Diseases
Mechanisms of Tissue Injury
Figure 4–18 Lupus nephritis. A, Focal lupus nephritis, with two necrotizing lesions in a glomerulus (segmental distribution) (H&E stain). B, Diffuse lupus nephritis. Note the marked global increase in cellularity throughout the glomerulus (H&E stain). C, Lupus nephritis showing a glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes (periodic acid Schiff stain). D, Electron micrograph of a renal glomerular capillary loop from a patient with SLE nephritis. Confluent subendothelial dense deposits correspond to “wire loops” seen by light microscopy. E, Deposition of IgG antibody in a granular pattern, detected by immunofluorescence. B, basement membrane; End, endothelium; Ep, epithelial cell with foot processes; Mes, mesangium; RBC, red blood cell in capillary lumen; US, urinary space; *, electron-dense deposits in subendothelial location.
Figure 4–19 Systemic lupus erythematosus involving the skin. A, An H&E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction. B, An immunofluorescence micrograph stained for IgG reveals deposits of immunoglobulin along the dermoepidermal junction. H&E, hematoxylin–eosin; IgG, immunoglobulin G.
Morphology
Blood Vessels
Kidneys
Skin
Joints
CNS
Other Organs
Clinical Manifestations
Summary
Systemic Lupus Erythematosus
Rheumatoid Arthritis
Sjögren Syndrome
Figure 4–20 Sjögren syndrome. A, Enlargement of the salivary gland. B, Histopathologic findings include intense lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia.
Pathogenesis
Morphology
Clinical Course
Summary
Sjögren Syndrome
Systemic Sclerosis (Scleroderma)
Figure 4–21 A model for the pathogenesis of systemic sclerosis. Unknown external stimuli cause vascular abnormalities and immune activation in genetically susceptible individuals, and both contribute to the excessive fibrosis.
Figure 4–22 Systemic sclerosis. A, Normal skin. B, Extensive deposition of dense collagen in the dermis. C, The extensive subcutaneous fibrosis has virtually immobilized the fingers, creating a clawlike flexion deformity. Loss of blood supply has led to cutaneous ulcerations.
Pathogenesis
Morphology
Skin
Gastrointestinal Tract
Musculoskeletal System
Lungs
Kidneys
Heart
Clinical Course
Summary
Systemic Sclerosis
Inflammatory Myopathies
Mixed Connective Tissue Disease
Polyarteritis Nodosa and Other Vasculitides
IgG4-Related Disease
Rejection of Transplants
Immune Recognition of Allografts
Figure 4–23 Recognition and rejection of allografts. In the direct pathway, donor class I and class II MHC antigens on antigen-presenting cells (APCs) in the graft (along with costimulators, not shown) are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively. CD4+ cells proliferate and produce cytokines (e.g., IFN-γ), which induce tissue damage by a local delayed-type hypersensitivity reaction. CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells. In the indirect pathway, graft antigens are displayed by host APCs and activate CD4+ T cells, which damage the graft by a local delayed-type hypersensitivity reaction and stimulate B lymphocytes to produce antibodies. IFN-γ, interferon-γ; MHC, major histocompatibility complex.
Effector Mechanisms of Graft Rejection
T Cell–Mediated Rejection
Antibody-Mediated Rejection
Morphology
Hyperacute Rejection
Acute Rejection
Chronic Rejection
Summary
Recognition and Rejection of Organ Transplants (Allografts)
Figure 4–24 Morphologic patterns of graft rejection. A, Hyperacute rejection of a kidney allograft associated with endothelial damage and thrombi in a glomerulus. B, Acute cellular rejection of a kidney allograft with inflammatory cells in the interstitium and between epithelial cells of the tubules. C, Acute humoral rejection of a kidney allograft (rejection vasculitis) with inflammatory cells and proliferating smooth muscle cells in the intima. D, Chronic rejection in a kidney allograft with graft arteriosclerosis. The arterial lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the intima.
Methods of Improving Graft Survival
Transplantation of Hematopoietic Stem Cells
Graft-Versus-Host Disease (GVHD)
Immune Deficiencies
Immune Deficiency Diseases
Primary (Congenital) Immune Deficiencies
Figure 4–25 Primary immune deficiency diseases. Shown are the principal pathways of lymphocyte development and the blocks in these pathways in selected primary immune deficiency diseases. The affected genes are indicated in parentheses for some of the disorders. ADA, adenosine deaminase; CD40L, CD40 ligand (also known as CD154); CVID, common variable immunodeficiency; SCID, severe combined immunodeficiency.
X-Linked Agammaglobulinemia: Bruton Disease
Common Variable Immunodeficiency
Isolated IgA Deficiency
Hyper-IgM Syndrome
Thymic Hypoplasia: DiGeorge Syndrome
Severe Combined Immunodeficiency
Defects in Lymphocyte Activation
Immune Deficiency with Thrombocytopenia and Eczema: Wiskott-Aldrich Syndrome
Genetic Deficiencies of Components of Innate Immunity
Complement Proteins
Phagocytes
Other Genetic Disorders of Innate Immunity
Summary
Primary (Congenital) Immune Deficiency Diseases
Secondary (Acquired) Immune Deficiencies
Acquired Immunodeficiency Syndrome (AIDS)
Epidemiology
Sexual Transmission
Parenteral Transmission
Mother-to-Infant Transmission
Etiology and Pathogenesis
Structure of HIV
Figure 4–26 The structure of human immunodeficiency virus (HIV). The HIV-1 virion. The viral particle is covered by a lipid bilayer derived from the host cell and studded with viral glycoproteins gp41 and gp120.
Life Cycle of HIV
Figure 4–27 Molecular basis of entry of human immunodeficiency virus (HIV) into host cells. Interactions with CD4 and a chemokine receptor (“coreceptor”).
Progression of HIV Infection
Figure 4–28 Pathogenesis of human immunodeficiency virus (HIV) infection. Initially, HIV infects T cells and macrophages directly or is carried to these cells by Langerhans cells. Viral replication in the regional lymph nodes leads to viremia and widespread seeding of lymphoid tissue. The viremia is controlled by the host immune response (not shown), and the patient then enters a phase of clinical latency. During this phase, viral replication in both T cells and macrophages continues unabated, but there is some immune containment of virus (not illustrated). There continues a gradual erosion of CD4+ cells by productive infection (or other mechanisms, not shown). Ultimately, CD4+ cell numbers decline and the patient develops clinical symptoms of full-blown AIDS. Macrophages are also parasitized by the virus early; they are not lysed by HIV and they transport the virus to tissues, particularly the brain.
Mechanisms of T Cell Depletion in HIV Infection
Figure 4–29 Mechanisms of CD4+ T cell loss in human immunodeficiency virus (HIV) infection. Some of the principal known and postulated mechanisms of T cell depletion after HIV infection are shown.
Table 4–11 Major Abnormalities of Immune Function in AIDS
Monocytes/Macrophages in HIV Infection
DCs in HIV Infection
B Cells and Other Lymphocytes in HIV Infection
Pathogenesis of CNS Involvement
Summary
Human Immunodeficiency Virus Life Cycle and the Pathogenesis of AIDS
Natural History and Clinical Course
Figure 4–30 Clinical and immune response to human immunodeficiency virus (HIV) infection. A, Clinical course. The early period after primary infection is characterized by dissemination of virus, development of an immune response to HIV, and often an acute viral syndrome. During the period of clinical latency, viral replication continues, and the CD4+ T cell count gradually decreases until it reaches a critical level below which there is a substantial risk of AIDS-associated diseases. B, Immune response to HIV infection. A cytotoxic T lymphocyte (CTL) response to HIV is detectable by 2 to 3 weeks after the initial infection and peaks by 9 to 12 weeks. Marked expansion of virus-specific CD8+ T cell clones occurs during this time, and up to 10% of a patient’s CTLs may be HIV-specific at 12 weeks. The humoral immune response to HIV peaks at about 12 weeks.
Clinical Features
Opportunistic Infections
Table 4–12 AIDS-Defining Opportunistic Infections and Neoplasms Found in Patients with Human Immunodeficiency Virus (HIV) infection
Neoplasms
CNS Involvement
Morphology
Amyloidosis
Figure 4–31 Structure of amyloid. A, Schematic diagram of an amyloid fiber showing fibrils (four are shown; as many as six may be present) wound around one another with regularly spaced binding of the Congo red dye. B, Congo red staining shows an apple-green birefringence under polarized light, a diagnostic feature of amyloid. C, Electron micrograph of 7.4- to 10-nm amyloid fibrils.
Figure 4–32 Pathogenesis of amyloidosis. The proposed mechanisms underlying deposition of the major forms of amyloid fibrils.
Pathogenesis of Amyloid Deposition
Classification of Amyloidosis
Table 4–13 Classification of Amyloidosis
Primary Amyloidosis: Immunocyte Dyscrasias with Amyloidosis
Reactive Systemic Amyloidosis
Familial (Hereditary) Amyloidosis
Localized Amyloidosis
Endocrine Amyloid
Amyloid of Aging
Figure 4–33 Amyloidosis: hepatic involvement. A, Staining of a section of the liver with Congo red reveals pink-red deposits of amyloid in the walls of blood vessels and along sinusoids. B, Note the yellow-green birefringence of the deposits when observed under the polarizing microscope.
Figure 4–34 Amyloidosis: renal and cardiac involvement. A, Amyloidosis of the kidney. The glomerular architecture is almost totally obliterated by the massive accumulation of amyloid. B, Cardiac amyloidosis. The atrophic myocardial fibers are separated by structureless, pink-staining amyloid.
Morphology
Kidney
Spleen
Liver
Heart
Other Organs
Clinical Course
Summary
Amyloidosis
Bibliography
Chapter 5 Neoplasia
Nomenclature
Benign Tumors
Malignant Tumors
Figure 5–1 Colonic polyp. This glandular tumor (adenoma) is seen projecting into the colonic lumen. The polyp is attached to the mucosa by a distinct stalk.
Figure 5–2 Mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resembles cartilage.
Table 5–1 Nomenclature of Tumors
Characteristics of Benign and Malignant Neoplasms
Differentiation and Anaplasia
Figure 5–3 Well-differentiated squamous cell carcinoma of the skin. The tumor cells are strikingly similar to normal squamous epithelial cells, with intercellular bridges and nests of keratin (arrow).
Figure 5–4 Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells.
Figure 5–5 High-power detail view of anaplastic tumor cells shows cellular and nuclear variation in size and shape. The prominent cell in the center field has an abnormal tripolar spindle.
Figure 5–6 Carcinoma in situ. A, Low-power view shows that the entire thickness of the epithelium is replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact, and there is no tumor in the subepithelial stroma. B, High-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface. The intact basement membrane (below) is not seen in this section.
Rate of Growth
Cancer Stem Cells and Lineages
Local Invasion
Figure 5–7 Fibroadenoma of the breast. The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue.
Figure 5–8 Microscopic view of fibroadenoma of the breast seen in Figure 5–7. The fibrous capsule (right) sharply delimits the tumor from the surrounding tissue.
Figure 5–9 Cut section of invasive ductal carcinoma of the breast. The lesion is retracted, infiltrating the surrounding breast substance, and was stony-hard on palpation.
Figure 5–10 Microscopic view of breast carcinoma seen in Figure 5–9 illustrates the invasion of breast stroma and fat by nests and cords of tumor cells (compare with Fig. 5–8). Note the absence of a well-defined capsule.
Metastasis
Figure 5–11 A liver studded with metastatic cancer.
Figure 5–12 Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of similar origin (leiomyosarcoma).
Summary
Characteristics of Benign and Malignant Tumors
Epidemiology
Cancer Incidence
Figure 5–13 Cancer incidence and mortality by site and sex.
Geographic and Environmental Variables
Table 5–2 Occupational Cancers
Age
Heredity
Autosomal Dominant Cancer Syndromes
Table 5–3 Inherited Predisposition to Cancer
Autosomal Recessive Syndromes of Defective DNA Repair
Familial Cancers of Uncertain Inheritance
Acquired Preneoplastic Lesions
Summary
Epidemiology of Cancer
Carcinogenesis: The Molecular Basis of Cancer
Genetic Lesions in Cancer
Karyotypic Changes in Tumors
Balanced Translocations
Figure 5–14 The chromosomal translocation and associated oncogene in chronic myelogenous leukemia.
Deletions
Gene Amplifications
Figure 5–15 Amplification of the NMYC gene in human neuroblastoma. The NMYC gene, present normally on chromosome 2p, becomes amplified and is seen either as extrachromosomal double minutes or as a chromosomally integrated homogeneous-staining region (HSR). The integration involves other autosomes, such as 4, 9, or 13.
Aneuploidy
MicroRNAs and Cancer
Epigenetic Modifications and Cancer
Figure 5–16 Role of microRNAs (miRNAs) in tumorigenesis. A, Reduced activity of an miRNA that inhibits translation of an oncogene gives rise to an excess of oncoproteins. B, Overactivity of an miRNA that targets a tumor suppression gene reduces the production of the tumor suppressor protein. Question marks in A and B are meant to indicate that the mechanisms by which changes in the level or activity of miRNA are not entirely known.
Summary
Genetic Lesions in Cancer
Carcinogenesis: A Multistep Process
Figure 5–17 Tumor progression and generation of heterogeneity. New subclones arise from the descendants of the original transformed cell by multiple mutations. With progression, the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive.
Hallmarks of Cancer
Figure 5–18 Six hallmarks of cancer. Most cancer cells acquire these properties during their development, typically by mutations in the relevant genes.
Self-Sufficiency in Growth Signals
Growth Factors
Growth Factor Receptors and Non-Receptor Tyrosine Kinases
Downstream Signal-Transducing Proteins
RAS Protein
Figure 5–19 Model for action of RAS genes. When a normal cell is stimulated through a growth factor receptor, inactive (GDP-bound) RAS is activated to a GTP-bound state. Activated RAS transduces proliferative signals to the nucleus along two pathways: the so-called RAF/ERK/MAP kinase pathway and the PI3 kinase/AKT pathway. GDP, guanosine diphosphate; GTP, guanosine triphosphate; MAP, mitogen-activated protein; PI3, phosphatidylinositol-3.
ABL
Nuclear Transcription Factors
Cyclins and Cyclin-Dependent Kinases
The Normal Cell Cycle
Figure 5–20 Role of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors in regulating the cell cycle. The shaded arrows represent the phases of the cell cycle during which specific cyclin–CDK complexes are active. As illustrated, cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 regulate the G1-to-S transition by phosphorylating the Rb protein (pRb). Cyclin A–CDK2 and cyclin A–CDK1 are active in the S phase. Cyclin B–CDK1 is essential for the G2-to-M transition. Two families of CDK inhibitors can block activity of CDKs and progression through the cell cycle. The so-called INK4 inhibitors, composed of p16, p15, p18, and p19, act on cyclin D–CDK4 and cyclin D–CDK6. The other family of three inhibitors, p21, p27, and p57, can inhibit all CDKs.
Alterations in Cell Cycle Control Proteins in Cancer Cells
Summary
Oncogenes That Promote Unregulated Proliferation (Self-Sufficiency in Growth Signals)
Insensitivity to Growth Inhibitory Signals
RB Gene: Governor of the Cell Cycle
Figure 5–21 Pathogenesis of retinoblastoma. Two mutations of the RB chromosomal locus, on 13q14, lead to neoplastic proliferation of the retinal cells. In the familial form, all somatic cells inherit one mutant RB gene from a carrier parent. The second mutation affects the RB locus in one of the retinal cells after birth. In the sporadic form, both mutations at the RB locus are acquired by the retinal cells after birth.
Summary
Insensitivity to Growth Inhibitory Signals
Figure 5–22 The role of Rb in regulating the G1–S checkpoint of the cell cycle. Hypophosphorylated Rb in complex with the E2F transcription factors binds to DNA, recruits chromatin remodeling factors (histone deacetylases and histone methyltransferases), and inhibits transcription of genes whose products are required for the S phase of the cell cycle. When Rb is phosphorylated by the cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 complexes, it releases E2F. The latter then activates transcription of S-phase genes. The phosphorylation of Rb is inhibited by CDKIs, because they inactivate cyclin-CDK complexes. Virtually all cancer cells show dysregulation of the G1–S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of Rb; these genes are RB, CDK4, cyclin D, and CDKN2A [p16]. EGF, epidermal growth factor; PDGF, platelet-derived growth factor.
Summary
RB Gene: Governor of the Cell Cycle
TP53 Gene: Guardian of the Genome
Figure 5–23 The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair, by transcriptional upregulation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of TP53, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
Summary
TP53 Gene: Guardian of the Genome
Transforming Growth Factor-β Pathway
Contact Inhibition, NF2, and APC
Figure 5–24 A–C, The role of APC in regulating the stability and function of β-catenin. APC and β-catenin are components of the WNT signaling pathway. In resting cells (not exposed to WNT), β-catenin forms a macromolecular complex containing the APC protein. This complex leads to the destruction of β-catenin, and intracellular levels of β-catenin are low. When cells are stimulated by secreted WNT molecules, the destruction complex is deactivated, β-catenin degradation does not occur, and cytoplasmic levels increase. β-Catenin translocates to the nucleus, where it binds to TCF, a transcription factor that activates several genes involved in the cell cycle. When APC is mutated or absent, the destruction of β-catenin cannot occur. β-Catenin translocates to the nucleus and coactivates genes that promote the cell cycle, and cells behave as if they are under constant stimulation by the WNT pathway.
Figure 5–25 Simplified schema of CD95 receptor–induced and DNA damage–triggered pathways of apoptosis and mechanisms used by tumor cells to evade cell death: 1, Reduced CD95 level. 2, Inactivation of death-induced signaling complex by FLICE protein. 3, Reduced egress of cytochrome c from mitochondrion as a result of upregulation of BCL2. 4, Reduced levels of pro-apoptotic BAX resulting from loss of p53. 5, Loss of APAF-1. 6, Upregulation of inhibitors of apoptosis.
Summary
Transforming Growth Factor-β and APC–β-Catenin Pathways
Evasion of Cell Death
Autophagy
Summary
Evasion of Apoptosis
Limitless Replicative Potential
Figure 5–26 Sequence of events in the development of limitless replicative potential. Replication of somatic cells, which do not express telomerase, leads to shortened telomeres. In the presence of competent checkpoints, cells undergo arrest and enter nonreplicative senescence. In the absence of checkpoints, DNA repair pathways are inappropriately activated, leading to the formation of dicentric chromosomes. At mitosis, the dicentric chromosomes are pulled apart, generating random double-stranded breaks, which then activate DNA repair pathways, leading to the random association of double-stranded ends and the formation, again, of dicentric chromosomes. Cells undergo numerous rounds of this bridge–fusion–breakage cycle, which generates massive chromosomal instability and numerous mutations. If cells fail to reexpress telomerase, they eventually undergo mitotic catastrophe and death. Reexpression of telomerase allows the cells to escape the bridge–fusion–breakage cycle, thus promoting their survival and tumorigenesis.
Summary
Limitless Replicative Potential
Development of Sustained Angiogenesis
Summary
Development of Sustained Angiogenesis
Ability to Invade and Metastasize
Invasion of Extracellular Matrix (ECM)
Figure 5–27 The metastatic cascade: The sequential steps involved in the hematogenous spread of a tumor.
Figure 5–28 A–D, Sequence of events in the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced adhesiveness, then secrete proteolytic enzymes, degrading the basement membrane. Binding to proteolytically generated binding sites and tumor cell migration follow.
Vascular Dissemination and Homing of Tumor Cells
Molecular Genetics of Metastasis
Summary
Invasion and Metastasis
Reprogramming Energy Metabolism
Evasion of the Immune System
Genomic Instability as an Enabler of Malignancy
Hereditary Nonpolyposis Colon Cancer Syndrome
Xeroderma Pigmentosum
Diseases with Defects in DNA Repair by Homologous Recombination
Cancers Resulting From Mutations Induced by Regulated Genomic Instability: Lymphoid Neoplasms
Summary
Genomic Instability as Enabler of Malignancy
Tumor-Promoting Inflammation as Enabler of Malignancy
Figure 5–29 Therapeutic targeting of hallmarks of cancer.
Multistep Carcinogenesis and Cancer Progression
Etiology of Cancer: Carcinogenic Agents
Figure 5–30 Molecular model for the evolution of colorectal cancers through the adenoma–carcinoma sequence.
Chemical Carcinogens
Direct-Acting Agents
Indirect-Acting Agents
Table 5–4 Major Chemical Carcinogens
Mechanisms of Action of Chemical Carcinogens
Summary

Chemical Carcinogens
Radiation Carcinogenesis
Summary
Radiation Carcinogenesis
Viral and Microbial Oncogenesis
Oncogenic RNA Viruses
Figure 5–31 Pathogenesis of human T cell lymphotropic virus (HTLV-1)–induced T cell leukemia/lymphoma. HTLV-1 infects many T cells and initially causes polyclonal proliferation by autocrine and paracrine pathways triggered by the TAX gene. Simultaneously, TAX neutralizes growth inhibitory signals by affecting TP53 and CDKN2A/p16 genes. Ultimately, a monoclonal T cell leukemia/lymphoma results when one proliferating T cell suffers additional mutations.
Summary
Oncogenic RNA Viruses
Oncogenic DNA Viruses
Human Papillomavirus
Epstein-Barr Virus
Summary
Oncogenic DNA Viruses
Hepatitis B and Hepatitis C Viruses
Summary
Hepatitis B and Hepatitis C Viruses
Helicobacter pylori
Summary
Helicobacter pylori
Host Defense Against Tumors: Tumor Immunity
Tumor Antigens
Products of Mutated Oncogenes and Tumor Suppressor Genes
Figure 5–32 Tumor antigens recognized by CD8+ T cells.
Products of Other Mutated Genes
Overexpressed or Aberrantly Expressed Cellular Proteins
Tumor Antigens Produced by Oncogenic Viruses
Oncofetal Antigens
Altered Cell Surface Glycolipids and Glycoproteins
Cell Type–Specific Differentiation Antigens
Antitumor Effector Mechanisms
Cytotoxic T Lymphocytes
Natural Killer Cells
Macrophages
Humoral Mechanisms
Immune Surveillance and Immune Evasion by Tumors
Summary
Immune Surveillance
Clinical Aspects of Neoplasia
Effects of Tumor on Host
Cancer Cachexia
Paraneoplastic Syndromes
Grading and Staging of Cancer
Table 5–5 Paraneoplastic Syndromes
Summary
Clinical Aspects of Tumors
Laboratory Diagnosis of Cancer
Morphologic Methods
Figure 5–33 A, Normal Papanicolaou smear from the uterine cervix. Large, flat cells with small nuclei are typical. B, Abnormal smear containing a sheet of malignant cells with large hyperchromatic nuclei. Nuclear pleomorphism is evident, and one cell is in mitosis. A few interspersed neutrophils, much smaller in size and with compact, lobate nuclei, are seen.
Tumor Markers
Molecular Diagnosis
Molecular Profiling of Tumors
Expression Profiling
Figure 5–34 Diverse tumor types that share a common mutation, BRAF (V600E), may be candidates for treatments with the same drug, called PLX4032.
Whole Genome Sequencing
Figure 5–35 Complementary DNA (cDNA) microarray analysis. Messenger RNA (mRNA) is extracted from the samples, reverse transcribed to cDNA, and labeled with fluorescent molecules. In the case illustrated, red fluorescent molecules were used for normal cDNA, and green molecules were used for tumor cDNA. The labeled cDNAs are mixed and applied to a gene chip, which contains thousands of DNA probes representing known genes. The labeled cDNAs hybridize to spots that contain complementary sequences. The hybridization is detected by laser scanning of the chip, and the results are read in units of red or green fluorescence intensity. In the example shown, spot A has high red fluorescence, indicating that a greater number of cDNAs from neoplastic cells hybridized to gene A. Thus, gene A seems to be upregulated in tumor cells.
Figure 5–36 A paradigm shift: Classification of cancer according to therapeutic targets rather than cell of origin and morphology.
Summary
Laboratory Diagnosis of Cancer
Bibliography
Chapter 6 Genetic and Pediatric Diseases
Genetic Diseases
Nature of Genetic Abnormalities Contributing to Human Disease
Mutations in Protein-Coding Genes
Alterations in Protein-Coding Genes Other Than Mutations
Sequence and Copy Number Variations (Polymorphisms)
Epigenetic Changes
Alterations in Non-Coding RNAs
Figure 6–1 Generation of microRNAs and their mode of action in regulating gene function. pri-miRNA, primary microRNA transcript; pre-miRNA, precursor microRNA; RISC, RNA-induced silencing complex.
Mendelian Disorders: Diseases Caused by Single-Gene Defects
Table 6–1 Estimated Prevalence of Selected Mendelian Disorders Among Liveborn Infants
Table 6–2 Biochemical Basis and Inheritance Pattern for Selected Mendelian Disorders
Transmission Patterns of Single-Gene Disorders
Disorders of Autosomal Dominant Inheritance
Disorders of Autosomal Recessive Inheritance
X-Linked Disorders
Summary
Transmission Patterns of Single-Gene Disorders
Diseases Caused by Mutations in Genes Encoding Structural Proteins
Marfan Syndrome
Morphology
Ehlers-Danlos Syndromes
Summary
Marfan Syndrome
Ehlers-Danlos Syndromes
Diseases Caused by Mutations in Genes Encoding Receptor Proteins or Channels
Familial Hypercholesterolemia
Normal Cholesterol Metabolism
Figure 6–2 Low-density lipoprotein (LDL) metabolism and the role of the liver in its synthesis and clearance. Lipolysis of very-low-density lipoprotein (VLDL) by lipoprotein lipase in the capillaries releases triglycerides, which are then stored in fat cells and used as a source of energy in skeletal muscles. IDL (intermediate-density lipoprotein) remains in the blood and is taken up by the liver.
Pathogenesis of Familial Hypercholesterolemia
Summary
Familial Hypercholesterolemia
Cystic Fibrosis
Figure 6–3 The LDL receptor pathway and regulation of cholesterol metabolism. The yellow arrows show three regulatory functions of free intracellular cholesterol: (1) suppression of cholesterol synthesis by inhibition of HMG-CoA reductase, (2) stimulating the storage of excess cholesterol as esters, and (3) inhibition of synthesis of LDL receptors. HMG-CoA reductase, 3-hydroxy-3-methylglutaryl–coenzyme A reductase; LDL, low-density lipoprotein.
Figure 6–4 Top, In cystic fibrosis (CF), a chloride channel defect in the sweat duct causes increased chloride and sodium concentration in sweat. Bottom, Patients with CF have decreased chloride secretion and increased sodium and water reabsorption in the airways, leading to dehydration of the mucus layer coating epithelial cells, defective mucociliary action, and mucous plugging. CFTR, cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel responsible for intracellular sodium conduction.
Figure 6–5 Mild to moderate changes of cystic fibrosis in the pancreas. The ducts are dilated and plugged with eosinophilic mucin, and the parenchymal glands are atrophic and replaced by fibrous tissue.
Figure 6–6 Lungs of a patient who died of cystic fibrosis. Extensive mucous plugging and dilation of the tracheobronchial tree are apparent. The pulmonary parenchyma is consolidated by a combination of both secretions and pneumonia; the greenish discoloration is the product of Pseudomonas infections.
Pathogenesis
Morphology
Clinical Course
Table 6–3 Clinical Features and Diagnostic Criteria for Cystic Fibrosis
Summary
Cystic Fibrosis
Diseases Caused by Mutations in Genes Encoding Enzyme Proteins
Phenylketonuria
Figure 6–7 The phenylalanine hydroxylase system. NADH, nicotinamide adenine dinucleotide, reduced form.
Galactosemia
Summary
Phenylketonuria
Galactosemia
Lysosomal Storage Diseases
Figure 6–8 Pathogenesis of lysosomal storage diseases. In this example, a complex substrate is normally degraded by a series of lysosomal enzymes (A, B, and C) into soluble end products. If there is a deficiency or malfunction of one of the enzymes (e.g., B), catabolism is incomplete, and insoluble intermediates accumulate in the lysosomes.
Table 6–4 Lysosomal Storage Disorders
Tay-Sachs Disease (GM2 Gangliosidosis: Deficiency in Hexosaminidase β Subunit)
Figure 6–9 Ganglion cells in Tay-Sachs disease. A, Under the light microscope, a large neuron has obvious lipid vacuolation. B, A portion of a neuron under the electron microscope shows prominent lysosomes with whorled configurations. Part of the nucleus is shown above.
Niemann-Pick Disease Types A and B
Figure 6–10 Niemann-Pick disease in liver. The hepatocytes and Kupffer cells have a foamy, vacuolated appearance resulting from deposition of lipids.
Niemann-Pick Disease Type C
Gaucher Disease
Figure 6–11 Gaucher disease involving the bone marrow. A, Gaucher cells with abundant lipid-laden granular cytoplasm. B, Electron micrograph of Gaucher cells with elongated distended lysosomes.
Mucopolysaccharidoses
Summary
Lysosomal Storage Diseases
Glycogen Storage Diseases (Glycogenoses)
Table 6–5 Principal Subgroups of Glycogenoses
Summary
Glycogen Storage Diseases
Diseases Caused by Mutations in Genes Encoding Proteins That Regulate Cell Growth
Figure 6–12 Top, A simplified scheme of normal glycogen metabolism in the liver and skeletal muscles. Middle, The effects of an inherited deficiency of hepatic enzymes involved in glycogen metabolism. Bottom, The consequences of a genetic deficiency in the enzymes that metabolize glycogen in skeletal muscles.
Complex Multigenic Disorders
Cytogenetic Disorders
Figure 6–13 G-banded karyotype from a normal male (46,XY). Also shown is the banding pattern of the X-chromosome with nomenclature of arms, regions, bands, and sub-bands.
Numeric Abnormalities
Structural Abnormalities
Figure 6–14 Types of chromosomal rearrangements.
General Features of Chromosomal Disorders
Cytogenetic Disorders Involving Autosomes
Trisomy 21 (Down Syndrome)
22q11.2 Deletion Syndrome
Figure 6–15 Clinical features and karyotypes of the three most common autosomal trisomies.
Summary
Cytogenetic Disorders Involving Autosomes
Cytogenetic Disorders Involving Sex Chromosomes
Klinefelter Syndrome
Turner Syndrome
Figure 6–16 Clinical features and karyotypes of Turner syndrome.
Summary
Cytogenetic Disorders Involving Sex Chromosomes
Single-Gene Disorders with Atypical Patterns of Inheritance
Triplet Repeat Mutations: Fragile X Syndrome
Figure 6–17 Fragile X pedigree. X and Y chromosomes are shown. Note that in the first generation, all sons are normal and all females are carriers. During oogenesis in the carrier female, premutation expands to full mutation; hence, in the next generation, all males who inherit the X with full mutation are affected. However, only 50% of females who inherit the full mutation are affected, and often only mildly.
Figure 6–18 A model for the action of familial mental retardation protein (FMRP) in neurons. FMRP plays a critical role in regulating the translation of axonal proteins from bound RNAs. These locally produced proteins, in turn, play diverse roles in the microenvironment of the synapse.
Pathogenesis
Summary
Fragile X Syndrome
Diseases Caused by Mutations in Mitochondrial Genes
Diseases Caused by Alterations of Imprinted Regions: Prader-Willi and Angelman Syndromes
Figure 6–19 Sites of expansion and the affected sequence in selected diseases caused by nucleotide repeat mutations. UTR, untranslated region. *Though not strictly a trinucleotide-repeat disease, progressive myoclonus epilepsy is caused, like others in this group, by a heritable DNA expansion. The expanded segment is in the promoter region of the gene.
Figure 6–20 Genetics of Angelman and Prader-Willi syndromes.
Summary
Genomic Imprinting
Pediatric Diseases
Table 6–6 Causes of Death by Age
Congenital Anomalies
Figure 6–21 Human malformations can range in severity from the incidental to the lethal. A, Polydactyly (one or more extra digits) and syndactyly (fusion of digits), have little functional consequence when they occur in isolation. B, Similarly, cleft lip, with or without associated cleft palate, is compatible with life when it occurs as an isolated anomaly; in this case, however, the child had an underlying malformation syndrome (trisomy 13) and expired because of severe cardiac defects. C, Stillbirth representing a severe and essentially lethal malformation, in which the midface structures are fused or ill-formed; in almost all cases, this degree of external dysmorphogenesis is associated with severe internal anomalies such as maldevelopment of the brain and cardiac defects.
Figure 6–22 Disruptions occur in a developing organ because of an extrinsic abnormality that interferes with normal morphogenesis. Amniotic bands are a frequent cause of disruptions. In the gross specimen shown, the placenta is at the right of the diagram, and the band of amnion extends from the top portion of the amniotic sac to encircle the leg of the fetus.
Figure 6–23 A, Pathogenesis of the oligohydramnios (Potter) sequence. B, Infant with oligohydramnios (Potter) sequence. Note flattened facial features and deformed foot (talipes equinovarus).
Etiology
Table 6–7 Causes of Congenital Malformations in Humans
Pathogenesis
Summary
Congenital Anomalies
Perinatal Infections
Prematurity and Fetal Growth Restriction
Respiratory Distress Syndrome of the Newborn
Pathogenesis
Morphology
Figure 6–24 Pathophysiology of respiratory distress syndrome (see text).
Clinical Features
Figure 6–25 Hyaline membrane disease (hematoxylin-eosin stain). Alternating atelectasis and dilation of the alveoli can be seen. Note the eosinophilic thick hyaline membranes lining the dilated alveoli.
Summary
Neonatal Respiratory Distress Syndrome
Necrotizing Enterocolitis
Figure 6–26 Necrotizing enterocolitis. A, At postmortem examination in a severe case, the entire small bowel was markedly distended with a perilously thin wall (usually this appearance implies impending perforation). B, The congested portion of the ileum corresponds to areas of hemorrhagic infarction and transmural necrosis seen on microscopy. Submucosal gas bubbles (pneumatosis intestinalis) can be seen in several areas (arrows).
Sudden Infant Death Syndrome
Table 6–8 Factors Associated with Sudden Infant Death Syndrome (SIDS)
Pathogenesis
Morphology
Summary
Sudden Infant Death Syndrome
Fetal Hydrops
Immune Hydrops
Table 6–9 Major Causes of Fetal Hydrops*
Figure 6–27 Hydrops fetalis. A, Generalized accumulation of fluid in the fetus. B, Fluid accumulation particularly prominent in the soft tissues of the neck. This condition has been termed cystic hygroma. Cystic hygromas are characteristically seen with, but not limited to, constitutional chromosomal anomalies such as 45,X karyotypes.
Nonimmune Hydrops
Figure 6–28 Bone marrow from an infant infected with parvovirus B19. The arrows point to two erythroid precursors with large homogeneous intranuclear inclusions and a surrounding peripheral rim of residual chromatin.
Figure 6–29 Numerous islands of extramedullary hematopoiesis (small blue cells) are scattered among mature hepatocytes in this histologic preparation from an infant with nonimmune hydrops fetalis.
Morphology
Clinical Course
Figure 6–30 Kernicterus. Severe hyperbilirubinemia in the neonatal period—for example, secondary to immune hydrolysis—results in deposition of bilirubin pigment (arrows) in the brain parenchyma. This occurs because the blood–brain barrier is less well developed in the neonatal period than it is in adulthood. Infants who survive develop long-term neurologic sequelae.
Summary
Fetal Hydrops
Tumors and Tumor-Like Lesions of Infancy and Childhood
Benign Tumors
Figure 6–31 Congenital capillary hemangioma at birth (A) and at 2 years of age (B) after the lesion had undergone spontaneous regression.
Malignant Tumors
Figure 6–32 Sacrococcygeal teratoma. Note the size of the lesion compared with that of the infant.
Table 6–10 Common Malignant Neoplasms of Infancy and Childhood
Neuroblastoma
Figure 6–33 A, Neuroblastoma. This tumor is composed of small cells embedded in a finely fibrillar matrix (neuropil). A Homer-Wright pseudo-rosette (tumor cells arranged concentrically around a central core of neuropil) is seen in the upper right corner. B, Ganglioneuromas, arising from spontaneous or therapy-induced maturation of neuroblastomas, are characterized by clusters of large cells with vesicular nuclei and abundant eosinophilic cytoplasm (arrow), representing neoplastic ganglion cells. Spindle-shaped Schwann cells are present in the background stroma.
Morphology
Clinical Course and Prognosis
Table 6–11 Staging of Neuroblastomas
Summary
Neuroblastoma
Retinoblastoma
Morphology
Clinical Features
Figure 6–34 Retinoblastoma. A, Poorly cohesive tumor in retina is seen abutting the optic nerve. B, Higher-power view showing Flexner-Wintersteiner rosettes (arrow) and numerous mitotic figures.
Wilms Tumor
Figure 6–35 Wilms tumor in the lower pole of the kidney with the characteristic tan to gray color and well-circumscribed margins.
Morphology
Clinical Course
Figure 6–36 A, Wilms tumor with tightly packed blue cells consistent with the blastemal component and interspersed primitive tubules, representing the epithelial component. Although multiple mitotic figures are seen, none are atypical in this field. B, Focal anaplasia was present in other areas within this Wilms tumor, characterized by cells with hyperchromatic, pleomorphic nuclei and abnormal mitoses.
Summary
Wilms Tumor
Molecular Diagnosis of Mendelian and Complex Disorders
Molecular Diagnosis of Copy Number Abnormalities
Fluorescence in Situ Hybridization (FISH)
Array-Based Genomic Hybridization
Figure 6–37 Fluorescence in situ hybridization (FISH). A, Interphase nucleus from a male patient with suspected trisomy 18. Three different fluorescent probes have been used in a “FISH cocktail”; the green probe hybridizes to the X chromosome centromere (one copy), the red probe to the Y chromosome centromere (one copy), and the aqua probe to the chromosome 18 centromere (three copies). B, A metaphase spread in which two fluorescent probes have been used, one hybridizing to chromosome region 22q13 (green) and the other hybridizing to chromosome region 22q11.2 (red). There are two 22q13 signals. One of the two chromosomes does not stain with the probe for 22q11.2, indicating a microdeletion in this region. This abnormality gives rise to the 22q11.2 deletion syndrome (DiGeorge syndrome).
Direct Detection of DNA Mutations by Polymerase Chain Reaction (PCR) Analysis
Figure 6–38 Array comparative genomic hybridization (CGH) is performed by hybridization of fluorescently labeled test DNA and control DNA on a slide that contains thousands of probes corresponding to defined chromosomal regions across the human genome. The resolution with most currently available array CGH technology is on the order of approximately 10 kb. A, Higher-power view of the array demonstrates copy number aberrations in the test Cy5-labeled sample (red), including regions of amplification (spots with excess of red signal) and deletion (spots with excess of green signal); yellow spots correspond to regions of normal (diploid) copy number. B, The hybridization signals are digitized, resulting in a virtual karyotype of the genome of the “test” sample. In the illustrated example, array CGH of a cancer cell line identifies an amplification on the distal long arm of chromosome 8, which corresponds to increased copy number of the oncogene MYC.
Figure 6–39 Microarray-based DNA sequencing. Left panel, A low-power digitized scan of a “gene chip” that is no larger than a nickel in size but is capable of sequencing thousands of base pairs of DNA. High-throughput microarrays have been used for sequencing whole organisms (such as viruses), organelles (such as the mitochondria), and entire human chromosomes. Right panel, A high-resolution view of the gene chip illustrates hybridization patterns corresponding to a stretch of DNA sequence. Typically, a computerized algorithm is available that can convert the individual hybridization patterns across the entire chip into actual sequence data within a matter of minutes (“conventional” sequencing technologies would require days to weeks for such analysis). Here, the sequence on top is the reference (wild-type) sequence, while the lower one corresponds to the test sample sequence. As shown, the computerized algorithm has identified a C→G mutation in the test sample.
Figure 6–40 Allele-specific polymerase chain reaction (PCR) analysis for mutation detection in a heterogeneous sample containing an admixture of normal and mutant DNA. Nucleotides complementary to the mutant and wild-type nucleotides at the queried base position are labeled with different fluorophores such that incorporation into the resulting PCR product yields fluorescent signals of variable intensity in accordance with the ratio of mutant to wild-type DNA present.
Linkage Analysis and Genome-Wide Association Studies
Figure 6–41 Principle of next-generation sequencing. Several alternative approaches currently are available for “NextGen” sequencing, and one of the more commonly used platforms is illustrated. A, Short fragments of genomic DNA (“template”) between 100 and 500 base pairs in length are immobilized on a solid phase platform such as a glass slide, using universal capture primers that are complementary to adapters that have previously been added to ends of the template fragments. The addition of fluorescently labeled complementary nucleotides, one per template DNA per cycle, occurs in a “massively parallel” fashion, at millions of templates immobilized on the solid phase at the same time. A four-color imaging camera captures the fluorescence emanating from each template location (corresponding to the specific incorporated nucleotide), following which the fluorescent dye is cleaved and washed away, and the entire cycle is repeated. B, Powerful computational programs can decipher the images to generate sequences complementary to the template DNA at the end of one “run,” and these sequences are then mapped back to the reference genomic sequence, in order to identify alterations.
Indications for Genetic Analysis
Bibliography
Chapter 7 Environmental and Nutritional Diseases
Health Effects of Climate Change
Figure 7–1 Climate change, past and future. A, Correlation of CO2 levels measured at the Mauna Loa Observatory in Hawaii with average global temperature trends over the past 50 years. “Global temperature” in any given year was deduced at the Hadley Center (United Kingdom) from measurements taken at over 3000 weather stations located around the globe. B, Predicted temperature increases during the 21st century. Different computer models plot anticipated rises in global temperatures of 2°C to 5°C by the year 2100.
Toxicity of Chemical and Physical Agents
Figure 7–2 Human exposure to pollutants. Pollutants contained in air, water, and soil are absorbed through the lungs, gastrointestinal tract, and skin. In the body, they may act at the site of absorption, but they generally are transported through the bloodstream to various organs, where they may be stored or metabolized. Metabolism of xenobiotics may result in the formation of water-soluble compounds, which are excreted, or in activation of the agent, creating a toxic metabolite.
Figure 7–3 Xenobiotic metabolism. Xenobiotics can be metabolized to nontoxic metabolites and eliminated from the body (detoxification). However, their metabolism also may result in activation of the chemical, leading to formation of a reactive metabolite that is toxic to cellular components. If repair is not effective, short- and long-term effects develop.
Environmental Pollution
Air Pollution
Outdoor Air Pollution
Table 7–1 Health Effects of Outdoor Air Pollutants
Morphology
Indoor Air Pollution
Summary
Environmental Diseases and Environmental Pollution
Metals as Environmental Pollutants
Lead
Figure 7–4 Pathologic features of lead poisoning.
Morphology
Figure 7–5 Lead poisoning. Impaired remodeling of calcified cartilage in the epiphyses (arrows) of the wrist has caused a marked increase in their radiodensity, so that they are as radiopaque as the cortical bone.
Mercury
Arsenic
Cadmium
Summary
Toxic Effects of Heavy Metals
Industrial and Agricultural Exposures
Table 7–2 Human Diseases Associated With Occupational Exposures
Effects of Tobacco
Figure 7–6 The effects of smoking on survival. The study compared age-specific death rates for current cigarette smokers with that of individuals who never smoke regularly (British Doctors Study). The difference in survival, measured at age 75, between smokers and nonsmokers is 7.5 years.
Figure 7–7 Adverse effects of smoking. The more common are in boldface.
Table 7–3 Effects of Selected Tobacco Smoke Constituents
Table 7–4 Organ-Specific Carcinogens in Tobacco Smoke
Figure 7–8 The risk of lung cancer is determined by the number of cigarettes smoked.
Figure 7–9 Multiplicative increase in the risk of laryngeal cancer from the interaction between cigarette smoking and alcohol consumption.
Summary
Health Effects of Tobacco
Effects of Alcohol
Figure 7–10 Metabolism of ethanol: oxidation of ethanol to acetaldehyde by three different routes, and the generation of acetic acid. Note that oxidation by alcohol dehydrogenase (ADH) takes place in the cytosol; the cytochrome P-450 system and its CYP2E1 isoform are located in the ER (microsomes), and catalase is located in peroxisomes. Oxidation of acetaldehyde by aldehyde dehydrogenase (ALDH) occurs in mitochondria.
Summary
Alcohol—Metabolism and Health Effects
Injury by Therapeutic Drugs and Drugs of Abuse
Injury by Therapeutic Drugs: Adverse Drug Reactions
Figure 7–11 Adverse reaction to minocycline, a long-acting tetracycline derivative. A, Diffuse blue-gray pigmentation of the forearm, secondary to minocycline administration. B, Deposition of drug metabolite/iron/melanin pigment particles in the dermis.
Exogenous Estrogens and Oral Contraceptives
Exogenous Estrogens
Table 7–5 Some Common Adverse Drug Reactions and Their Agents
Oral Contraceptives
Acetaminophen
Aspirin (Acetylsalicylic Acid)
Injury by Nontherapeutic Toxic Agents (Drug Abuse)
Cocaine
Table 7–6 Common Drugs of Abuse
Heroin
Figure 7–12 The effect of cocaine on neurotransmission. The drug inhibits reuptake of the neurotransmitters dopamine and norepinephrine in the central and peripheral nervous systems.
Marijuana
Other Illicit Drugs
Figure 7–13 A, Laceration of the scalp: The bridging strands of fibrous tissues are evident. B, Contusion resulting from blunt trauma. The skin is intact, but hemorrhage of subcutaneous vessels has produced extensive discoloration.
Summary
Drug Injury
Injury by Physical Agents
Mechanical Trauma
Morphology
Thermal Injury
Thermal Burns
Morphology
Hyperthermia
Hypothermia
Electrical Injury
Injury Produced by Ionizing Radiation
DNA Damage and Carcinogenesis
Fibrosis
Figure 7–14 Effects of ionizing radiation on DNA and their consequences. The effects on DNA can be direct or, most important, indirect, through free radical formation.
Figure 7–15 Vascular changes and fibrosis of salivary glands produced by radiation therapy of the neck region. A, Normal salivary gland; B, fibrosis caused by radiation; C, fibrosis and vascular changes consisting of fibrointimal thickening and arteriolar sclerosis. V, vessel lumen; I, thickened intima.
Morphology
Effects on Organ Systems
Figure 7–16 Overview of the major morphologic consequences of radiation injury. Early changes occur in hours to weeks; late changes occur in months to years. ARDS, acute respiratory distress syndrome.
Table 7–7 Estimated Threshold Doses for Acute Radiation Effects on Specific Organs
Table 7–8 Effects of Whole-Body Ionizing Radiation
Total-Body Irradiation
Summary
Radiation Injury
Nutritional Diseases
Malnutrition
Protein-Energy Malnutrition
Marasmus
Kwashiorkor
Figure 7–17 Childhood malnutrition. A, Marasmus. Note the loss of muscle mass and subcutaneous fat; the head appears to be too large for the emaciated body. B, Kwashiorkor. The infant shows generalized edema, seen as ascites and puffiness of the face, hands, and legs.
Secondary Protein-Energy Malnutrition
Morphology
Anorexia Nervosa and Bulimia
Vitamin Deficiencies
Vitamin A
Function
Figure 7–18 Vitamin A metabolism.
Deficiency States
Figure 7–19 Vitamin A deficiency: major consequences in the eye and in the production of keratinizing metaplasia of specialized epithelial surfaces, and its possible role in epithelial metaplasia. Not depicted are night blindness and immune deficiency.
Vitamin A Toxicity
Vitamin D
Metabolism
Figure 7–20 A, Normal vitamin D metabolism. B, Vitamin D deficiency. There is inadequate substrate for the renal hydroxylase (1), yielding a deficiency of 1,25-(OH)2D (2), and deficient absorption of calcium and phosphorus from the gut (3), with consequent depressed serum levels of both (4). The hypocalcemia activates the parathyroid glands (5), causing mobilization of calcium and phosphorus from bone (6a). Simultaneously, parathyroid hormone (PTH) induces wasting of phosphate in the urine (6b) and calcium retention. Consequently, the serum levels of calcium are normal or nearly normal, but the phosphate is low; hence, mineralization is impaired (7).
Functions
Deficiency States
Figure 7–21 Rickets. A, Normal costochondral junction of a young child. Note cartilage palisade formation and orderly transition from cartilage to new bone. B, Rachitic costochondral junction in which the palisade of cartilage is absent. Darker trabeculae are well-formed bone; paler trabeculae consist of uncalcified osteoid. C, Note bowing of legs as a consequence of the formation of poorly mineralized bone in a child with rickets.
Morphology
Toxicity
Vitamin C (Ascorbic Acid)
Figure 7–22 Major consequences of vitamin C deficiency caused by impaired formation of collagen. They include bleeding tendency due to poor vascular support, inadequate formation of osteoid matrix, and impaired wound healing.
Function
Deficiency States
Toxicity
Summary
Nutritional Diseases
Obesity
Table 7–9 Vitamins: Major Functions and Deficiency Syndromes
Table 7–10 Selected Trace Elements and Deficiency Syndromes
Figure 7–23 Energy balance regulatory circuitry. When sufficient energy is stored in adipose tissue and the individual is well fed, afferent adiposity signals (insulin, leptin, ghrelin, peptide YY) are delivered to the central neuronal processing units, in the hypothalamus. Here the adiposity signals inhibit anabolic circuits and activate catabolic circuits. The effector arms of these central circuits then influence energy balance by inhibiting food intake and promoting energy expenditure. This in turn reduces the energy stores, and pro-adiposity signals are blunted. Conversely, when energy stores are low, the available anabolic circuits take over, at the expense of catabolic circuits, to generate energy stores in the form of adipose tissue.
Leptin
Adipose Tissue
Gut Hormones
Clinical Consequences of Obesity
Summary
Obesity
Diet and Systemic Diseases
Diet and Cancer
Bibliography
Chapter 8 General Pathology of Infectious Diseases
General Principles of Microbial Pathogenesis
Categories of Infectious Agents
Prions
Viruses
Table 8–1 Classes of Human Pathogens
Table 8–2 Selected Human Viral Diseases and Their Pathogens
Figure 8–1 Examples of viral inclusions. A, Cytomegalovirus infection in the lung. Infected cells show distinct nuclear (long arrow) and ill-defined cytoplasmic (short arrows) inclusions. B, Varicella-zoster virus infection in the skin. Herpes simplex virus and varicella-zoster virus both cause characteristic cytopathologic changes, including fusion of epithelial cells, which produces multinucleate cells with molding of nuclei to one another (long arrow), and eosinophilic haloed nuclear inclusions (short arrow). C, Hepatitis B viral infection in liver. In chronic infections, infected hepatocytes show diffuse granular (“ground-glass”) cytoplasm, reflecting accumulated hepatitis B surface antigen (HBsAg).
Bacteria
Figure 8–2 Molecules on the surface of gram-negative and gram-positive bacteria involved in the pathogenesis of infection.
Figure 8–3 The variety of bacterial morphology. The bacteria are indicated by arrows. A, Gram stain preparation of sputum from a patient with pneumonia. Gram-positive, elongated cocci in pairs and short chains (Streptococcus pneumoniae) and a neutrophil are evident. B, Gram stain preparation of a bronchoalveolar lavage specimen showing gram-negative intracellular rods typical of members of Enterobacteriaceae such as Klebsiella pneumoniae or Escherichia coli. C, Silver stain preparation of brain tissue from a patient with Lyme disease meningoencephalitis. Two helical spirochetes (Borrelia burgdorferi) are indicated by arrows. A, B, and C are at different magnifications.
Table 8–3 Selected Human Bacterial Diseases and Their Pathogens
Normal Microbiome
Fungi
Figure 8–4 Meningeal blood vessels with angioinvasive Mucor species. Note the irregular width and near right-angle branching of the hyphae.
Protozoa
Helminths
Figure 8–5 Coiled Trichinella spiralis larva within a skeletal muscle cell.
Ectoparasites
Special Techniques for Identifying Infectious Agents
Table 8–4 Special Techniques for Identifying Infectious Agents
New and Emerging Infectious Diseases
Agents of Bioterrorism
Table 8–5 Potential Agents of Bioterrorism
Transmission and Dissemination of Microbes
Routes of Entry of Microbes
Skin
Gastrointestinal Tract
Respiratory Tract
Urogenital Tract
Spread and Dissemination of Microbes Within the Body
Figure 8–6 Routes of entry and dissemination of microbes. To enter the body, microbes penetrate epithelial or mucosal barriers. Infection may remain localized at the site of entry or spread to other sites in the body. Most common microbes (selected examples are shown) spread through the lymphatics or bloodstream (either freely or within inflammatory cells). However, certain viruses and bacterial toxins also may travel through nerves.
Release from the Body and Transmission of Microbes
Summary
Transmission of Microbes
How Microorganisms Cause Disease
Mechanisms of Viral Injury
Figure 8–7 Mechanisms by which viruses cause injury to cells.
Mechanisms of Bacterial Injury
Bacterial Virulence
Bacterial Adherence to Host Cells
Virulence of Intracellular Bacteria
Bacterial Toxins
Figure 8–8 Mechanism of anthrax exotoxin action. The B component, also called “protective antigen,” binds a cell-surface protein, is cleaved by a host protease, and forms a heptamer. Three A subunits of edema factor (EF) or lethal factor (LF) bind to the B heptamer, enter the cell, and are released into the cytoplasm. EF binds calcium and calmodulin to form an adenylate cyclase that increases intracellular cAMP, which causes efflux of water and interstitial edema. LF is a protease that destroys mitogen-activated protein kinase kinases (MAPKKs), leading to cell death. cAMP, cyclic adenosine monophosphate.
Injurious Effects of Host Immune Responses
Summary
How Microorganisms Cause Disease
Immune Evasion by Microbes
Figure 8–9 An overview of mechanisms used by viral and bacterial pathogens to evade innate and adaptive immunity.
Table 8-6 Mechanisms of Antigenic Variation
Summary
Immune Evasion by Microbes
Spectrum of Inflammatory Responses to Infection
Suppurative (Purulent) Inflammation
Figure 8–10 Pneumococcal pneumonia. Note the intra-alveolar polymorphonuclear exudate and intact alveolar septa.
Morphology
Mononuclear and Granulomatous Inflammation
Figure 8–11 Mononuclear and granulomatous inflammation. A, Acute viral hepatitis characterized by a predominantly lymphocytic infiltrate. B, Secondary syphilis in the dermis with perivascular lymphoplasmacytic infiltrate and endothelial proliferation. C, Granulomatous inflammation in response to tuberculosis. Note the zone of caseation (asterisk), which normally forms the center of the granuloma, with a surrounding rim of activated epithelioid macrophages, some of which have fused to form giant cells (arrows); this in turn is surrounded by a zone of activated T lymphocytes. This high-magnification view highlights the histologic features; the granulomatous response typically takes the form of a three-dimensional sphere with the offending organism in the central area.
Morphology
Cytopathic-Cytoproliferative Reaction
Morphology
Tissue Necrosis
Figure 8–12 Schistosoma haematobium infection of the bladder with numerous calcified eggs and extensive scarring.
Morphology
Chronic Inflammation and Scarring
Morphology
Infections in People with Immunodeficiencies
Figure 8–13 In the absence of appropriate T cell–mediated immunity, granulomatous host response does not occur. Mycobacterium avium infection in a patient with AIDS, showing massive intracellular macrophage infection with acid-fast organisms (filamentous and pink in this acid-fast stain preparation). The intracellular bacteria persist and even proliferate within macrophages, because there are inadequate T cells to mount a granulomatous response. AIDS, acquired immunodeficiency syndrome.
Morphology
Summary
Patterns of Host Responses to Microbes
Bibliography
Chapter 9 Blood Vessels
Structure and Function of Blood Vessels
Figure 9–1 Regional vascular specializations. Although all vessels share the same general constituents, the thickness and composition of the various layers differ as a function of hemodynamic forces and tissue requirements.
Vascular Organization
Endothelial Cells
Table 9–1 Endothelial Cell Properties and Functions
Figure 9–2 Basal and activated endothelial cell states. Normal blood pressure, laminar flow, and stable growth factor levels promote a basal endothelial cell state that maintains a nonthrombotic surface and appropriate vascular wall smooth muscle tone. Injury or exposure to certain mediators results in endothelial activation, a state in which endothelial cells have adhesive, procoagulant surfaces and release factors that lead to smooth muscle contraction and/or proliferation and matrix synthesis.
Vascular Smooth Muscle Cells
Summary
Vascular Structure and Function
Congenital Anomalies
Blood Pressure Regulation
Figure 9–3 Blood pressure regulation.
Figure 9–4 Interplay of renin, angiotensin, aldosterone, and atrial natriuretic peptide in blood pressure regulation (see text).
Summary
Blood Pressure Regulation
Hypertensive Vascular Disease
Epidemiology of Hypertension
Table 9–2 Types and Causes of Hypertension (Systolic and Diastolic)
Figure 9–5 Hypertensive vascular disease. A, Hyaline arteriolosclerosis. The arteriolar wall is thickened with the deposition of amorphous proteinaceous material (hyalinized), and the lumen is markedly narrowed. B, Hyperplastic arteriolosclerosis (“onion-skinning”) (arrow) causing luminal obliteration (periodic acid–Schiff stain).
Pathogenesis
Mechanisms of Essential Hypertension
Morphology
Summary
Hypertension
Vascular Wall Response to Injury
Intimal Thickening: A Stereotypical Response to Vascular Injury
Figure 9–6 Stereotypical response to vascular injury. Schematic diagram of intimal thickening, emphasizing intimal smooth muscle cell migration and proliferation associated with extracellular matrix synthesis. Intimal smooth muscle cells may derive from the underlying media or may be recruited from circulating precursors; they are depicted in a color different from that of the medial smooth muscle cells, to emphasize their distinct phenotype.
Arteriosclerosis
Atherosclerosis
Epidemiology of Atherosclerosis
Figure 9–7 The basic structure of an atheromatous plaque.
Constitutional Risk Factors
Table 9–3 Major Risk Factors for Atherosclerosis
Modifiable Major Risk Factors
Figure 9–8 Estimated 10-year risk of coronary artery disease in 55-year-old men and women as a function of established risk factors—hyperlipidemia, hypertension, smoking, and diabetes. BP, blood pressure; ECG, electrocardiogram; HDL-C, high-density lipoprotein cholesterol; LVH, left ventricular hypertrophy.
Additional Risk Factors
Figure 9–9 Prognostic value of C-reactive protein (CRP) in coronary artery disease. Relative risk (y-axis) reflects the risk of a cardiovascular event (e.g., myocardial infarction). The x-axis shows the 10-year risk of a cardiovascular event calculated from the traditional risk factors identified in the Framingham Study. In each risk group, CRP levels further stratify the patients.
Figure 9–10 Response to injury in atherogenesis: 1, Normal. 2, Endothelial injury with monocyte and platelet adhesion. 3, Monocyte and smooth muscle cell migration into the intima, with macrophage activation. 4, Macrophage and smooth muscle cell uptake of modified lipids and further activation. 5, Intimal smooth muscle cell proliferation with ECM elaboration, forming a well-developed plaque.
Figure 9–11 Fatty streaks. A, Aorta with fatty streaks (arrows), mainly near the ostia of branch vessels. B, Fatty streak in an experimental hypercholesterolemic rabbit, demonstrating intimal, macrophage-derived foam cells (arrow).
Figure 9–12 Atherosclerotic lesions. A, Aorta with mild atherosclerosis composed of fibrous plaques, one denoted by the arrow. B, Aorta with severe diffuse complicated lesions, including an ulcerated plaque (open arrow), and a lesion with overlying thrombus (closed arrow).
Figure 9–13 Atherosclerotic plaque in the coronary artery. A, Overall architecture demonstrating fibrous cap (F) and a central necrotic (largely lipid) core (C); collagen (blue) is stained with Masson trichrome. The lumen (L) is moderately narrowed by this eccentric lesion, which leaves part of the vessel wall unaffected (arrow). B, Moderate-power view of the plaque shown in A, stained for elastin (black); the internal and external elastic membranes are attenuated and the media of the artery is thinned under the most advanced plaque (arrow). C, High-power view of the junction of the fibrous cap and core, showing scattered inflammatory cells, calcification (arrowheads), and neovascularization (small arrows).
Pathogenesis
Endothelial Injury
Hemodynamic Disturbances
Lipids
Inflammation
Infection
Smooth Muscle Proliferation and Matrix Synthesis
Morphology
Fatty Streaks
Atherosclerotic Plaque
Clinical Consequences of Atherosclerotic Disease
Figure 9–14 Summary of the natural history, morphologic features, main pathogenic events, and clinical complications of atherosclerosis.
Atherosclerotic Stenosis
Acute Plaque Change
Figure 9–15 Vulnerable and stable atherosclerotic plaque. Stable plaques have densely collagenized and thickened fibrous caps with minimal inflammation and negligible underlying atheromatous cores, whereas vulnerable plaques have thin fibrous caps, large lipid cores, and increased inflammation.
Figure 9–16 Atherosclerotic plaque rupture. A, Plaque rupture without superimposed thrombus, in a patient who died suddenly. B, Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal myocardial infarction. In both A and B, an arrow points to the site of plaque rupture.
Morphology
Summary
Atherosclerosis
Aneurysms and Dissections
Figure 9–17 Aneurysms. A, Normal vessel. B, True aneurysm, saccular type. The wall bulges outward and may be attenuated but is otherwise intact. C, True aneurysm, fusiform type. There is circumferential dilation of the vessel. D, False aneurysm. The wall is ruptured, creating a collection of blood (hematoma) bounded externally by adherent extravascular tissues. E, Dissection. Blood has entered the wall of the vessel and separated (dissected) the layers.
Figure 9–18 Cystic medial degeneration. A, Cross-section of aortic media from a patient with Marfan syndrome, showing marked elastin fragmentation and areas devoid of elastin that resemble cystic spaces (asterisks). B, Normal media for comparison, showing the regular layered pattern of elastic tissue. In both A and B, elastin is stained black.
Pathogenesis
Abdominal Aortic Aneurysm
Morphology
Clinical Consequences
Figure 9–19 Abdominal aortic aneurysm. A, External view of a large aortic aneurysm that ruptured at the site is indicated by the arrow. B, Opened view, with the location of the rupture tract indicated by a probe. The wall of the aneurysm is attenuated, and the lumen is filled by a large, layered thrombus.
Thoracic Aortic Aneurysm
Aortic Dissection
Figure 9–20 Aortic dissection. A, An opened aorta with a proximal dissection originating from a small, oblique intimal tear (identified by the probe) associated with an intramural hematoma. Note that the intimal tear occurred in a region largely free of atherosclerotic plaque. The distal edge of the intramural hematoma (black arrows) lies at the edge of a large area of atherosclerosis (white arrow), which arrested the propagation of the dissection. B, Histologic preparation showing the dissection and intramural hematoma (asterisk). Aortic elastic layers are black and blood is red in this section, stained with the Movat stain.
Pathogenesis
Morphology
Clinical Consequences
Figure 9–21 Classification of dissections. Type A (proximal) involves the ascending aorta, either as part of a more extensive dissection (DeBakey type I), or in isolation (DeBakey type II). Type B (distal, or DeBakey type III) dissections arise after the takeoff of the great vessels.
Summary
Aneurysms and Dissections
Vasculitis
Noninfectious Vasculitis
Immune Complex–Associated Vasculitis
Figure 9–22 Vascular sites involved in the more common vasculitides and their presumptive etiology. Note the considerable overlap in distributions. ANCA, anti-neutrophil cytoplasmic antibody; SLE, systemic lupus erythematosus.
Anti-Neutrophil Cytoplasmic Antibodies
Anti-Endothelial Cell Antibodies
Giant Cell (Temporal) Arteritis
Figure 9–23 Temporal (giant cell) arteritis. A, H&E-stained section of temporal artery showing giant cells near the fragmented internal elastic membrane (arrow), along with medial and adventitial inflammation. B, Elastic tissue stain demonstrating focal destruction of the internal elastic membrane (arrow) and associated medial attenuation and scarring. H&E, hematoxylin-eosin.
Pathogenesis
Morphology
Clinical Features of Giant Cell Arteritis
Takayasu Arteritis
Figure 9–24 Takayasu arteritis. A, Aortic arch angiogram showing reduced flow of contrast material into the great vessels and narrowing of the brachiocephalic, carotid, and subclavian arteries (arrows). B, Cross-sections of the right carotid artery from the patient shown in A demonstrating marked intimal thickening and luminal narrowing. The white circles correspond to the original vessel wall; the inner core of tan tissue is the area of intimal hyperplasia. C, Histologic appearance in active Takayasu aortitis illustrating destruction and fibrosis of the arterial media associated with mononuclear infiltrates and inflammatory giant cells (arrows).
Morphology
Clinical Features of Takayasu Aortitis
Polyarteritis Nodosa
Morphology
Clinical Features of PAN
Figure 9–25 Polyarteritis nodosa, associated with segmental fibrinoid necrosis and thrombotic occlusion of a small artery. Note that part of the vessel (upper right, arrow) is uninvolved.
Kawasaki Disease
Morphology
Clinical Features of Kawasaki Disease
Microscopic Polyangiitis
Figure 9–26 ANCA-associated small vessel vasculitis. A, Microscopic polyangiitis (leukocytoclastic vasculitis) with fragmented neutrophils in the thickened vessel wall. B and C, Wegener granulomatosis. B, Vasculitis of a small artery with adjacent granulomatous inflammation including giant cells (arrows). C, Lung from a patient with Wegener granulomatosis, demonstrating large nodular cavitating lesions.
Morphology
Clinical Features of Microscopic Polyangiitis
Wegener Granulomatosis
Morphology
Clinical Features of Wegener Granulomatosis
Churg-Strauss Syndrome
Thromboangiitis Obliterans (Buerger Disease)
Morphology
Clinical Features of Buerger Disease
Figure 9–27 Thromboangiitis obliterans (Buerger disease). The lumen is occluded by thrombus containing abscesses (arrow) and the vessel wall is infiltrated with leukocytes.
Vasculitis Associated with Other Noninfectious Disorders
Infectious Vasculitis
Summary
Vasculitis
Disorders of Blood Vessel Hyperreactivity
Raynaud Phenomenon
Myocardial Vessel Vasospasm
Veins and Lymphatics
Varicose Veins of the Extremities
Clinical Features of Varicose Veins
Varicosities of Other Sites
Thrombophlebitis and Phlebothrombosis
Superior and Inferior Vena Cava Syndromes
Lymphangitis and Lymphedema
Tumors
Table 9–4 Classification of Vascular Tumors and Tumor-like Conditions
Benign Tumors and Tumor-Like Conditions
Vascular Ectasias
Hemangiomas
Figure 9–28 Hemangiomas. A, Hemangioma of the tongue. B, Histologic appearance in juvenile capillary hemangioma. C, Pyogenic granuloma of the lip. D, Histologic appearance in cavernous hemangioma.
Lymphangiomas
Figure 9–29 Bacillary angiomatosis. A, Characteristic cutaneous lesion. B, Histologic features are those of acute inflammation and capillary proliferation. Inset, Modified silver (Warthin-Starry) stain demonstrates clusters of tangled bacilli (black).
Glomus Tumors (Glomangiomas)
Bacillary Angiomatosis
Intermediate-Grade (Borderline) Tumors
Kaposi Sarcoma
Pathogenesis
Morphology
Clinical Features of KS
Figure 9–30 Kaposi sarcoma. A, Characteristic coalescent cutaneous red-purple macules and plaques. B, Histologic view of the nodular stage, demonstrating sheets of plump, proliferating spindle cells and slitlike vascular spaces.
Hemangioendotheliomas
Figure 9–31 Angiosarcoma. A, Angiosarcoma of the right ventricle. B, Moderately differentiated angiosarcoma with dense clumps of atypical cells lining distinct vascular lumina. C, Immunohistochemical staining of angiosarcoma for the endothelial cell marker CD31.
Malignant Tumors
Angiosarcomas
Morphology
Hemangiopericytomas
Summary
Vascular Tumors
Pathology of Vascular Intervention
Endovascular Stenting
Figure 9–32 Restenosis after angioplasty and stenting. A, Gross view demonstrating residual atherosclerotic plaque (arrows) and a new, glistening intimal proliferative lesion. B, Histologic view shows a thickened neointima separating and overlying the stent wires (the black diamond indicated by the arrow), which encroaches on the lumen (indicated by the asterisk).
Vascular Replacement
Bibliography
Chapter 10 Heart
Overview of Heart Disease
Heart Failure
Figure 10–1 Left ventricular hypertrophy, with and without dilation, viewed in transverse sections. Compared with a normal heart (center), the pressure-overloaded heart (left) has an increased mass, a thick wall, and a smaller lumen. The volume-overloaded heart (right) has an increased mass, larger lumen, and enlarged size, but a normal wall thickness.
Left-Sided Heart Failure
Morphology
Heart
Lungs
Clinical Features
Right-Sided Heart Failure
Morphology
Liver and Portal System
Pleural, Pericardial, and Peritoneal Spaces
Subcutaneous Tissues
Clinical Features
Summary
Heart Failure
Congenital Heart Disease
Table 10–1 Frequency of Congenital Cardiac Malformations*
Table 10–2 Selected Examples of Gene Defects Associated With Congenital Heart Disease*
Pathogenesis
Clinical Features
Left-to-Right Shunts
Figure 10–2 Common congenital left-to-right shunts (arrows indicate direction of blood flow). A, Atrial septal defect (ASD). B, Ventricular septal defect (VSD). C, Patent ductus arteriosus (PDA). Ao, aorta; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.
Atrial Septal Defects and Patent Foramen Ovale
Morphology
Clinical Features
Ventricular Septal Defects
Figure 10–3 Ventricular septal defect of the membranous type (arrow).
Morphology
Clinical Features
Patent Ductus Arteriosus
Clinical Features
Right-to-Left Shunts
Tetralogy of Fallot
Figure 10–4 Common congenital right-to-left shunts (cyanotic congenital heart disease). A, Tetralogy of Fallot (arrow indicates direction of blood flow). B, Transposition of the great vessels with and without VSD. Ao, aorta; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.
Morphology
Clinical Features
Transposition of the Great Arteries
Clinical Features
Obstructive Lesions
Aortic Coarctation
Figure 10–5 Coarctation of the aorta with (“infantile” or preductal form) and without a patent ductus arteriosus (PDA) (“adult” or postductal form); arrow indicates direction of blood flow. Ao, aorta; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.
Morphology
Clinical Features
Figure 10–6 Coarctation of the aorta, postductal type. The coarctation is a segmental narrowing of the aorta (arrow). Such lesions typically manifest later in life than preductal coarctations. The dilated ascending aorta and major branch vessels are to the left of the coarctation. The lower extremities are perfused predominantly by way of dilated, tortuous collateral channels.
Summary
Congenital Heart Disease
Ischemic Heart Disease
Epidemiology
Figure 10–7 Diagram of sequential progression of coronary artery lesions leading to various acute coronary syndromes.
Pathogenesis
Acute Plaque Change
Angina Pectoris
Myocardial Infarction
Figure 10–8 Progression of myocardial necrosis after coronary artery occlusion. A transmural segment of myocardium that is dependent on the occluded vessel for perfusion constitutes the area at risk (outlined). Necrosis begins in the subendocardial region in the center of the ischemic zone and with time expands to involve the entire wall thickness. Note that a very narrow zone of myocardium immediately beneath the endocardium is spared from necrosis because it can be oxygenated by diffusion from the ventricle.
Figure 10–9 Dependence of myocardial infarction on the location and nature of the diminished perfusion. Left, Patterns of transmural infarction resulting from major coronary artery occlusion. Right ventricle may be involved with occlusion of right main coronary artery (not depicted). Right, Patterns of infarction resulting from partial or transient occlusion (top), global hypotension superimposed on fixed three-vessel disease (middle), or occlusion of small intramyocardial vessels (bottom).
Table 10–3 Evolution of Morphologic Changes in Myocardial Infarction
Figure 10–10 Acute myocardial infarct of the posterolateral left ventricle demonstrated by a lack of triphenyltetrazolium chloride staining in areas of necrosis (arrow); the absence of staining is due to enzyme leakage after cell death. Note the anterior scar (arrowhead), indicative of remote infarction. The myocardial hemorrhage at the right edge of the infarct (asterisk) is due to ventricular rupture, and was the acute cause of death in this patient (specimen is oriented with the posterior wall at the top).
Figure 10–11 Microscopic features of myocardial infarction and its repair. A, One-day-old infarct showing coagulative necrosis and wavy fibers, compared with adjacent normal fibers (at right). Necrotic cells are separated by edema fluid. B, Dense neutrophilic infiltrate in the area of a 2- to 3-day-old infarct. C, Nearly complete removal of necrotic myocytes by phagocytic macrophages (7 to 10 days). D, Granulation tissue characterized by loose connective tissue and abundant capillaries. E, Healed myocardial infarct consisting of a dense collagenous scar. A few residual cardiac muscle cells are present. D and E are Masson’s trichrome stain, which stains collagen blue.
Pathogenesis
Coronary Artery Occlusion
Myocardial Response to Ischemia
Patterns of Infarction
Morphology
Infarct Modification by Reperfusion
Figure 10–12 Reperfused myocardial infarction. A, The transverse heart slice (stained with triphenyl tetrazolium chloride) exhibits a large anterior wall myocardial infarction that is hemorrhagic because of bleeding from damaged vessels. Posterior wall is at top. B, Hemorrhage and contraction bands, visible as prominent hypereosinophilic cross-striations spanning myofibers (arrow), are seen microscopically.
Clinical Features
Figure 10-13 Multiple measurements of troponin I and myocardial form of creatine kinase (CK-MB) at different time points can be used to estimate the size and timing of MIs.
Consequences and Complications of Myocardial Infarction
Figure 10–14 Complications of myocardial infarction. A–C, Cardiac rupture. A, Anterior free wall myocardial rupture (arrow). B, Ventricular septal rupture (arrow). C, Papillary muscle rupture. D, Fibrinous pericarditis, with a hemorrhagic, roughened epicardial surface overlying an acute infarct. E, Recent expansion of an anteroapical infarct with wall stretching and thinning (arrow) and mural thrombus. F, Large apical left ventricular aneurysm (arrow).
Chronic Ischemic Heart Disease
Morphology
Clinical Features
Cardiac Stem Cells
Summary
Ischemic Heart Disease
Arrhythmias
Sudden Cardiac Death
Figure 10–15 Pathways in the progression of ischemic heart disease showing the relationships among coronary artery disease and its major sequelae.
Summary
Arrhythmias
Hypertensive Heart Disease
Systemic (Left-Sided) Hypertensive Heart Disease
Figure 10–16 Hypertensive heart disease. A, Systemic (left-sided) hypertensive heart disease. There is marked concentric thickening of the left ventricular wall causing reduction in lumen size. The left ventricle and left atrium are on the right in this four-chamber view of the heart. A pacemaker is present incidentally in the right ventricle (arrow). Note also the left atrial dilation (asterisk) due to stiffening of the left ventricle and impaired diastolic relaxation, leading to atrial volume overload. B, Chronic cor pulmonale. The right ventricle (shown on the left side of this picture) is markedly dilated and hypertrophied with a thickened free wall and hypertrophied trabeculae. The shape and volume of the left ventricle have been distorted by the enlarged right ventricle.
Morphology
Clinical Features
Pulmonary Hypertensive Heart Disease—Cor Pulmonale
Table 10–4 Disorders Predisposing to Cor Pulmonale
Morphology
Summary
Hypertensive Heart Disease
Valvular Heart Disease
Degenerative Valve Disease
Figure 10–17 Calcific valvular degeneration. A, Calcific aortic stenosis of a previously normal valve (viewed from above the valve). Nodular masses of calcium are heaped up within the sinuses of Valsalva (arrow). Note that the commissures are not fused, as in rheumatic aortic valve stenosis (Fig. 10–19, C). B, Calcific aortic stenosis occurring on a congenitally bicuspid valve. One cusp has a partial fusion at its center, called a raphe (arrow). C and D, Mitral annular calcification, with calcific nodules within the annulus (attachment margin) of the mitral leaflets (arrows). C, Left atrial view. D, Cut section demonstrating the extension of the calcification into the underlying myocardium. Such involvement of adjacent structures near the interventricular septum can impinge on the conduction system.
Table 10–5 Etiology of Acquired Heart Valve Disease
Calcific Aortic Stenosis
Morphology
Clinical Features
Myxomatous Mitral Valve
Pathogenesis
Morphology
Clinical Features
Figure 10–18 Myxomatous degeneration of the mitral valve. There is prominent hooding with prolapse of the posterior mitral leaflet (arrow) into the left atrium; the atrium also is dilated, reflecting long-standing valvular insufficiency and volume overload. The left ventricle is on the right in this four-chamber view.
Rheumatic Valvular Disease
Pathogenesis
Morphology
Clinical Features
Figure 10–19 Acute and chronic rheumatic heart disease. A, Acute rheumatic mitral valvulitis superimposed on chronic rheumatic heart disease. Small vegetations (verrucae) are visible along the line of closure of the mitral valve leaflet (arrows). Previous episodes of rheumatic valvulitis have caused fibrous thickening and fusion of the chordae tendineae. B, Microscopic appearance of an Aschoff body in acute rheumatic carditis; there is central necrosis associated with a circumscribed collection of mononuclear inflammatory cells, including some activated macrophages with prominent nucleoli and central wavy (caterpillar) chromatin (arrows). C and D, Mitral stenosis with diffuse fibrous thickening and distortion of the valve leaflets, commissural fusion (arrows), and thickening and shortening of the chordae tendineae. There is marked left atrial dilation as seen from above the valve (C). D, Anterior leaflet of an opened rheumatic mitral valve; note the inflammatory neovascularization (arrow). E, Surgically removed specimen of rheumatic aortic stenosis, demonstrating thickening and distortion of the cusps with commissural fusion.
Infective Endocarditis
Pathogenesis
Morphology
Clinical Features
Figure 10–20 The major forms of vegetative endocarditis. The acute rheumatic fever phase of rheumatic heart disease is marked by the appearance of small, warty, inflammatory vegetations along the lines of valve closure; as the inflammation resolves, substantial scarring can result. Infective endocarditis (IE) is characterized by large, irregular, often destructive masses that can extend from valve leaflets onto adjacent structures (e.g., chordae or myocardium). Nonbacterial thrombotic endocarditis (NBTE) typically manifests with small to medium-sized, bland, nondestructive vegetations at the line of valve closure. Libman-Sacks endocarditis (LSE) is characterized by small to medium-sized inflammatory vegetations that can be attached on either side of valve leaflets; these heal with scarring.
Noninfected Vegetations
Nonbacterial Thrombotic Endocarditis
Figure 10–21 Infective endocarditis. A, Subacute endocarditis caused by Streptococcus viridans on a previously myxomatous mitral valve. The large, friable vegetations are denoted by arrows. B, Acute endocarditis caused by Staphylococcus aureus on congenitally bicuspid aortic valve with extensive cuspal destruction and ring abscess (arrow).
Figure 10–22 Nonbacterial thrombotic endocarditis (NBTE). A, Small thrombotic vegetations along the line of closure of the mitral valve leaflets (arrows). B, Photomicrograph of NBTE lesion, showing bland thrombus, with virtually no inflammation in the valve cusp (C) or the thrombotic deposit (t). The thrombus is only loosely attached to the cusp (arrow).
Libman-Sacks Endocarditis
Carcinoid Heart Disease
Pathogenesis
Morphology
Prosthetic Cardiac Valves
Figure 10–23 Carcinoid heart disease. A, Characteristic endocardial fibrotic lesion “coating” the right ventricle and tricuspid valve, and extending onto the chordae tendineae. B, Microscopic appearance of the thickened intima, which contains smooth muscle cells and abundant acid mucopolysaccharides (blue-green in this Movat stain, which colors the underlying endocardial elastic tissue black).
Summary
Valvular Heart Disease
Cardiomyopathies
Figure 10–24 The three major forms of cardiomyopathy. Dilated cardiomyopathy leads primarily to systolic dysfunction, whereas restrictive and hypertrophic cardiomyopathies result in diastolic dysfunction. Note the changes in atrial and/or ventricular dilation and in ventricular wall thickness. Ao, aorta; LA, left atrium; LV, left ventricle.
Dilated Cardiomyopathy
Table 10–6 Cardiomyopathies: Functional Patterns, Causes
Pathogenesis
Morphology
Clinical Features
Figure 10–25 Causes and consequences of dilated and hypertrophic cardiomyopathy. A significant fraction of dilated cardiomyopathies—and virtually all hypertrophic cardiomyopathies—have a genetic origin. Dilated cardiomyopathies can be caused by mutations in cytoskeletal, sarcomeric, nuclear envelope, or mitochondrial proteins; hypertrophic cardiomyopathies typically are caused by sarcomeric protein mutations. Although the two forms of cardiomyopathy differ in cause and morphology, they have common clinical end points. LV, left ventricle.
Figure 10–26 Dilated cardiomyopathy (DCM). A, Four-chamber dilation and hypertrophy are evident. A small mural thrombus can be seen at the apex of the left ventricle (arrow). B, The nonspecific histologic picture in typical DCM, with myocyte hypertrophy and interstitial fibrosis (collagen is blue in this Masson trichrome–stained preparation).
Figure 10–27 Arrhythmogenic right ventricular cardiomyopathy. A, The right ventricle is markedly dilated with focal, almost transmural replacement of the free wall by adipose tissue and fibrosis. The left ventricle has a grossly normal appearance in this heart; it can be involved (albeit to a lesser extent) in some instances. B, The right ventricular myocardium (red) is focally replaced by fibrous connective tissue (blue, arrow) and fat (Masson trichrome stain).
Arrhythmogenic Right Ventricular Cardiomyopathy
Hypertrophic Cardiomyopathy
Figure 10–28 Hypertrophic cardiomyopathy with asymmetric septal hypertrophy. A, The septal muscle bulges into the left ventricular outflow tract, giving rise to a “banana-shaped” ventricular lumen, and the left atrium is enlarged. The anterior mitral leaflet has been moved away from the septum to reveal a fibrous endocardial plaque (arrow) (see text). B, Histologic appearance demonstrating disarray, extreme hypertrophy, and characteristic branching of myocytes, as well as interstitial fibrosis.
Pathogenesis
Morphology
Clinical Features
Restrictive Cardiomyopathy
Morphology
Myocarditis
Figure 10–29 Myocarditis. A, Lymphocytic myocarditis, with edema and associated myocyte injury. B, Hypersensitivity myocarditis, characterized by perivascular eosinophil-rich inflammatory infiltrates. C, Giant cell myocarditis, with lymphocyte and macrophage infiltrates, extensive myocyte damage, and multinucleate giant cells. D, Chagas myocarditis. A myofiber distended with trypanosomes (arrow) is present, along with mononuclear inflammation and myofiber necrosis.
Pathogenesis
Morphology
Clinical Features
Summary
Cardiomyopathy
Pericardial Disease
Pericarditis
Morphology
Clinical Features
Figure 10–30 Acute suppurative (purulent, exudative) pericarditis, caused by extension from a pneumonia.
Pericardial Effusions
Cardiac Tumors
Metastatic Neoplasms
Primary Neoplasms
Figure 10–31 Atrial myxoma. A, A large pedunculated lesion arises from the region of the fossa ovalis and extends into the mitral valve orifice. B, Abundant amorphous extracellular matrix contains scattered multinucleate myxoma cells (arrowheads) in various groupings, including abnormal vascular formations (arrow).
Morphology
Clinical Features
Other Cardiac Tumors
Cardiac Transplantation
Figure 10–32 Rejection of cardiac allografts. A, Acute cardiac allograft rejection, typified by a lymphocyte infiltrate associated with cardiac myocyte damage. Note the similarity of rejection and viral myocarditis (Fig. 10–29, A). B, Allograft arteriopathy, with severe concentric intimal thickening producing critical stenosis. The internal elastic lamina (arrow) and media are intact. (Movat pentachrome stain.)
Bibliography
Chapter 11 Hematopoietic and Lymphoid Systems
Red Cell Disorders
Table 11–1 Classification of Anemia According to Underlying Mechanism
Table 11–2 Adult Reference Ranges for Red Blood Cells*
Summary
Pathology of Anemias
Causes
Morphology
Clinical Manifestations
Anemia Of Blood Loss: Hemorrhage
Hemolytic Anemias
Hereditary Spherocytosis
Figure 11–1 Pathogenesis of hereditary spherocytosis. Left panel, Normal organization of the major red cell membrane skeleton proteins. Mutations in α-spectrin, β-spectrin, ankyrin, band 4.2, and band 3 that weaken the association of the membrane skeleton with the overlying plasma membrane cause red cells to shed membrane vesicles and transform into spherocytes (right panel). The nondeformable spherocytes are trapped in the splenic cords and phagocytosed by macrophages. GP, glycophorin.
Figure 11–2 Hereditary spherocytosis—peripheral blood smear. Note the anisocytosis and several hyperchromic spherocytes. Howell-Jolly bodies (small nuclear remnants) are also present in the red cells of this asplenic patient.
Pathogenesis
Morphology
Clinical Features
Sickle Cell Anemia
Incidence
Figure 11–3 Sickle cell anemia—peripheral blood smear. A, Low magnification shows sickle cells, anisocytosis, poikilocytosis, and target cells. B, Higher magnification shows an irreversibly sickled cell in the center.
Figure 11–4 Pathophysiology of sickle cell disease.
Pathogenesis
Morphology
Clinical Course
Thalassemia
Table 11–3 Clinical and Genetic Classification of Thalassemias
Figure 11–5 Distribution of β-globin gene mutations associated with β-thalassemia. Arrows denote sites at which point mutations giving rise to β+ or β0 thalassemia have been identified.
Figure 11–6 Pathogenesis of β-thalassemia major. Note that aggregates of excess α-globin are not visible on routine blood smears. Blood transfusions constitute a double-edged sword, diminishing the anemia and its attendant complications but also adding to the systemic iron overload.
Pathogenesis
β-Thalassemia
α-Thalassemia
Morphology
Clinical Course
Glucose-6-Phosphate Dehydrogenase Deficiency
Pathogenesis
Clinical Features

Figure 11–7 Glucose-6-phosphate dehydrogenase deficiency after oxidant drug exposure—peripheral blood smear. Inset, Red cells with precipitates of denatured globin (Heinz bodies) revealed by supravital staining. As the splenic macrophages pluck out these inclusions, “bite cells” like the one in this smear are produced.
Paroxysmal Nocturnal Hemoglobinuria
Pathogenesis
Immunohemolytic Anemias
Warm Antibody Immunohemolytic Anemias
Table 11–4 Classification of Immunohemolytic Anemias
Cold Antibody Immunohemolytic Anemias
Hemolytic Anemias Resulting from Mechanical Trauma to Red Cells
Figure 11–8 Microangiopathic hemolytic anemia—peripheral blood smear. This specimen from a patient with hemolytic uremic syndrome contains several fragmented red cells.
Malaria
Pathogenesis
Clinical Features
SummaRy
Hemolytic Anemias
Hereditary Spherocytosis
Sickle Cell Anemia
Thalassemias
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Immunohemolytic Anemias
Malaria
Anemias of Diminished Erythropoiesis
Iron Deficiency Anemia
Figure 11–9 Regulation of iron absorption. Duodenal epithelial cell uptake of heme and nonheme iron discussed in the text is depicted. When the storage sites of the body are replete with iron and erythropoietic activity is normal, plasma hepcidin levels are high. This situation leads to downregulation of ferroportin and trapping of most of the absorbed iron, which is lost when duodenal epithelial cells are shed into the gut. Conversely, when body iron stores decrease or erythropoiesis is stimulated, hepcidin levels fall and ferroportin activity increases, allowing a greater fraction of the absorbed iron to be transferred into plasma transferrin. DMT1, divalent metal transporter-1.
Pathogenesis
Clinical Features
Figure 11–10 Iron deficiency anemia—peripheral blood smear. Note the increased central pallor of most of the red cells. Scattered, fully hemoglobinized cells, from a recent blood transfusion, stand out in contrast.
Anemia of Chronic Disease
Pathogenesis
Clinical Features
Megaloblastic Anemias
Figure 11–11 Comparison of normoblasts (left) and megaloblasts (right)—bone marrow aspirate. Megaloblasts are larger, have relatively immature nuclei with finely reticulated chromatin, and abundant basophilic cytoplasm.
Pathogenesis
Morphology
Folate (Folic Acid) Deficiency Anemia
Pathogenesis
Clinical Features
Vitamin B12 (Cobalamin) Deficiency Anemia (Pernicious Anemia)
Pathogenesis
Clinical Features
Aplastic Anemia
Pathogenesis
Morphology
Clinical Course
Myelophthisic Anemia
Summary
Anemias of Diminished Erythropoiesis
Iron Deficiency Anemia
Anemia of Chronic Disease
Megaloblastic Anemia
Aplastic Anemia
Myelophthisic Anemia
Polycythemia
White Cell Disorders
Non-Neoplastic Disorders of White Cells
Leukopenia
Table 11–5 Pathophysiologic Classification of Polycythemia
Neutropenia/Agranulocytosis
Pathogenesis
Morphology
Clinical Features
Reactive Leukocytosis
Infectious Mononucleosis
Table 11–6 Causes of Leukocytosis
Pathogenesis
Morphology
Figure 11–12 Atypical lymphocytes in infectious mononucleosis—peripheral blood smear. The cell on the left is a normal small resting lymphocyte with a compact nucleus and scant cytoplasm. By contrast, the atypical lymphocyte on the right has abundant cytoplasm and a large nucleus with dispersed chromatin.
Clinical Features
Reactive Lymphadenitis
Acute Nonspecific Lymphadenitis
Morphology
Chronic Nonspecific Lymphadenitis
Morphology
Follicular Hyperplasia
Paracortical Hyperplasia
Sinus Histiocytosis
Cat-Scratch Disease
Morphology
Neoplastic Proliferations of White Cells
Lymphoid Neoplasms
Figure 11–13 Origin of lymphoid neoplasms. Stages of B and T cell differentiation from which specific lymphoid and tumors emerge are shown. BLB, pre-B lymphoblast; CLP, common lymphoid progenitor; DN, CD4−/CD8− (double-negative) pro-T cell; DP, CD4+/CD8+ (double-positive) pre-T cell; GC, germinal center B cell; MC, mantle zone B cell; MZ, marginal zone B cell; NBC, naive B cell; PC, plasma cell; PTC, peripheral T cell.
Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
Table 11–7 WHO Classification of Lymphoid Neoplasms*
Pathogenesis
Clinical Features of Acute Leukemias
Laboratory Findings in Acute Leukemias
Table 11–8 Characteristics of the More Common Lymphoid Leukemias, Non-Hodgkin Lymphomas, and Plasma Cell Tumors
Figure 11–14 Morphologic comparison of lymphoblasts and myeloblasts. A, Lymphoblastic leukemia/lymphoma. Lymphoblasts have condensed nuclear chromatin, small nucleoli, and scant agranular cytoplasm. B, Acute myeloid leukemia. Myeloblasts have delicate nuclear chromatin, prominent nucleoli, and fine azurophilic cytoplasmic granules.
Morphology
Genetic Features
Immunophenotypic Features
Prognosis
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Figure 11–15 Small lymphocytic lymphoma/chronic lymphocytic leukemia—lymph node. A, Low-power view shows diffuse effacement of nodal architecture. B, At high power, a majority of the tumor cells have the appearance of small, round lymphocytes. A “prolymphocyte,” a larger cell with a centrally placed nucleolus, also is present in this field (arrow).
Pathogenesis
Morphology
Immunophenotypic and Genetic Features
Clinical Features
Follicular Lymphoma
Figure 11–16 Follicular lymphoma—lymph node. A, Nodular aggregates of lymphoma cells are present throughout. B, At high magnification, small lymphoid cells with condensed chromatin and irregular or cleaved nuclear outlines (centrocytes) are mixed with a population of larger cells with nucleoli (centroblasts).
Pathogenesis
Morphology
Immunophenotypic Features
Clinical Features
Mantle Cell Lymphoma
Morphology
Immunophenotypic and Genetic Features
Clinical Features
Diffuse Large B Cell Lymphoma
Pathogenesis
Morphology
Immunophenotypic Features
Figure 11–17 Diffuse large B cell lymphoma—lymph node. The tumor cells have large nuclei with open chromatin and prominent nucleoli.
Subtypes of Diffuse Large B Cell Lymphoma
Clinical Features
Burkitt Lymphoma
Pathogenesis
Morphology
Immunophenotypic Features
Clinical Features
Figure 11–18 Burkitt lymphoma—lymph node. The tumor cells and their nuclei are fairly uniform, giving a monotonous appearance. Note the high level of mitotic activity (arrowheads) and prominent nucleoli. The “starry sky” pattern produced by interspersed, lightly staining, normal macrophages is better appreciated at a lower magnification.
Multiple Myeloma and Related Plasma Cell Tumors
Multiple Myeloma
Solitary Plasmacytoma
Pathogenesis Of Myeloma
Monoclonal Gammopathy of Undetermined Significance
Lymphoplasmacytic Lymphoma
Heavy-Chain Disease
Primary Amyloidosis
Figure 11–19 Multiple myeloma. A, Radiograph of the skull, lateral view. The sharply punched-out bone defects are most obvious in the calvaria. B, Bone marrow aspirate. Normal marrow cells are largely replaced by plasma cells, including atypical forms with multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing immunoglobulin.
Morphology
Clinical Features
Hodgkin Lymphoma
Classification
Figure 11–20 Hodgkin lymphoma—lymph node. A binucleate Reed-Sternberg cell with large, inclusion-like nucleoli and abundant cytoplasm is surrounded by lymphocytes, macrophages, and an eosinophil.
Figure 11–21 Hodgkin lymphoma, nodular sclerosis type—lymph node. A distinctive “lacunar cell” with a multilobed nucleus containing many small nucleoli is seen lying within a clear space created by retraction of its cytoplasm. It is surrounded by lymphocytes.
Figure 11–22 Hodgkin lymphoma, nodular sclerosis type—lymph node. A low-power view shows well-defined bands of pink, acellular collagen that have subdivided the tumor cells into nodules.
Figure 11–23 Hodgkin lymphoma, mixed-cellularity type—lymph node. A diagnostic, binucleate Reed-Sternberg cell is surrounded by eosinophils, lymphocytes, and histiocytes.
Figure 11–24 Hodgkin lymphoma, lymphocyte-predominance type—lymph node. Numerous mature-looking lymphocytes surround scattered, large, pale-staining lymphocytic and histiocytic variants (“popcorn” cells).
Morphology
Pathogenesis
Staging and Clinical Features
Table 11–9 Clinical Differences Between Hodgkin and Non-Hodgkin Lymphomas
Table 11–10 Clinical Staging of Hodgkin and Non-Hodgkin Lymphomas (Ann Arbor Classification)*
Miscellaneous Lymphoid Neoplasms
Extranodal Marginal Zone Lymphoma
Hairy Cell Leukemia
Mycosis Fungoides and Sézary Syndrome
Adult T Cell Leukemia/Lymphoma
Peripheral T Cell Lymphomas
Summary
Lymphoid Neoplasms
Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia
Follicular Lymphoma
Mantle Cell Lymphoma
Diffuse Large B Cell Lymphoma
Burkitt Lymphoma
Multiple Myeloma
Hodgkin Lymphoma
Myeloid Neoplasms
Acute Myeloid Leukemia
Pathogenesis
Morphology
Classification
Figure 11–25 Acute promyelocytic leukemia—bone marrow aspirate. The neoplastic promyelocytes have abnormally coarse and numerous azurophilic granules. Other characteristic findings include the presence of several cells with bilobed nuclei and a cell in the center of the field that contains multiple needle-like Auer rods.
Immunophenotype
Prognosis
Table 11–11 WHO Classification of Acute Myeloid Leukemia (AML)
Myelodysplastic Syndromes
Pathogenesis
Morphology
Chronic Myeloproliferative Disorders
Chronic Myelogenous Leukemia
Figure 11–26 Chronic myelogenous leukemia—peripheral blood smear. Granulocytic forms at various stages of differentiation are present.
Pathogenesis
Morphology
Clinical Features
Polycythemia Vera
Morphology
Clinical Course
Primary Myelofibrosis
Figure 11–27 Primary myelofibrosis—peripheral blood smear. Two nucleated erythroid precursors and several teardrop-shaped red cells (dacryocytes) are evident. Immature myeloid cells were present in other fields. An identical histologic picture can be seen in other diseases producing marrow distortion and fibrosis.
Pathogenesis
Morphology
Clinical Course
Summary
Myeloid Neoplasms
Histiocytic Neoplasms
Langerhans Cell Histiocytoses
Bleeding Disorders
Disseminated Intravascular Coagulation
Figure 11–28 Pathophysiology of disseminated intravascular coagulation.
Table 11–12 Major Disorders Associated with Disseminated Intravascular Coagulation
Pathogenesis
Morphology
Clinical Course
Thrombocytopenia
Immune Thrombocytopenic Purpura
Table 11–13 Causes of Thrombocytopenia
Heparin-Induced Thrombocytopenia
Thrombotic Microangiopathies: Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome
Pathogenesis
Coagulation Disorders
Figure 11–29 Structure and function of factor VIII–von Willebrand factor (vWF) complex. Factor VIII and vWF circulate as a complex. vWF also is present in the subendothelial matrix of normal blood vessels. Factor VIII takes part in the coagulation cascade by activating factor X by means of factor IX (not shown). vWF causes adhesion of platelets to subendothelial collagen, primarily through the glycoprotein Ib (GpIb) platelet receptor.
Deficiencies of Factor VIII–von Willebrand Factor Complex
von Willebrand Disease
Hemophilia A—Factor VIII Deficiency
Hemophilia B—Factor IX Deficiency
Summary
Bleeding Disorders
Disseminated Intravascular Coagulation
Immune Thrombocytopenic Purpura
Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome
von Willebrand Disease
Hemophilia
Disorders That Affect The Spleen And Thymus
Splenomegaly
Disorders of the Thymus
Thymic Hyperplasia
Thymoma
Morphology
Clinical Features
Bibliography
Red Cell Disorders
White Cell Disorders
BLEEDING Disorders
Disorders That Affect the Spleen and Thymus
Chapter 12 Lung
Figure 12–1 Microscopic structure of the alveolar wall. Note that the basement membrane (yellow) is thin on one side and widened where it is continuous with the interstitial space. Portions of interstitial cells are shown.
Atelectasis (Collapse)
Acute Lung Injury
Figure 12–2 Various forms of acquired atelectasis.
Table 12–1 Clinical Disorders Associated with the Development of Acute Lung Injury/Acute Respiratory Distress Syndrome
Acute Respiratory Distress Syndrome
Pathogenesis
Morphology
Clinical Features
Figure 12–3 The normal alveolus (left), compared with the injured alveolus in the early phase of acute lung injury and the acute respiratory distress syndrome. Under the influence of proinflammatory cytokines such as interleukins IL-8 and IL-1 and tumor necrosis factor (TNF) (released by macrophages), neutrophils initially undergo sequestration in the pulmonary microvasculature, followed by margination and egress into the alveolar space, where they undergo activation. Activated neutrophils release a variety of factors such as leukotrienes, oxidants, proteases, and platelet-activating factor (PAF), which contribute to local tissue damage, accumulation of edema fluid in the air spaces, surfactant inactivation, and hyaline membrane formation. Subsequently, the release of macrophage-derived fibrogenic cytokines such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PGDF) stimulate fibroblast growth and collagen deposition associated with the healing phase of injury.
Summary
Acute Respiratory Distress Syndrome
Obstructive Versus Restrictive Pulmonary Diseases
Figure 12–4 A, Diffuse alveolar damage in acute lung injury and acute respiratory distress syndrome. Some alveoli are collapsed; others are distended. Many are lined by bright pink hyaline membranes (arrow). B, The healing stage is marked by resorption of hyaline membranes with thickening of alveolar septa containing inflammatory cells, fibroblasts, and collagen. Numerous reactive type II pneumocytes also are seen at this stage (arrows), associated with regeneration and repair.
Table 12–2 Disorders Associated with Airflow Obstruction: The Spectrum of Chronic Obstructive Pulmonary Disease
Obstructive Lung (Airway) Diseases
Emphysema
Figure 12–5 Schematic representation of overlap between chronic obstructive lung diseases.
Types of Emphysema
Centriacinar (Centrilobular) Emphysema
Panacinar (Panlobular) Emphysema
Distal Acinar (Paraseptal) Emphysema
Irregular Emphysema
Figure 12–6 Major patterns of emphysema. A, Diagram of normal structure of the acinus, the fundamental unit of the lung. B, Centriacinar emphysema with dilation that initially affects the respiratory bronchioles. C, Panacinar emphysema with initial distention of all the peripheral structures (i.e., the alveolus and alveolar duct); the disease later extends to affect the respiratory bronchioles.
Figure 12–7 Loss of cellular homeostasis in emphysema pathogenesis. Exposure to inhaled toxins (such as cigarette smoke) leads to epithelial cell death, inflammation, and extracellular matrix proteolysis. In susceptible persons, mesenchymal cell survival and reparative functions are impaired by direct effects of inhaled toxic substances and inflammatory mediators and by the loss of the peri- and extracellular matrix. The result is loss of structural cells of the alveolar wall and the associated matrix components.
Pathogenesis
Morphology
Figure 12–8 Pulmonary emphysema. There is marked enlargement of air spaces, with destruction of alveolar septa but without fibrosis. Note presence of black anthracotic pigment.
Clinical Features
Summary
Emphysema
Conditions Related to Emphysema
Figure 12–9 Bullous emphysema with large apical and subpleural bullae.
Chronic Bronchitis
Figure 12–10 Chronic bronchitis. The lumen of the bronchus is above. Note the marked thickening of the mucous gland layer (approximately twice-normal) and squamous metaplasia of lung epithelium.
Pathogenesis
Morphology
Clinical Features
Summary
Chronic Bronchitis
Asthma
Pathogenesis
Types of Asthma
Atopic Asthma
Non-Atopic Asthma
Figure 12–11 A and B, Comparison of a normal bronchus with that in a patient with asthma. Note the accumulation of mucus in the bronchial lumen resulting from an increase in the number of mucus-secreting goblet cells in the mucosa and hypertrophy of submucosal glands. In addition, there is intense chronic inflammation due to recruitment of eosinophils, macrophages, and other inflammatory cells. Basement membrane underlying the mucosal epithelium is thickened, and smooth muscle cells exhibit hypertrophy and hyperplasia. C, Inhaled allergens (antigens) elicit a TH2-dominated response favoring IgE production and eosinophil recruitment (priming or sensitization). D, On reexposure to antigen (Ag), the immediate reaction is triggered by antigen-induced cross-linking of IgE bound to IgE receptors on mast cells in the airways. These cells release preformed mediators. Collectively, either directly or through neuronal reflexes, the mediators induce bronchospasm, increase vascular permeability and mucus production, and recruit additional mediator-releasing cells from the blood. E, The arrival of recruited leukocytes (neutrophils, eosinophils, basophils, lymphocytes, and monocytes) signals the initiation of the late phase of asthma and a fresh round of mediator release from leukocytes, endothelium, and epithelial cells. Factors, particularly from eosinophils (e.g., major basic protein, eosinophil cationic protein), also cause damage to the epithelium. IgE, immunoglobulin E.
Drug-Induced Asthma
Occupational Asthma
Morphology
Clinical Features
Figure 12–12 Bronchial biopsy specimen from an asthmatic patient showing sub-basement membrane fibrosis, eosinophilic inflammation, and smooth muscle hyperplasia.
Summary
Asthma
Bronchiectasis
Figure 12–13 Bronchiectasis in a patient with cystic fibrosis who underwent lung resection for transplantation. Cut surface of lung shows markedly dilated bronchi, filled with purulent mucus, which are seen extending to subpleural regions.
Pathogenesis
Morphology
Clinical Features
Chronic Interstitial (Restrictive, Infiltrative) Lung Diseases
Fibrosing Diseases
Idiopathic Pulmonary Fibrosis
Table 12–3 Major Categories of Chronic Interstitial Lung Disease
Figure 12–14 Schematic representation of current understanding of the pathogenesis of idiopathic pulmonary fibrosis.
Figure 12–15 Usual interstitial pneumonia. The fibrosis, which varies in intensity, is more pronounced in the subpleural region.
Figure 12–16 Usual interstitial pneumonia. Fibroblastic focus with fibers running parallel to surface and bluish myxoid extracellular matrix. Honeycombing is present to the left.
Pathogenesis
Morphology
Clinical Features
Nonspecific Interstitial Pneumonia
Cryptogenic Organizing Pneumonia
Figure 12–17 Cryptogenic organizing pneumonia. Some alveolar spaces are filled with balls of fibroblasts (Masson bodies). Although compressed, adjacent alveoli are relatively normal.
Pulmonary Involvement in Collagen Vascular Diseases
Table 12–4 Mineral Dust–Induced Lung Disease
Summary
Chronic Interstitial Lung Diseases
Pneumoconioses
Pathogenesis
Coal Worker’s Pneumoconiosis
Morphology
Clinical Features
Figure 12–18 Progressive massive fibrosis in a coal worker. Large amount of black pigment is associated with fibrosis.
Silicosis
Morphology
Clinical Features
Figure 12–19 Advanced silicosis seen on transection of lung. Scarring has contracted the upper lobe into a small dark mass (arrow). Note the dense pleural thickening.
Figure 12–20 Several coalescent collagenous silicotic nodules.
Asbestosis and Asbestos-Related Diseases
Figure 12–21 High-power detail of an asbestos body, revealing the typical beading and knobbed ends (arrow).
Pathogenesis
Morphology
Clinical Features
Figure 12–22 Asbestosis. Markedly thickened visceral pleura covers the lateral and diaphragmatic surface of lung. Note also severe interstitial fibrosis diffusely affecting the lower lobe of the lung.
Summary
Pneumoconioses
Drug- and Radiation-Induced Pulmonary Diseases
Granulomatous Diseases
Sarcoidosis
Epidemiology
Figure 12–23 Sarcoid. Characteristic peribronchial noncaseating granulomas with many giant cells.
Etiology and Pathogenesis
Morphology
Clinical Features
Table 12–5 Selected Causes of Hypersensitivity Pneumonitis
Summary
Sarcoidosis
Hypersensitivity Pneumonitis
Morphology
Clinical Features
Figure 12–24 Hypersensitivity pneumonitis, histologic appearance. Loosely formed interstitial granulomas and chronic inflammation are characteristic.
Pulmonary Eosinophilia
Smoking-Related Interstitial Diseases
Figure 12–25 Desquamative interstitial pneumonia. There is accumulation of large numbers of macrophages within the alveolar spaces with only slight fibrous thickening of the alveolar walls.
Pulmonary Diseases of Vascular Origin
Pulmonary Embolism, Hemorrhage, and Infarction
Figure 12–26 Large saddle embolus from the femoral vein lying astride the main left and right pulmonary arteries.
Morphology
Clinical Features
Figure 12–27 A small, roughly wedge-shaped hemorrhagic pulmonary infarct of recent occurrence.
Summary
Pulmonary Embolism
Pulmonary Hypertension
Pathogenesis
Morphology
Clinical Features
Figure 12–28 Vascular changes in pulmonary hypertension. A, Gross photograph of atheroma, a finding usually limited to large vessels. B, Marked medial hypertrophy. C, Plexiform lesion characteristic of advanced pulmonary hypertension seen in small arteries.
Diffuse Alveolar Hemorrhage Syndromes
Goodpasture Syndrome
Morphology
Idiopathic Pulmonary Hemosiderosis
Pulmonary Angiitis and Granulomatosis (Wegener Granulomatosis)
Figure 12–29 A, Lung biopsy specimen from a person with a diffuse alveolar hemorrhage syndrome demonstrates large numbers of intra-alveolar hemosiderin-laden macrophages on a background of thickened fibrous septa. B, The tissue has been stained with Prussian blue, an iron stain that highlights the abundant intracellular hemosiderin.
Pulmonary Infections
Community-Acquired Acute Pneumonias
Figure 12–30 Lung defense mechanisms. A, Innate defenses against infection: 1, In the normal lung, removal of microbial organisms depends on entrapment in the mucous blanket and removal by means of the mucociliary elevator; 2, phagocytosis by alveolar macrophages that can kill and degrade organisms and remove them from the air spaces by migrating onto the mucociliary elevator; or 3, phagocytosis and killing by neutrophils recruited by macrophage factors. 4, Serum complement may enter the alveoli and be activated by the alternative pathway to provide the opsonin C3b, which enhances phagocytosis. 5, Organisms, including those ingested by phagocytes, may reach the draining lymph nodes to initiate immune responses. B, Additional mechanisms operate after development of adaptive immunity. 1, Secreted IgA can block attachment of the microorganism to epithelium in the upper respiratory tract. 2, In the lower respiratory tract, serum antibodies (IgM, IgG) are present in the alveolar lining fluid. They activate complement more efficiently by the classic pathway, yielding C3b (not shown). In addition, IgG is opsonic. 3, The accumulation of immune T cells is important for controlling infections by viruses and other intracellular microorganisms. PMN, polymorphonuclear cell.
Figure 12–31 The anatomic distribution of bronchopneumonia and lobar pneumonia.
Streptococcus pneumoniae Infections
Table 12–6 The Pneumonia Syndromes and Implicated Pathogens
Morphology
Pneumonias Caused by Other Important Pathogens
Figure 12–32 A, Acute pneumonia. The congested septal capillaries and extensive neutrophil exudation into alveoli correspond to early red hepatization. Fibrin nets have not yet formed. B, Early organization of intra-alveolar exudates, seen in areas to be streaming through the pores of Kohn (arrow). C, Advanced organizing pneumonia, featuring transformation of exudates to fibromyxoid masses richly infiltrated by macrophages and fibroblasts.
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
Klebsiella pneumoniae
Figure 12–33 Gross view of lobar pneumonia with gray hepatization. The lower lobe is uniformly consolidated.
Pseudomonas aeruginosa
Legionella pneumophila
Community-Acquired Atypical Pneumonias
Morphology
Clinical Features
Figure 12–34 Viral pneumonia. The thickened alveolar walls are infiltrated with lymphocytes and some plasma cells, which are spilling over into alveolar spaces. Note focal alveolar edema in the center and early fibrosis at upper right.
Influenza Infections
Influenza Virus Type A/H1N1 Infection
Summary
Acute Pneumonias
Hospital-Acquired Pneumonias
Aspiration Pneumonia
Lung Abscess
Morphology
Clinical Features
Chronic Pneumonias
Tuberculosis
Epidemiology
Etiology
Figure 12–35 Sequence of events in the natural history of primary pulmonary tuberculosis. This sequence commences with inhalation of virulent strains of Mycobacterium and culminates in the development of immunity and delayed hypersensitivity to the organism. A, Events occurring in the first 3 weeks after exposure. B, Events thereafter. The development of resistance to the organism is accompanied by conversion to a positive result on tuberculin skin testing. Cells and bacteria are not drawn to scale. IFN-γ, interferon γ; iNOS, inducible nitric oxide synthase; MHC, major histocompatibility complex; MTB, Mycobacterium tuberculosis; NRAMP1, gene encoding natural resistance–associated macrophage protein 1; TNF, tumor necrosis factor.
Pathogenesis
Primary Tuberculosis
Figure 12–36 Primary pulmonary tuberculosis, Ghon complex. The gray-white parenchymal focus (arrow) is under the pleura in the lower part of the upper lobe. Hilar lymph nodes with caseation are seen on the left.
Morphology
Figure 12–37 The morphologic spectrum of tuberculosis. A and B, A characteristic tubercle at low magnification (A) and at higher power (B) shows central granular caseation surrounded by epithelioid and multinucleate giant cells. This is the usual response seen in persons who have developed cell-mediated immunity to the organism. Inset: Acid-fast stain shows rare positive organisms. C, Occasionally, even in immunocompetent patients, tubercular granulomas may not show central caseation; hence, irrespective of the presence or absence of caseous necrosis, use of special stains for acid-fast organisms is indicated when granulomas are present. D, In this specimen from an immunosuppressed patient, sheets of foamy macrophages packed with mycobacteria are seen (acid-fast stain).
Secondary Tuberculosis (Reactivation Tuberculosis)
Figure 12–38 Secondary pulmonary tuberculosis. The upper parts of both lungs are riddled with gray-white areas of caseation and multiple areas of softening and cavitation.
Figure 12–39 Miliary tuberculosis of the spleen. The cut surface shows numerous gray-white granulomas.
Figure 12–40 The natural history and spectrum of tuberculosis.
Morphology
Clinical Features
Summary
Tuberculosis
Nontuberculous Mycobacterial Disease
Histoplasmosis, Coccidioidomycosis, and Blastomycosis
Epidemiology
Morphology
Clinical Features
Figure 12–41 A, Histoplasma capsulatum yeast forms fill phagocytes in a lymph node of a patient with disseminated histoplasmosis (silver stain). B, Coccidioidomycosis with intact spherules within multinucleated giant cells. C, Blastomycosis, with rounded budding yeasts, larger than neutrophils. Note the characteristic thick wall and nuclei (not seen in other fungi). D, Silver stain highlights the broad-based budding seen in Blastomyces immitis organisms.
Pneumonia in the Immunocompromised Host
Cytomegalovirus Infections
Figure 12–42 Cytomegalovirus infection of the lung. A typical distinct nuclear and multiple cytoplasmic inclusions are seen in an enlarged cell.
Morphology
Cytomegalovirus Mononucleosis
Cytomegalovirus Infection in Immunosuppressed Persons
Pneumocystis Pneumonia
Figure 12–43 Pneumocystis pneumonia. A, The alveoli are filled with a characteristic foamy acellular exudate. B, Silver stain demonstrates cup-shaped and round cysts within the exudate.
Morphology
Opportunistic Fungal Infections
Candidiasis
Morphology
Clinical Features
Figure 12–44 The morphology of fungal infections. A, Candida organism has pseudohyphae and budding yeasts (silver stain). B, Invasive aspergillosis (gross appearance) of the lung in a bone marrow transplant recipient. C, Gomori methenamine-silver (GMS) stain shows septate hyphae with acute-angle branching, consistent with Aspergillus. D, Cryptococcosis of the lung in a patient with AIDS. The organisms are somewhat variable in size.
Cryptococcosis
Morphology
Clinical Features
The Opportunistic Molds
Morphology
Clinical Features
Pulmonary Disease in Human Immunodeficiency Virus Infection
Lung Tumors
Carcinomas
Etiology and Pathogenesis
Morphology
Table 12–7 Histologic Classification of Malignant Epithelial Lung Tumors
Figure 12–45 Precursor lesions of squamous cell carcinomas that may antedate the appearance of invasive tumor by years. A–C, Some of the earliest (and “mild”) changes in smoking-damaged respiratory epithelium include goblet cell hyperplasia (A), basal cell (or reserve cell) hyperplasia (B), and squamous metaplasia (C). D, More ominous changes include the appearance of squamous dysplasia, characterized by the presence of disordered squamous epithelium, with loss of nuclear polarity, nuclear hyperchromasia, pleomorphism, and mitotic figures. E and F, Squamous dysplasia may, in turn, progress through the stages of mild, moderate, and severe dysplasia. Carcinoma in situ (CIS) (E) is the stage that immediately precedes invasive squamous carcinoma (F). Apart from the lack of basement membrane disruption in CIS, the cytologic features of CIS are similar to those in frank carcinoma. Unless treated, CIS eventually progresses to invasive cancer.
Figure 12–46 A, Squamous cell carcinoma usually begins as a central (hilar) mass and grows contiguously into the peripheral parenchyma as seen here. B, Well-differentiated squamous cell carcinoma showing keratinization and pearls.
Figure 12–47 Glandular lesions of the lung. A, Atypical adenomatous hyperplasia with cuboidal epithelium and mild interstitial fibrosis. B, Adenocarcinoma in situ, mucinous subtype, with characteristic growth along preexisting alveolar septa, without invasion. C, Gland-forming adenocarcinoma; inset shows thyroid transcription factor 1 (TTF-1) positivity, which is seen in a majority of pulmonary adenocarcinomas.
Table 12–8 Comparison of Small Cell Lung Carcinoma (SCLC) and Non–Small Cell Lung Carcinoma (NSCLC)
Figure 12–48 Small cell carcinoma with small deeply basophilic cells and areas of necrosis (top left). Note basophilic staining of vascular walls due to encrustation by DNA from necrotic tumor cells (Azzopardi effect).
Clinical Course
Summary
Carcinomas of the Lung
Carcinoid Tumors
Morphology
Figure 12-49 Bronchial carcinoid. A, Carcinoid growing as a spherical, pale mass (arrow) protruding into the lumen of the bronchus. B, Histologic appearance demonstrating small, rounded, uniform nuclei and moderate cytoplasm.
Pleural Lesions
Pleural Effusion and Pleuritis
Pneumothorax, Hemothorax, and Chylothorax
Malignant Mesothelioma
Morphology
Figure 12–50 Malignant mesothelioma. Note the thick, firm, white pleural tumor that ensheathes this bisected lung.
Lesions of the Upper Respiratory Tract
Acute Infections
Nasopharyngeal Carcinoma
Laryngeal Tumors
Nonmalignant Lesions
Carcinoma of the Larynx
Figure 12–51 Laryngeal squamous cell carcinoma (arrow) arising in a supraglottic location (above the true vocal cord).
Acknowledgment
Bibliography
Chapter 13 Kidney and Its Collecting System
Clinical Manifestations Of Renal Diseases
Glomerular Diseases
Figure 13–1 Schematic diagram of a lobe of a normal glomerulus.
Mechanisms of Glomerular Injury and Disease
Figure 13–2 Low-power electron micrograph of rat glomerulus. B, basement membrane; CL, capillary lumen; End, endothelium; Ep, visceral epithelial cells (podocytes) with foot processes; Mes, mesangium; US, urinary space.
Glomerulonephritis Caused by Circulating Immune Complexes
Table 13–1 Glomerular Diseases
Glomerulonephritis Caused by In Situ Immune Complexes
Figure 13–3 Antibody-mediated glomerular injury. Injury can result either from the deposition of circulating immune complexes or from formation of complexes in situ. A, Deposition of circulating immune complexes gives a granular immunofluorescence pattern. B, Anti-glomerular basement membrane (anti-GBM) antibody glomerulonephritis is characterized by a linear immunofluorescence pattern. C, Antibodies against some glomerular components deposit in a granular pattern.
Anti-Glomerular Basement Membrane Antibody–Mediated Glomerulonephritis
Figure 13–4 Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy. A, Granular, characteristic of circulating and in situ immune complex deposition. B, Linear, characteristic of classic anti-glomerular basement membrane (anti-GBM) antibody glomerulonephritis.
Figure 13–5 Podocyte injury. The postulated sequence may be initiated by antibodies to podocyte antigens, toxins, cytokines, or other factors. The common features are podocyte injury leading to foot process effacement and variable degrees of podocyte detachment, and degradation of the basement membrane. These defects permit plasma proteins to be lost into the urinary space.
Mediators of Immune Injury
Other Mechanisms of Glomerular Injury
Podocyte Injury
Nephron Loss
Summary
Glomerular Injury
The Nephrotic Syndrome
Table 13–2 Causes of Nephrotic Syndrome
Minimal-Change Disease
Morphology
Clinical Course
Figure 13–6 Minimal-change disease. A, Under the light microscope the silver methenamine–stained glomerulus appears normal, with a delicate basement membrane. B, Schematic diagram illustrating diffuse effacement of foot processes of podocytes with no immune deposits.
Focal Segmental Glomerulosclerosis
Figure 13–7 High-power view of focal and segmental glomerulosclerosis (periodic acid–Schiff stain), seen as a mass of scarred, obliterated capillary lumens with accumulations of matrix material that has replaced a portion of the glomerulus.
Pathogenesis
Morphology
Clinical Course
Membranous Nephropathy
Figure 13–8 Membranous nephropathy. A, Diffuse thickening of the glomerular basement membrane (periodic acid–Schiff stain). B, Schematic diagram illustrating subepithelial deposits, effacement of foot processes, and the presence of spikes of basement membrane material between the immune deposits.
Pathogenesis
Morphology
Clinical Course
Membranoproliferative Glomerulonephritis and Dense Deposit Disease
Figure 13–9 A, Membranoproliferative glomerulonephritis (MPGN), showing mesangial cell proliferation, basement membrane thickening, leukocyte infiltration, and accentuation of lobular architecture. B, Schematic representation of patterns in the two types of MPGN. In type I there are subendothelial deposits; in type II, now called dense deposit disease, intramembranous characteristically dense deposits are seen. In both types, mesangial interposition gives the appearance of split basement membranes when viewed by light microscopy.
Pathogenesis
Morphology
Clinical Course
Summary
The Nephrotic Syndrome
The Nephritic Syndrome
Acute Postinfectious (Poststreptococcal) Glomerulonephritis
Pathogenesis
Morphology
Clinical Course
Figure 13–10 Poststreptococcal glomerulonephritis. A, Glomerular hypercellularity is caused by intracapillary leukocytes and proliferation of intrinsic glomerular cells. Note the red cell casts in the tubules. B, Typical electron-dense subepithelial “hump” (arrow) and intramembranous deposits. BM, basement membrane; CL, capillary lumen; E, endothelial cell; Ep, visceral epithelial cells (podocytes).
IgA Nephropathy
Figure 13–11 IgA nephropathy. Characteristic immunofluorescence deposition of IgA, principally in mesangial regions, is evident. IgA, immunoglobulin A.
Pathogenesis
Morphology
Clinical Course
Hereditary Nephritis
Pathogenesis
Morphology
Clinical Course
Summary
The Nephritic Syndrome
Rapidly Progressive Glomerulonephritis
Pathogenesis
Anti-Glomerular Basement Membrane Antibody–Mediated Crescentic Glomerulonephritis
Figure 13–12 Crescentic glomerulonephritis (GN) (Jones silver methenamine stain). Note the areas of necrosis with rupture of capillary loops (arrows) and destruction of normal glomerular structures, and the adjacent crescent-shaped mass of proliferating cells and leukocytes filling the urinary space. The segmental distribution of the necrotizing and crescentic GN is typical of ANCA (antineutrophil cytoplasmic antibody)-associated crescentic GN.
Morphology
Immune Complex–Mediated Crescentic Glomerulonephritis
Morphology
Pauci-Immune Crescentic Glomerulonephritis
Morphology
Clinical Course
Summary
Rapidly Progressive Glomerulonephritis
Diseases Affecting Tubules and Interstitium
Tubulointerstitial Nephritis
Acute Pyelonephritis
Figure 13–13 Pathways of renal infection. Hematogenous infection results from bacteremic spread. More common is ascending infection, which results from a combination of urinary bladder infection, vesicoureteral reflux, and intrarenal reflux.
Figure 13–14 Acute pyelonephritis. The cortical surface is studded with focal pale abscesses, more numerous in the upper pole and middle region of the kidney; the lower pole is relatively unaffected. Between the abscesses there is dark congestion of the renal surface.
Pathogenesis
Morphology
Clinical Course
Chronic Pyelonephritis and Reflux Nephropathy
Chronic Obstructive Pyelonephritis
Chronic Reflux–Associated Pyelonephritis (Reflux Nephropathy)
Figure 13–15 Typical coarse scars of chronic pyelonephritis associated with vesicoureteral reflux. The scars are usually located at the upper or lower poles of the kidney and are associated with underlying blunted calyces.
Morphology
Clinical Course
Drug-Induced Interstitial Nephritis
Pathogenesis
Morphology
Clinical Course
Figure 13–16 Drug-induced interstitial nephritis, with prominent eosinophilic and mononuclear infiltrate.
Summary
Tubulointerstitial Nephritis
Acute Tubular Injury
Figure 13–17 Pathophysiologic mechanisms of acute kidney injury. Various toxic injuries can directly damage tubules, which in turn directly decreases GFR and lowers urine output through multiple mechanisms. Ischemia and consequent vasoconstriction contribute directly to diminished GFR, and further contribute indirectly through injury to the tubules. Tubular cells, which are highly metabolically active and uniquely sensitive to diminished blood supply within the kidney, release several vasoconstrictor substances as part of the response to hypoxia, which then further exacerbates the overall injury.
Pathogenesis
Morphology
Clinical Course
Summary
Acute Tubular Injury
Diseases Involving Blood Vessels
Arterionephrosclerosis
Pathogenesis
Morphology
Clinical Course
Figure 13–18 Benign nephrosclerosis. High-power view of two arterioles with hyaline deposition, marked thickening of the walls, and a narrowed lumen.
Malignant Hypertension
Pathogenesis
Morphology
Clinical Course
Figure 13–19 Malignant hypertension. A, Fibrinoid necrosis of afferent arteriole (periodic acid–Schiff stain). B, Hyperplastic arteriolosclerosis (onionskin lesion).
Thrombotic Microangiopathies
Pathogenesis
Morphology
Clinical Course
Summary
Vascular Diseases of the Kidney
Chronic Kidney Disease
Figure 13–20 Chronic glomerulonephritis. A Masson trichrome preparation shows complete replacement of virtually all glomeruli by blue-staining collagen.
Morphology
Clinical Course
Cystic Diseases of the Kidney
Simple Cysts
Autosomal Dominant (Adult) Polycystic Kidney Disease
Figure 13–21 Autosomal dominant adult polycystic kidney, viewed from the external surface (A) and bisected (B). The kidney is markedly enlarged (centimeter rule is shown for scale), with numerous dilated cysts.
Pathogenesis
Morphology
Clinical Course
Autosomal Recessive (Childhood) Polycystic Kidney Disease
Morphology
Clinical Course
Medullary Diseases with Cysts
Morphology
Clinical Course
Summary
Cystic Diseases
Urinary Outflow Obstruction
Renal Stones
Table 13–3 Prevalence of Various Types of Renal Stones
Pathogenesis
Morphology
Clinical Course
Hydronephrosis
Figure 13–22 Hydronephrosis of the kidney, with marked dilation of the pelvis and calyces and thinning of renal parenchyma.
Pathogenesis
Morphology
Clinical Course
Tumors
Tumors of the Kidney
Oncocytoma
Renal Cell Carcinoma
Clear Cell Carcinomas
Papillary Renal Cell Carcinomas
Chromophobe Renal Carcinomas
Figure 13–23 Renal cell carcinoma: Representative cross-section showing yellowish, spherical neoplasm in one pole of the kidney. Note the tumor in the dilated, thrombosed renal vein.
Figure 13–24 High-power detail of the clear cell pattern of renal cell carcinoma.
Morphology
Clinical Course
Summary
Renal Cell Carcinoma
Wilms Tumor
Bibliography
Chapter 14 Oral Cavity and Gastrointestinal Tract
Oral Cavity
Oral Inflammatory Lesions
Aphthous Ulcers (Canker Sores)
Herpes Simplex Virus Infections
Figure 14–1 Aphthous ulcer. Single ulceration with an erythematous halo surrounding a yellowish fibrinopurulent membrane.
Oral Candidiasis (Thrush)
Summary
Oral Inflammatory Lesions
Proliferative and Neoplastic Lesions of the Oral Cavity
Fibrous Proliferative Lesions
Figure 14–2 Fibrous proliferations. A, Fibroma. Smooth pink exophytic nodule on the buccal mucosa. B, Pyogenic granuloma. Erythematous hemorrhagic exophytic mass arising from the gingival mucosa.
Leukoplakia and Erythroplakia
Morphology
Figure 14–3 Leukoplakia. A, Clinical appearance of leukoplakia is highly variable. In this example, the lesion is smooth with well-demarcated borders and minimal elevation. B, Histologic appearance of leukoplakia showing dysplasia, characterized by nuclear and cellular pleomorphism and loss of normal maturation.
Squamous Cell Carcinoma
Figure 14–4 Oral squamous cell carcinoma. A, Clinical appearance demonstrating ulceration and induration of the oral mucosa. B, Histologic appearance demonstrating numerous nests and islands of malignant keratinocytes invading the underlying connective tissue stroma.
Pathogenesis
Morphology
Summary
Lesions of the Oral Cavity
Diseases of Salivary Glands
Xerostomia
Sialadenitis
Neoplasms
Figure 14–5 Mucocele. A, Fluctuant fluid-filled lesion on the lower lip subsequent to trauma. B, Cystlike cavity (right) filled with mucinous material and lined by organizing granulation tissue.
Table 14–1 Histopathologic Classification and Prevalence of the Most Common Benign and Malignant Salivary Gland Tumors
Pleomorphic Adenoma
Figure 14–6 Pleomorphic adenoma. A, Low-power view showing a well-demarcated tumor with adjacent normal salivary gland parenchyma. B, High-power view showing epithelial cells as well as myoepithelial cells within chondroid matrix material.
Morphology
Mucoepidermoid Carcinoma
Morphology
Summary
Diseases of Salivary Glands
Odontogenic Cysts and Tumors
Summary
Odontogenic Cysts and Tumors
Esophagus
Obstructive and Vascular Diseases
Mechanical Obstruction
Functional Obstruction
Ectopia
Esophageal Varices
Pathogenesis
Morphology
Clinical Features
Figure 14–7 Esophageal varices. A, Angiogram showing several tortuous esophageal varices. Although the angiogram is striking, endoscopy is more commonly used to identify varices. B, Collapsed varices are present in this postmortem specimen corresponding to the angiogram in A. The polypoid areas are sites of variceal hemorrhage that were ligated with bands. C, Dilated varices beneath intact squamous mucosa.
Esophagitis
Lacerations
Chemical and Infectious Esophagitis
Reflux Esophagitis
Figure 14–8 Viral esophagitis. A, Postmortem specimen with multiple herpetic ulcers in the distal esophagus. B, Multinucleate squamous cells containing herpesvirus nuclear inclusions. C, Cytomegalovirus-infected endothelial cells with nuclear and cytoplasmic inclusions.
Pathogenesis
Morphology
Clinical Features
Figure 14–9 Esophagitis. A, Reflux esophagitis with scattered intraepithelial eosinophils. B, Eosinophilic esophagitis with numerous intraepithelial eosinophils.
Eosinophilic Esophagitis
Barrett Esophagus
Figure 14–10 Barrett esophagus. A, Normal gastroesophageal junction. B, Barrett esophagus. Note the small islands of paler squamous mucosa within the Barrett mucosa. C, Histologic appearance of the gastroesophageal junction in Barrett esophagus. Note the transition between esophageal squamous mucosa (left) and metaplastic mucosa containing goblet cells (right).
Morphology
Clinical Features
Esophageal Tumors
Adenocarcinoma
Pathogenesis
Morphology
Clinical Features
Figure 14–11 Esophageal adenocarcinoma. A, Adenocarcinoma usually occurs distally and, as in this case, often involves the gastric cardia. B, Esophageal adenocarcinoma growing as back-to-back glands.
Squamous Cell Carcinoma
Figure 14–12 Esophageal squamous cell carcinoma. A, Squamous cell carcinoma most frequently is found in the midesophagus, where it commonly causes strictures. B, Squamous cell carcinoma composed of nests of malignant cells that partially recapitulate the stratified organization of squamous epithelium.
Pathogenesis
Morphology
Clinical Features
Summary
Diseases of the Esophagus
Stomach
Inflammatory Disease of the Stomach
Acute Gastritis
Figure 14–13 Mechanisms of gastric injury and protection. This diagram illustrates the progression from more mild forms of injury to ulceration that may occur with acute or chronic gastritis. Ulcers include layers of necrotic debris (N), inflammation (I), and granulation tissue (G); a fibrotic scar (S), which develops over time, is present only in chronic lesions.
Pathogenesis
Morphology
Acute Peptic Ulceration
Pathogenesis
Morphology
Clinical Features
Chronic Gastritis
Helicobacter pylori Gastritis
Epidemiology
Figure 14–14 Chronic gastritis. A, Spiral-shaped Helicobacter pylori bacilli are highlighted in this Warthin-Starry silver stain. Organisms are abundant within surface mucus. B, Intraepithelial and lamina propria neutrophils are prominent. C, Lymphoid aggregates with germinal centers and abundant subepithelial plasma cells within the superficial lamina propria are characteristic of H. pylori gastritis. D, Intestinal metaplasia, recognizable as the presence of goblet cells admixed with gastric foveolar epithelium, can develop and is a risk factor for development of gastric adenocarcinoma.
Pathogenesis
Morphology
Clinical Features
Autoimmune Gastritis
Table 14–2 Characteristics of Helicobacter pylori–Associated and Autoimmune Gastritis
Pathogenesis
Morphology
Clinical Features
Peptic Ulcer Disease
Epidemiology
Pathogenesis
Morphology
Clinical Features
Figure 14–15 Acute gastric perforation in a patient presenting with free air under the diaphragm. A, Mucosal defect with clean edges. B, The necrotic ulcer base (arrow) is composed of granulation tissue.
Summary
Acute and Chronic Gastritis
Neoplastic Disease of the Stomach
Gastric Polyps
Inflammatory and Hyperplastic Polyps
Morphology
Fundic Gland Polyps
Gastric Adenoma
Morphology
Gastric Adenocarcinoma
Epidemiology
Figure 14–16 Gastric adenocarcinoma. A, Intestinal-type adenocarcinoma consisting of an elevated mass with heaped-up borders and central ulceration. Compare with the peptic ulcer in Figure 14-15, A. B, Linitis plastica. The gastric wall is markedly thickened, and rugal folds are partially lost. C, Signet ring cells with large cytoplasmic mucin vacuoles and peripherally displaced, crescent-shaped nuclei.
Pathogenesis
Morphology
Clinical Features
Lymphoma
Carcinoid Tumor
Morphology
Clinical Features
Figure 14–17 Gastrointestinal carcinoid tumor (neuroendocrine tumor). A, Carcinoid tumors often form a submucosal nodule composed of tumor cells embedded in dense fibrous tissue. B, High magnification shows the bland cytology that typifies carcinoid tumors. The chromatin texture, with fine and coarse clumps, frequently assumes a “salt and pepper” pattern. Despite their innocuous appearance, carcinoids can be aggressive.
Gastrointestinal Stromal Tumor
Epidemiology
Pathogenesis
Morphology
Clinical Features
Summary
Gastric Polyps and Tumors
Small and Large Intestines
Intestinal Obstruction
Hirschsprung Disease
Figure 14–18 Intestinal obstruction. The four major mechanical causes of intestinal obstruction are (1) herniation of a segment in the umbilical or inguinal regions, (2) adhesion between loops of intestine, (3) volvulus, and (4) intussusception.
Figure 14–19 Hirschsprung disease. A, Preoperative barium enema study showing constricted rectum (bottom of the image) and dilated sigmoid colon. Ganglion cells were absent in the rectum, but present in the sigmoid colon. B, Corresponding intraoperative appearance of the dilated sigmoid colon.
pathogenesis
Morphology
Abdominal Hernia
Summary
Intestinal Obstruction
Vascular Disorders of Bowel
Ischemic Bowel Disease
Pathogenesis
Morphology
Clinical Features
Figure 14–20 Ischemia. A, Characteristic attenuated and partially detached villous epithelium in acute jejunal ischemia. Note the hyperchromatic nuclei of proliferating crypt cells. B, Chronic colonic ischemia with atrophic surface epithelium and fibrotic lamina propria.
Hemorrhoids
Morphology
Clinical Features
Summary
Vascular Disorders of Bowel
Diarrheal Disease
Malabsorptive Diarrhea
Table 14–3 Defects in Malabsorptive and Diarrheal Disease
Cystic Fibrosis
Celiac Disease
Figure 14–21 Left panel, The morphologic alterations that may be present in celiac disease, including villous atrophy, increased numbers of intraepithelial lymphocytes (IELs), and epithelial proliferation with crypt elongation. Right panel, A model for the pathogenesis of celiac disease. Note that both innate and adaptive immune mechanisms are involved in the tissue responses to gliadin.
Figure 14–22 Celiac disease. A, Advanced cases of celiac disease show complete loss of villi, or total villous atrophy. Note the dense plasma cell infiltrates in the lamina propria. B, Infiltration of the surface epithelium by T lymphocytes, which can be recognized by their densely stained nuclei (labeled T). Compare with elongated, pale-staining epithelial nuclei (labeled E).
Pathogenesis
Morphology
Clinical Features
Environmental (Tropical) Enteropathy
Lactase (Disaccharidase) Deficiency
Abetalipoproteinemia
Irritable Bowel Syndrome
Microscopic Colitis
Graft-Versus-Host Disease
Summary
Malabsorptive Diarrhea
Infectious Enterocolitis
Table 14–4 Features of Bacterial Enterocolitides
Cholera
Pathogenesis
Clinical Features
Campylobacter Enterocolitis
Figure 14–23 Bacterial enterocolitis. A, Campylobacter jejuni infection produces acute, self-limited colitis. Neutrophils can be seen within surface and crypt epithelium and a crypt abscess is present at the lower right. B, Enteroinvasive Escherichia coli infection is similar to other acute, self-limited colitides. Note the maintenance of normal crypt architecture and spacing, despite abundant intraepithelial neutrophils.
Pathogenesis
Morphology
Clinical Features
Shigellosis
Pathogenesis
Morphology
Clinical Features
Escherichia coli
Salmonellosis
Pathogenesis
Typhoid Fever
Pseudomembranous Colitis
Figure 14–24 Clostridium difficile colitis. A, The colon is coated by tan pseudomembranes composed of neutrophils, dead epithelial cells, and inflammatory debris (endoscopic view). B, Typical pattern of neutrophils emanating from a crypt is reminiscent of a volcanic eruption.
Morphology
Clinical Features
Norovirus
Rotavirus
Parasitic Disease
Summary
Infectious Enterocolitis
Inflammatory Intestinal Disease
Sigmoid Diverticulitis
Pathogenesis
Morphology
Clinical Features
Figure 14–25 Sigmoid diverticular disease. A, Stool-filled diverticula are regularly arranged. B, Cross-section showing the outpouching of mucosa beneath the muscularis propria. C, Low-power photomicrograph of a sigmoid diverticulum showing protrusion of the mucosa and submucosa through the muscularis propria.
Summary
Sigmoid Diverticulitis
Inflammatory Bowel Disease
Figure 14–26 Distribution of lesions in inflammatory bowel disease. The distinction between Crohn disease and ulcerative colitis is based primarily on morphology.
Table 14–5 Features That Differ Between Crohn Disease and Ulcerative Colitis
Epidemiology
Figure 14–27 A model of pathogenesis of inflammatory bowel disease (IBD). Aspects of both Crohn disease and ulcerative colitis are shown.
Figure 14–28 Gross pathology of Crohn disease. A, Small intestinal stricture. B, Linear mucosal ulcers and thickened intestinal wall. C, Creeping fat.
Pathogenesis
Crohn Disease
Figure 14–29 Microscopic pathology of Crohn disease. A, Haphazard crypt organization results from repeated injury and regeneration. B, Noncaseating granuloma. C, Transmural Crohn disease with submucosal and serosal granulomas (arrows).
Morphology
Clinical Features
Ulcerative Colitis
Morphology
Clinical Features
Figure 14–30 Pathology of ulcerative colitis. A, Total colectomy with pancolitis showing active disease, with red, granular mucosa in the cecum (left) and smooth, atrophic mucosa distally (right). B, Sharp demarcation between active ulcerative colitis (bottom) and normal (top). C, This full-thickness histologic section shows that disease is limited to the mucosa. Compare with Figure 14–28, C.
Indeterminate Colitis
Colitis-Associated Neoplasia
Summary
Inflammatory Bowel Disease
Colonic Polyps and Neoplastic Disease
Inflammatory Polyps
Hamartomatous Polyps
Juvenile Polyps
Morphology
Peutz-Jeghers Syndrome
Table 14–6 Gastrointestinal (GI) Polyposis Syndromes
Hyperplastic Polyps
Morphology
Adenomas
Figure 14–31 Hamartomatous polyps. A, Juvenile polyp. Note the surface erosion and cystically dilated crypts filled with mucus, neutrophils, and debris. B, Peutz-Jeghers polyp. Complex glandular architecture and bundles of smooth muscle help to distinguish Peutz-Jeghers polyps from juvenile polyps.
Figure 14–32 Hyperplastic polyp. A, Polyp surface with irregular tufting of epithelial cells. B, Tufting results from epithelial overcrowding. C, Epithelial crowding produces a serrated architecture when glands are cut in cross-section.
Figure 14–33 Colonic adenomas. A, Pedunculated adenoma (endoscopic view). B, Adenoma with a velvety surface. C, Low-magnification photomicrograph of a pedunculated tubular adenoma.
Figure 14–34 Histologic appearance of colonic adenomas. A, Tubular adenoma with a smooth surface and rounded glands. In this case, crypt dilation and rupture, with associated reactive inflammation, can be seen at the bottom of the field. B, Villous adenoma with long, slender projections that are reminiscent of small intestinal villi. C, Dysplastic epithelial cells (top) with an increased nuclear-to-cytoplasmic ratio, hyperchromatic and elongated nuclei, and nuclear pseudostratification. Compare with the nondysplastic epithelium below. D, Sessile serrated adenoma lined by goblet cells without typical cytologic features of dysplasia. This lesion is distinguished from a hyperplastic polyp by involvement of the crypts. Compare with the hyperplastic polyp in Figure 14–32.
Morphology
Familial Syndromes
Familial Adenomatous Polyps
Table 14–7 Common Patterns of Sporadic and Familial Colorectal Neoplasia
Figure 14–35 Familial adenomatous polyposis. A, Hundreds of small colonic polyps are present along with a dominant polyp (right). B, Three tubular adenomas are present in this single microscopic field.
Hereditary Nonpolyposis Colorectal Cancer
Adenocarcinoma
Epidemiology
Figure 14–36 Morphologic and molecular changes in the adenoma-carcinoma sequence. It is postulated that loss of one normal copy of the tumor suppressor gene APC occurs early. Persons may be born with one mutant allele, making them extremely prone to the development of colon cancer, or inactivation of APC may occur later in life. This is the “first hit” according to Knudson’s hypothesis. The loss of the intact copy of APC follows (“second hit”). Other mutations involving KRAS, SMAD2, and SMAD4, and the tumor suppressor gene TP53, lead to the emergence of carcinoma, in which additional mutations occur. Although there may be a preferred temporal sequence for these changes, it is the aggregate effect of the mutations, rather than their order of occurrence, that appears most critical.
Figure 14–37 Morphologic and molecular changes in the mismatch repair pathway of colon carcinogenesis. Defects in mismatch repair genes result in microsatellite instability and permit accumulation of mutations in numerous genes. If these mutations affect genes involved in cell survival and proliferation, cancer may develop. LOH, loss of heterozygosity.
Pathogenesis
Morphology
Clinical Features
Figure 14–38 Colorectal carcinoma. A, Circumferential, ulcerated rectal cancer. Note the anal mucosa at the bottom of the image. B, Cancer of the sigmoid colon that has invaded through the muscularis propria and is present within subserosal adipose tissue (left). Areas of chalky necrosis are present within the colon wall (arrow).
Figure 14–39 Histologic appearance of colorectal carcinoma. A, Well-differentiated adenocarcinoma. Note the elongated, hyperchromatic nuclei. Necrotic debris, present in the gland lumen, is typical. B, Poorly differentiated adenocarcinoma forms a few glands but is largely composed of infiltrating nests of tumor cells. C, Mucinous adenocarcinoma with signet ring cells and extracellular mucin pools.
Figure 14–40 Metastatic colorectal carcinoma. A, Lymph node metastasis. Note the glandular structures within the subcapsular sinus. B, Solitary subpleural nodule of colorectal carcinoma metastatic to the lung. C, Liver containing two large and many smaller metastases. Note the central necrosis within metastases.
Table 14–8 AJCC Tumor-Node-Metastasis (TNM) Classification of Colorectal Carcinoma
Table 14–9 AJCC Colorectal Cancer Staging and Survival
Summary
Colonic Polyps, Adenomas, and Adenocarcinomas
Appendix
Acute Appendicitis
Pathogenesis
Morphology
Clinical Features
Tumors of the Appendix
Summary
Appendix
Bibliography
Oral Cavity
Esophagus
Inflammatory Disease of the Stomach
Neoplastic Disease of the Stomach
Intestinal Obstruction
Vascular Disorders
Malabsorptive Diarrhea
Infectious Enterocolitis
Sigmoid Diverticulitis
Inflammatory Bowel Disease
Colonic Polyps and Neoplastic Disease
Appendix
Chapter 15 Liver, Gallbladder, and Biliary Tract
The Liver
Table 15–1 Clinical Consequences of Liver Disease
Table 15–2 Laboratory Evaluation of Liver Disease
Clinical Syndromes
Hepatic Failure
Clinical Features
Jaundice and Cholestasis
Bilirubin and Bile Acids
Pathogenesis
Figure 15–1 Bilirubin metabolism and elimination. 1, Normal bilirubin production (0.2 to 0.3 g/day) is derived primarily from the breakdown of senescent circulating red cells, with a minor contribution from degradation of tissue heme-containing proteins. 2, Extrahepatic bilirubin is bound to serum albumin and delivered to the liver. 3 and 4, Hepatocellular uptake (3) and glucuronidation (4) by glucuronosyltransferase in the hepatocytes generate bilirubin monoglucuronides and diglucuronides, which are water-soluble and readily excreted into bile. 5, Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and reexcretion into bile.
Table 15–3 Main Causes of Jaundice
Summary
Jaundice and Cholestasis
Hepatic Encephalopathy
Cirrhosis
Figure 15–2 Liver fibrosis. In the normal liver, the perisinusoidal space (space of Disse) contains a delicate framework of extracellular matrix components. In liver fibrosis, stellate cells are activated to produce a dense layer of matrix material that is deposited in the perisinusoidal space. Collagen deposition blocks the endothelial fenestrations and prevents the free exchange of materials from the blood. Kuppfer cells also are activated and produce cytokines that are involved in fibrosis. Note that this illustration is not to scale; the space of Disse is actually much narrower than shown.
Pathogenesis
Clinical Features
Summary
Cirrhosis
Portal Hypertension
Ascites
Figure 15–3 Some clinical consequences of portal hypertension in the setting of cirrhosis. The most important manifestations are in bold type.
Pathogenesis
Portosystemic Shunt
Splenomegaly
Hepatorenal Syndrome
Portopulmonary Hypertension and Hepatopulmonary Syndrome
Drug- or Toxin-Induced Liver Disease
Table 15–4 Different Forms of Drug- or Toxin-Induced Hepatic Injury
Summary
Drug- or Toxin-Induced Liver Disease
Acute and Chronic Hepatitis
Figure 15–4 Microscopic architecture of the liver parenchyma. Both a lobule and an acinus are represented. The idealized classic lobule is represented as hexagonal centered on a central vein (CV), also known as terminal hepatic venule, and has portal tracts at three of its apices. The portal tracts contain branches of the portal vein (PV), hepatic artery (HA), and the bile duct (BD) system. Regions of the lobule generally are referred to as periportal, midzonal, and centrilobular, according to their proximity to portal spaces and central vein. Another useful way to subdivide the liver architecture is to use the blood supply as a point of reference. Using this approach, triangular acini can be recognized. Acini have at their base branches of portal vessels that penetrate the parenchyma (“penetrating vessels”). On the basis of the distance from the blood supply, the acinus is divided into zones 1 (closest to blood source), 2, and 3 (farthest from blood source).
Figure 15–5 A, Massive necrosis, cut section of liver. The liver is small (700 g), bile-stained, soft, and congested. B, Hepatocellular necrosis caused by acetaminophen overdose. Confluent necrosis is seen in the perivenular region (zone 3) (large arrow). There is little inflammation. The residual normal tissue is indicated by the asterisk.
Table 15–5 Main Morphologic Features of Acute and Chronic Viral Hepatitis
Figure 15–6 Acute viral hepatitis showing disruption of lobular architecture, inflammatory cells in sinusoids, and apoptotic cells (arrow).
Figure 15–7 Chronic hepatitis showing portal tract expansion by a dense infiltrate of mononuclear cells (arrow) and interface hepatitis with spillover of inflammation into the parenchyma (arrowhead). The prominent lymphoid infiltrate is typical of the cause of disease in this biopsy: chronic hepatitis C.
Figure 15–8 Cirrhosis resulting from chronic viral hepatitis. Note the irregular nodularity of the liver surface.
Morphology
Viral Hepatitis
Hepatitis A Virus
Table 15–6 The Hepatitis Viruses
Hepatitis B Virus
Figure 15–9 The sequence of serologic markers in acute hepatitis A infection. HAV, hepatitis A virus. There are no routinely available tests for IgG anti-HAV; therefore the presence of this antibody is inferred from the difference between total and IgM-HAV.
Epidemiology and Transmission
Figure 15–10 The potential outcomes with hepatitis B infection in adults, with their approximate annual frequencies in the United States. *Estimated rate of recovery from chronic hepatitis is 0.5% to 1% per year. **The risk of hepatocellular carcinoma is 0.02% per year for chronic hepatitis B and 2.5% per year when cirrhosis has developed.
HBV Structure and Genome
Clinical Course
Figure 15–11 The sequence of serologic markers in acute hepatitis B infection. A, Resolution of active infection. B, Progression to chronic infection. See text for abbreviations.
Figure 15-12 Ground-glass hepatocytes in chronic hepatitis B, caused by accumulation of HBsAg in cytoplasm, have large, pale, finely granular, pink cytoplasmic inclusions on hematoxylin-eosin staining; immunostaining (inset) confirms that the endoplasmic reticulum is ballooned with surface antigen (brown). HBsAg, hepatitis B surface antigen.
Figure 15–13 The potential outcomes of hepatitis C infection in adults, with their approximate annual frequencies in the United States. The population estimates are for newly detected infection; because of the decades-long lag time for progression from acute infection to cirrhosis, the actual annual death rate from hepatitis C is about 10,000 per year and exceeded 22,000 deaths per year by 2008. *The risk of hepatocellular carcinoma is 1% to 4% per year.
Morphology
Hepatitis C Virus
Epidemiology and Transmission
Viral Structure and Genome
Clinical Course
Figure 15–14 Sequence of serologic markers for hepatitis C. A, Acute infection with resolution. B, Progression to chronic infection. See text for abbreviations.
Morphology
Hepatitis D Virus
Hepatitis E Virus
Clinical Features and Outcomes for Viral Hepatitis
Asymptomatic Infection
Acute Viral Hepatitis
Fulminant Hepatitis
Chronic Hepatitis
The Carrier State
Other Viral Infections of the Liver
Summary
Viral Hepatitis
Autoimmune Hepatitis
Morphology
Drug/Toxin-Mediated Injury Mimicking Hepatitis
Alcoholic and Nonalcoholic Fatty Liver Disease
Morphology
Figure 15–15 Fatty liver disease. Macrovesicular steatosis is most prominent around the central vein and extends outward to the portal tracts with increasing severity. The intracytoplasmic fat is seen as clear vacuoles. Some fibrosis (stained blue) is present in a characteristic perisinusoidal “chicken wire fence” pattern. (Masson trichrome stain.)
Figure 15-16 A, Alcoholic hepatitis with clustered inflammatory cells marking the site of a necrotic hepatocyte. A Mallory-Denk body is present in another hepatocyte (arrow). B, Steatohepatitis with many ballooned hepatocytes (arrowheads) containing prominent Mallory-Denk bodies; clusters of inflammatory cells are also seen; inset shows immunostaining for keratins 8 and 18 (brown), with most hepatocytes, including those with fat vacuoles, showing normal cytoplasmic staining, but in the ballooned cell (dotted line), the keratins are collapsed into the Mallory-Denk body, leaving the cytoplasm “empty.”
Figure 15–17 Alcoholic cirrhosis. The characteristic diffuse nodularity of the surface is induced by the underlying fibrous scarring. The average nodule size is 3 mm in this close-up view. The greenish tint is caused by bile stasis.
Figure 15–18 Steatohepatitis leading to cirrhosis. Small nodules are entrapped in blue-staining fibrous tissue; fatty accumulation is no longer seen in this “burned-out” stage. (Masson trichrome stain.)
Alcoholic Liver Disease
Pathogenesis
Figure 15–19 Alcoholic liver disease. The interrelationships among hepatic steatosis, alcoholic hepatitis, and alcoholic cirrhosis are shown, along with a depiction of key morphologic features at the microscopic level. As stated in the text, it should be noted that steatosis, alcoholic hepatitis, and cirrhosis may also develop independently and not along a continuum.
Clinical Features
Summary
Alcoholic Liver Disease
Nonalcoholic Fatty Liver Disease (NAFLD)
Pathogenesis
Summary
Nonalcoholic Fatty Liver Disease
Drug/Toxin-Mediated Injury with Steatosis
Morphology
Cholestatic Liver Diseases
Neonatal Cholestasis
Cholestasis of Sepsis
Figure 15–20 A, Cholestasis of sepsis. Prominent bile plugs are present in dilated canaliculi in the centrilobular region. B, Ductular cholestasis. Large, dark bile concretions within markedly dilated canals of Hering and ductules at the portal-parenchymal interface. This feature, indicative of current or impending severe sepsis, is related to endotoxemia.
Table 15–7 Main Features of Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis
Primary Biliary Cirrhosis
Pathogenesis
Clinical Course
Morphology
Figure 15–21 Primary biliary cirrhosis. A portal tract is markedly expanded by an infiltrate of lymphocytes and plasma cells. Note the granulomatous reaction to a bile duct undergoing destruction (florid duct lesion).
Figure 15–22 An example of ductular reaction in a fibrotic septum.
Figure 15–23 Primary biliary cirrhosis, end stage. This sagittal section demonstrates liver enlargement, nodularity indicative of cirrhosis, and green discoloration due to cholestasis.
Primary Sclerosing Cholangitis
Morphology
Figure 15–24 Primary sclerosing cholangitis. A bile duct undergoing degeneration is entrapped in a dense, “onion-skin” concentric scar.
Clinical Course
Drug/Toxin-Induced Cholestasis
Inherited Metabolic Diseases
Hemochromatosis
Pathogenesis
Morphology
Figure 15–25 Hereditary hemochromatosis. In this Prussian blue–stained histologic section, hepatocellular iron appears blue. The parenchymal architecture is normal.
Clinical Features
Wilson Disease
Pathogenesis
Morphology
Clinical Features
α1-Antitrypsin Deficiency
Pathogenesis
Morphology
Figure 15–26 α1-Antitrypsin deficiency. Periodic acid–Schiff stained histologic section of liver, highlighting the characteristic magenta cytoplasmic granules.
Clinical Course
Summary
Inherited Metabolic Diseases
Circulatory Disorders
Impaired Blood Flow into the Liver
Hepatic Artery Inflow
Portal Vein Obstruction and Thrombosis
Figure 15–27 Hepatic circulatory disorders. The forms and clinical manifestations of compromised blood flow are contrasted.
Impaired Blood Flow Through the Liver
Passive Congestion and Centrilobular Necrosis
Morphology
Figure 15–28 Centrilobular hemorrhagic necrosis (nutmeg liver). A, The cut liver section, in which major blood vessels are visible, is notable for a variegated mottled red appearance, representing hemorrhage in the centrilobular regions of the parenchyma. B, On microscopic examination, the centrilobular region is suffused with red blood cells, and hepatocytes are not readily visible. Portal tracts and the periportal parenchyma are intact.
Figure 15–29 Budd-Chiari syndrome. Thrombosis of the major hepatic veins has caused profound hepatic congestion.
Figure 15–30 Sinusoidal obstruction syndrome (formerly known as venoocclusive disease). A central vein is occluded by cells and newly formed collagen (arrow). There is also fibrosis in the sinusoidal spaces. Fibrous tissue is stained blue by the Masson trichrome stain.
Hepatic Vein Outflow Obstruction
Hepatic Vein Thrombosis (Budd-Chiari Syndrome)
Morphology
Sinusoidal Obstruction Syndrome
Summary
Circulatory Disorders
Other Inflammatory and Infectious Diseases
Liver Abscesses
Granulomatous Disease
Tumors and Hepatic Nodules
Benign Tumors
Focal Nodular Hyperplasia
Figure 15–31 Hepatic adenoma. A, Surgically resected specimen showing a discrete mass underneath the liver capsule with hemorrhagic necrosis (dark red areas). B, Photomicrograph showing adenoma, with cords of normal-appearing hepatocytes, absence of portal tracts, and prominent neovascularization (asterisks). A large zone of infarcted tumor is present.
Hepatic Adenoma
Precursor Lesions of Hepatocellular Carcinoma
Cellular Dysplasia
Figure 15–32 A, Large cell change. Very large hepatocytes with very large, often atypical nuclei are scattered among normal-size hepatocytes with round, typical nuclei. B, Small cell change (SCC). Normal-appearing hepatocytes are in the lower right corner. SCC is indicated by smaller than normal hepatocytes with thickened liver cell plates, and high nuclear:cytoplasmic ratio.
Dysplastic Nodules
Hepatocellular Carcinomas
Epidemiology
Pathogenesis
Morphology
Figure 15–33 A, Hepatitis C–related cirrhosis with a distinctively large nodule (arrows). Nodule-in-nodule growth in this dysplastic nodule suggests a high grade lesion. B, Histologically the region within the box in A shows a well-differentiated hepatocellular carcinoma (HCC) (right side) and a subnodule of moderately differentiated HCC within it (center, left).
Figure 15–34 Well-differentiated hepatocellular carcinoma has distortions of normal structures: Liver cell plates are markedly widened, and frequent “pseudoacinar” structures (arrows)—abnormal bile canaliculi—often contain bile.
Clinical Features
Summary
Liver Tumors
Disorders of the Gallbladder and the Extrahepatic Biliary Tract
Gallbladder Diseases
Cholelithiasis (Gallstones)
Pathogenesis
Morphology
Table 15–8 Risk Factors for Gallstones
Figure 15–35 Cholesterol gallstones. Mechanical manipulation during laparoscopic cholecystectomy has caused fragmentation of several cholesterol gallstones, revealing interiors that are pigmented because of entrapped bile pigments. The gallbladder mucosa is reddened and irregular as a result of coexistent acute and chronic cholecystitis.
Figure 15–36 Pigmented gallstones. Several faceted black gallstones are present in this otherwise unremarkable gallbladder removed from a patient who had a mechanical mitral valve prosthesis, leading to chronic intravascular hemolysis.
Clinical Features
Cholecystitis
Morphology
Acute Calculous Cholecystitis
Acute Acalculous Cholecystitis
Chronic Cholecystitis
Clinical Features
Disorders of Extrahepatic Bile Ducts
Choledocholithiasis and Cholangitis
Secondary Biliary Cirrhosis
Biliary Atresia
Clinical Course
Figure 15–37 Adenocarcinoma of the gallbladder. The opened gallbladder contains a large, exophytic tumor that virtually fills the lumen.
Summary
Diseases of the Gallbladder and Extrahepatic Bile Ducts
Tumors
Carcinoma of the Gallbladder
Morphology
Clinical Features
Cholangiocarcinomas
Figure 15–38 Cholangiocarcinoma. A, Massive neoplasm in the right lobe and widespread intrahepatic metastases. B, Tumor cells forming glandular structures surrounded by dense sclerotic stroma.
Morphology
Clinical Features
Bibliography
Chapter 16 Pancreas
Congenital Anomalies
Agenesis
Pancreas Divisum
Annular Pancreas
Ectopic Pancreas
Congenital Cysts
Pancreatitis
Acute Pancreatitis
Table 16–1 Etiologic Factors in Acute Pancreatitis
Figure 16–1 Acute pancreatitis. A, The microscopic field shows a region of fat necrosis (right) and focal pancreatic parenchymal necrosis (center). B, The pancreas has been sectioned longitudinally to reveal dark areas of hemorrhage in the pancreatic substance and a focal area of pale fat necrosis in the peripancreatic fat (upper left).
Figure 16–2 Proposed pathogenesis of acute pancreatitis.
Morphology
Pathogenesis
Clinical Features
Figure 16–3 Pancreatic pseudocyst. A, Cross-section revealing a poorly defined cyst with a necrotic brownish wall. B, Histologically, the cyst lacks a true epithelial lining and instead is lined by fibrin and granulation tissue, with typical changes of chronic inflammation.
Pancreatic Pseudocysts
Morphology
Chronic Pancreatitis
Figure 16–4 Chronic pancreatitis. A, Extensive fibrosis and atrophy has left only residual islets (left) and ducts (right), with a sprinkling of chronic inflammatory cells and acinar tissue. B, A higher-power view demonstrating dilated ducts with inspissated eosinophilic concretions in a patient with alcoholic chronic pancreatitis.
Morphology
Pathogenesis
Clinical Features
Summary
Pancreatitis
Pancreatic Neoplasms
Cystic Neoplasms
Serous Cystadenomas
Figure 16–5 Serous cystadenoma. A, Cross-section through a serous cystadenoma. Only a thin rim of normal pancreatic parenchyma remains. The cysts are relatively small and contain clear, straw-colored fluid. B, The cysts are lined by cuboidal epithelium without atypia.
Mucinous Cystic Neoplasms
Intraductal Papillary Mucinous Neoplasms
Figure 16–6 Mucinous cystic neoplasm. A, Cross-section through a mucinous multiloculated cyst in the tail of the pancreas. The cysts are large and filled with tenacious mucin. B, The cysts are lined by columnar mucinous epithelium, with a densely cellular “ovarian” stroma.
Figure 16–7 Intraductal papillary mucinous neoplasm. A, Cross-section through the head of the pancreas showing a prominent papillary neoplasm distending the main pancreatic duct. B, The papillary mucinous neoplasm involved the main pancreatic duct (left) and is extending down into the smaller ducts and ductules (right).
Pancreatic Carcinoma
Figure 16–8 Progression model for the development of pancreatic cancer. It is postulated that telomere shortening and mutations of the oncogene K-RAS occur at early stages, inactivation of the p16 tumor suppressor gene occurs at intermediate stages, and the inactivation of the TP53, SMAD4, and BRCA2 tumor suppressor genes occurs at late stages. Note that while there is a general temporal sequence of changes, the accumulation of multiple mutations is more important than their occurrence in a specific order. PanIN, pancreatic intraepithelial neoplasm. The numbers following the labels on the top refer to stages in the development of PanINs.
Figure 16–9 Carcinoma of the pancreas. A, A cross-section through the head of the pancreas and adjacent common bile duct showing both an ill-defined mass in the pancreatic substance (arrowheads) and the green discoloration of the duct resulting from total obstruction of bile flow. B, Poorly formed glands are present in a densely fibrotic (desmoplastic) stroma within the pancreatic substance.
Pathogenesis
Morphology
Clinical Features
Summary
Pancreatic Neoplasms
Bibliography
Chapter 17 Male Genital System and Lower Urinary Tract
Penis
Malformations
Inflammatory Lesions
Neoplasms
Figure 17–1 Carcinoma in situ (Bowen disease) of the penis. The epithelium above the intact basement membrane shows delayed maturation and disorganization (left). Higher magnification (right) shows several mitotic figures, some above the basal layer, a dyskeratotic cell, and nuclear pleomorphism.
Figure 17–2 Carcinoma of the penis. The glans penis is deformed by an ulcerated, infiltrative mass.
Summary
Lesions of the Penis
Scrotum, Testis, and Epididymis
Cryptorchidism and Testicular Atrophy
Summary
Cryptorchidism
Inflammatory Lesions
Vascular Disturbances
Testicular Neoplasms
Table 17–1 Summary of Testicular Tumors
Figure 17–3 Seminoma of the testis appearing as a well-circumscribed, pale, fleshy, homogeneous mass.
Figure 17–4 Seminoma of the testis. Microscopic examination reveals large cells with distinct cell borders, pale nuclei, prominent nucleoli, and a sparse lymphocytic infiltrate.
Figure 17–5 Embryonal carcinoma. In contrast with the seminoma illustrated in Figure 17–3, this tumor is a hemorrhagic mass.
Figure 17–6 Embryonal carcinoma. Note the sheets of undifferentiated cells and primitive gland-like structures. The nuclei are large and hyperchromatic.
Figure 17–7 Yolk sac tumor demonstrating areas of loosely textured, microcystic tissue and papillary structures resembling a developing glomerulus (Schiller-Duval bodies).
Figure 17–8 Choriocarcinoma. Both cytotrophoblastic cells with central nuclei (arrowhead, upper right) and syncytiotrophoblastic cells with multiple dark nuclei embedded in eosinophilic cytoplasm (arrow, middle) are present. Hemorrhage and necrosis are prominent.
Figure 17–9 Teratoma. Testicular teratomas contain mature cells from endodermal, mesodermal, and ectodermal lines. A–D, Four different fields from the same tumor specimen contain neural (ectodermal) (A), glandular (endodermal) (B), cartilaginous (mesodermal) (C), and squamous epithelial (D) elements.
Morphology
Clinical Features
Summary
Testicular Tumors
Prostate
Prostatitis
Figure 17–10 Adult prostate. The normal prostate contains several distinct regions, including a central zone (CZ), a peripheral zone (PZ), a transitional zone (TZ), and a periurethral zone. Most carcinomas arise from the peripheral glands of the organ and often are palpable during digital examination of the rectum. Nodular hyperplasia, by contrast, arises from more centrally situated glands and is more likely than carcinoma to produce urinary obstruction early in its course.
Clinical Features
Summary
Prostatitis
Benign Prostatic Hyperplasia (Nodular Hyperplasia)
Morphology
Clinical Features
Figure 17–11 Nodular prostatic hyperplasia. Well-defined nodules compress the urethra into a slitlike lumen.
Figure 17–12 Nodular hyperplasia of the prostate. A, Low-power photomicrograph demonstrates a well-demarcated nodule at the right of the field, with a portion of urethra seen to the left. In other cases of nodular hyperplasia, the nodularity is caused predominantly by stromal, rather than glandular, proliferation. B, Higher-power photomicrograph demonstrates the morphology of the hyperplastic glands, which are large, with papillary infolding.
Summary
Benign Prostatic Hyperplasia
Carcinoma of the Prostate
Figure 17–13 Adenocarcinoma of the prostate. Carcinomatous tissue is seen on the posterior aspect (lower left). Note the solid whiter tissue of cancer, in contrast with the spongy appearance of the benign peripheral zone on the contralateral side.
Figure 17–14 A, Adenocarcinoma of the prostate demonstrating small glands crowded in between larger benign glands. B, Higher magnification shows several small malignant glands with enlarged nuclei, prominent nucleoli, and dark cytoplasm, as compared with the larger, benign gland (top).
Pathogenesis
Morphology
Clinical Features
Summary
Carcinoma of the Prostate
Ureter, Bladder, and Urethra
Ureter
Urinary Bladder
Non-neoplastic Conditions
Neoplasms
Figure 17–15 Precursor lesions of invasive urothelial carcinoma.
Figure 17–16 Cystoscopic appearance of a papillary urothelial tumor, resembling coral, within the bladder.
Figure 17–17 Noninvasive low-grade papillary urothelial carcinoma. Higher magnification (right) shows slightly irregular nuclei with scattered mitotic figures (arrow).
Pathogenesis
Morphology
Clinical Features
Table 17–2 Noninvasive Papillary Urothelial Neoplasms
Figure 17–18 Carcinoma in situ (CIS) with enlarged hyperchromatic nuclei and a mitotic figure (arrow).
Sexually Transmitted Diseases
Table 17–3 Classification of Important Sexually Transmitted Diseases
Syphilis
Figure 17–19 Protean manifestations of syphilis.
Morphology
Primary Syphilis
Secondary Syphilis
Figure 17–20 A, Syphilitic chancre of the scrotum. Such lesions typically are painless despite the presence of ulceration, and they heal spontaneously. B, Histologic features of the chancre include a diffuse plasma cell infiltrate beneath squamous epithelium of skin.
Tertiary Syphilis
Congenital Syphilis
Serologic Tests for Syphilis
Summary
Syphilis
Gonorrhea
Figure 17–21 Neisseria gonorrhoeae. Gram stain of urethral discharge demonstrates characteristic gram-negative, intracellular diplococci (arrow).
Figure 17–22 Acute epididymitis caused by gonococcal infection. The epididymis is involved by an abscess. Normal testis is seen on the right.
Morphology
Clinical Features
Summary
Gonorrhea
Nongonococcal Urethritis and Cervicitis
Summary
Nongonococcal Urethritis and Cervicitis
Lymphogranuloma Venereum
Morphology
Chancroid (Soft Chancre)
Morphology
Granuloma Inguinale
Morphology
Summary
Lymphogranuloma Venereum, Chancroid, and Granuloma Inguinale
Trichomoniasis
Genital Herpes Simplex
Morphology
Clinical Features
Human Papillomavirus Infection
Morphology
Summary
Herpes Simplex Virus and Human Papillomavirus Infections
Bibliography
Chapter 18 Female Genital System and Breast
Vulva
Vulvitis
Non-neoplastic Epithelial Disorders
Lichen Sclerosus
Lichen Simplex Chronicus
Figure 18–1 Upper panel, Lichen sclerosus. Lower panel, Lichen simplex chronicus. The main features of the lesions are labeled.
Summary
Non-neoplastic Epithelial Disorders
Tumors
Condylomas
Figure 18–2 A, Numerous condylomas of the vulva. B, Histopathologic features of condyloma acuminatum include acanthosis, hyperkeratosis, and cytoplasmic vacuolation (koilocytosis, center).
Carcinoma of the Vulva
Morphology
Extramammary Paget Disease
Figure 18–3 Paget disease of the vulva, with large tumor cells with abundant clear cytoplasm scattered throughout the epidermis.
Summary
Squamous Cell Carcinoma of the Vulva
Paget Disease of the Vulva
Vagina
Vaginitis
Malignant Neoplasms
Squamous Cell Carcinoma
Clear Cell Adenocarcinoma
Sarcoma Botryoides
Cervix
Cervicitis
Morphology
Neoplasia of the Cervix
Figure 18–4 Development of the cervical transformation zone.
Figure 18–5 Possible consequences of human papillomavirus (HPV) infection. Progression is associated with integration of virus and acquisition of additional mutations as discussed in the text. CIN, cervical intraepithelial neoplasia.
Table 18–1 Natural History of Squamous Intraepithelial Lesions (SILs)
Pathogenesis
Cervical Intraepithelial Neoplasia (CIN)
Figure 18–6 Spectrum of cervical intraepithelial neoplasia (CIN), with normal squamous epithelium for comparison: CIN I with koilocytotic atypia; CIN II with progressive atypia in all layers of the epithelium; and CIN III (carcinoma in situ) with diffuse atypia and loss of maturation.
Morphology
Invasive Carcinoma of the Cervix
Figure 18–7 Cytologic features of cervical intraepithelial neoplasia (CIN) in a Papanicolaou smear. Superficial squamous cells may stain either red or blue. A, Normal exfoliated superficial squamous epithelial cells. B, CIN 1—low-grade squamous intraepithelial lesion (LSIL). C and D, CIN II and CIN III, respectively—both high-grade squamous intraepithelial lesions (HSILs). Note the reduction in cytoplasm and the increase in the nucleus-to-cytoplasm ratio as the grade of the lesion increases. This observation reflects the progressive loss of cellular differentiation on the surface of the cervical lesions from which these cells are exfoliated (Figure 18–6).
Figure 18–8 Cervical os with surrounding, invasive, exophytic cervical carcinoma.
Morphology
Clinical Course
Summary
Cervical Neoplasia
Endocervical Polyp
Body of Uterus
Endometritis
Adenomyosis
Endometriosis
Figure 18–9 Proposed origins of endometriosis.
Morphology
Clinical Features
Figure 18–10 Ovarian endometriosis. Sectioning of ovary reveals a large endometriotic cyst with degenerated blood (“chocolate cyst”).
Abnormal Uterine Bleeding
Table 18–2 Causes of Abnormal Uterine Bleeding by Age Group
Summary
Non-neoplastic Disorders of Endometrium
Proliferative Lesions of the Endometrium and Myometrium
Endometrial Hyperplasia
Figure 18–11 Endometrial hyperplasia. A, Anovulatory or “disordered” endometrium containing dilated glands. B, Complex hyperplasia without atypia, characterized by nests of closely packed glands. C, Complex hyperplasia with atypia, seen as glandular crowding and cellular atypia.
Endometrial Carcinoma
Pathogenesis
Morphology
Clinical Course
Figure 18–12 Endometrial carcinoma. A, Endometrioid type, infiltrating myometrium and growing in a cribriform pattern. B, Higher magnification reveals loss of polarity and nuclear atypia. C, Serous carcinoma of the endometrium, with papilla formation and marked cytologic atypia. D, Immunohistochemical staining reveals accumulation of p53, a finding associated with TP53 mutation.
Summary
Endometrial Hyperplasia and Endometrial Carcinoma
Endometrial Polyps
Leiomyoma
Figure 18–13 Uterine leiomyomas. A, The uterus is opened to reveal multiple submucosal, myometrial, and subserosal gray-white tumors, each with a characteristic whorled appearance on cut section B. Microscopic appearance of leiomyoma reveals bundles of normal-looking smooth muscle cells.
Morphology
Leiomyosarcoma
Morphology
Summary
Uterine Smooth Muscle Neoplasms
Fallopian Tubes
Figure 18–14 Pelvic inflammatory disease, bilateral and asymmetric. The tube and ovary to the left of the uterus is totally obscured by a hemorrhagic inflammatory mass. The tube is adherent to the adjacent ovary on the other side.
Summary
Fallopian Tube Disease
Ovaries
Follicle and Luteal Cysts
Polycystic Ovarian Disease
Tumors of the Ovary
Figure 18–15 Derivation, frequency, and age distribution for various ovarian neoplasms.
Surface Epithelial Tumors
Serous Tumors
Figure 18–16 Ovarian serous tumors. A, Borderline serous cystadenoma opened to display a cyst cavity lined by delicate papillary tumor growths. B, Cystadenocarcinoma. The cyst is opened to reveal a large, bulky tumor mass.
Morphology
Mucinous Tumors
Morphology
Endometrioid Tumors
Figure 18–17 Ovarian mucinous cystadenoma. A, Mucinous cystadenoma with multicystic appearance and delicate septa. Note the presence of glistening mucin within the cysts. B, Columnar cell lining of mucinous cystadenoma.
Brenner Tumor
Other Ovarian Tumors
Teratomas
Table 18–3 Salient Features of Ovarian Germ Cell and Sex Cord Neoplasms
Benign (Mature) Cystic Teratomas
Figure 18–18 Mature cystic teratoma (dermoid cyst) of the ovary. A ball of hair (bottom) and a mixture of tissues are evident.
Immature Malignant Teratomas
Specialized Teratomas
Clinical Correlations
Summary
Ovarian Tumors
Diseases of Pregnancy
Placental Inflammations and Infections
Ectopic Pregnancy
Morphology
Summary
Ectopic Pregnancy
Gestational Trophoblastic Disease
Hydatidiform Mole: Complete and Partial
Table 18–4 Features of Complete and Partial Hydatidiform Mole
Morphology
Figure 18–19 Complete hydatidiform mole, consisting of numerous swollen (hydropic) villi.
Invasive Mole
Figure 18–20 Complete hydatidiform mole. In this microscopic image, distended hydropic villi (below) and proliferation of the chorionic epithelium (above) are evident.
Gestational Choriocarcinoma
Morphology
Figure 18–21 Choriocarcinoma. This field contains both neoplastic cytotrophoblasts and multinucleate syncytiotrophoblasts.
Placental Site Trophoblastic Tumor
Summary
Gestational Trophoblastic Disease
Preeclampsia/Eclampsia (Toxemia of Pregnancy)
Morphology
Clinical Features
Figure 18–22 Histopathologic findings in a series of women seeking evaluation of breast “lumps.”
Summary
Preeclampsia/Eclampsia
Breast
Fibrocystic Changes
Nonproliferative Changes
Cysts and Fibrosis
Figure 18–23 Fibrocystic change seen in breast biopsy specimens. The scattered, poorly demarcated white areas represent foci of fibrosis. In the specimen at the lower right, a transected empty cyst is evident; in the two specimens on the left, unopened blue dome cysts are seen.
Morphology
Proliferative Change
Epithelial Hyperplasia
Figure 18–24 Fibrocystic change of the nonproliferative type in a breast biopsy specimen. Visible in this field are dilated ducts, producing microcysts and, at right, the wall of a large cyst lined with epithelial cells.
Figure 18–25 Epithelial hyperplasia in a breast biopsy specimen. The duct lumen is filled with a heterogeneous population of cells of differing morphology. Irregular slitlike fenestrations are prominent at the periphery.
Morphology
Sclerosing Adenosis
Figure 18–26 Sclerosing adenosis, breast biopsy. The involved terminal duct lobular unit is enlarged, and the acini are compressed and distorted by surrounding dense stroma. Unlike in breast carcinoma, the acini are arranged in a swirling pattern, and the outer border is well circumscribed.
Morphology
Relationship of Fibrocystic Changes to Breast Carcinoma
Summary
Fibrocystic Changes
Inflammatory Processes
Morphology
Morphology
Tumors of the Breast
Fibroadenoma
Morphology
Phyllodes Tumor
Figure 18–27 Fibroadenoma. A, The radiograph shows a characteristic well-circumscribed mass. B, In this gross specimen, a rubbery well-circumscribed mass is clearly demarcated from the surrounding adipose tissue. C, In this micrograph, the proliferation of intralobular stroma can be seen to compress the entrapped glands, creating a “pushing” border that is sharply delineated from the surrounding normal tissue.
Intraductal Papilloma
Morphology
Carcinoma
Epidemiology and Risk Factors
Age
Geographic Variations
Table 18–5 Breast Cancer Risk Factors
Race/Ethnicity
Other Risk Factors
Figure 18–28 Comedo ductal carcinoma in situ (DCIS). Several adjacent ducts are filled by tumor associated with large central zones of necrosis and calcified debris. This type of DCIS most frequently is detected as radiologic calcifications.
Figure 18–29 Lobular carcinoma in situ. A monomorphic population of small, rounded, loosely cohesive cells fills and expands the acini of a lobule. The underlying lobular architecture is intact.
Figure 18–30 Invasive ductal carcinoma is evident in this breast biopsy specimen. The hard, fibrotic lesion infiltrates the surrounding tissue, causing retraction.
Figure 18–31 Invasive breast carcinomas of no special type (insets show each tumor at higher magnification). A, Well-differentiated carcinoma consists of tubular or cribriform glands containing cells with small monomorphic nuclei within a desmoplastic response. B, Moderately differentiated carcinoma demonstrates less tubule formation and more solid nests of cells with pleomorphic nuclei. C, Poorly differentiated carcinoma infiltrates as ragged sheets of pleomorphic cells containing numerous mitotic figures and areas of tumor necrosis.
Pathogenesis
Genetic Changes
Hormonal Influences
Environmental Variables
Morphology
Noninvasive (in situ) Carcinoma
Invasive (Infiltrating) Carcinoma
Common Features of Invasive Cancers
Clinical Course
Figure 18–32 Special types of breast carcinoma. A, Medullary carcinoma. The highly pleomorphic tumor cells grow in cohesive sheets and are associated with a prominent reactive infiltrate of lymphocytes and plasma cells. B, Mucinous (colloid) carcinoma. The tumor cells are present in small clusters within large pools of mucin. Note the characteristic well-circumscribed border, which mimics the appearance of benign masses.
Summary
Breast Carcinoma
Lesions of the Male Breast
Gynecomastia
Carcinoma
Bibliography
Chapter 19 Endocrine System
Pituitary
Figure 19–1 Normal architecture of the anterior pituitary. The gland is populated by several distinct cell types containing a variety of stimulating (trophic) hormones. Each of the hormones has different staining characteristics, resulting in a mixture of cell types in routine histologic preparations. Note also the presence of a fine reticulin network.
Figure 19–2 The adenohypophysis (anterior pituitary) releases six hormones: adrenocorticotropic hormone (ACTH), or corticotropin; follicle-stimulating hormone (FSH); growth hormone (GH), or somatotropin; luteinizing hormone (LH); prolactin (PRL); and thyroid-stimulating hormone (TSH), or thyrotropin. These hormones are in turn under the control of various stimulatory and inhibitory hypothalamic releasing factors. The stimulatory releasing factors are corticotropin-releasing hormone (CRH), growth hormone–releasing hormone (GHRH), gonadotropin-releasing hormone (GnRH), and thyrotropin-releasing hormone (TRH). The inhibitory hypothalamic factors are growth hormone inhibitory hormone (GIH), or somatostatin, and prolactin inhibitory factor (PIF), which is the same as dopamine.
Hyperpituitarism and Pituitary Adenomas
Table 19–1 Classification of Pituitary Adenomas
Figure 19–3 Pituitary adenoma. This massive, nonfunctioning adenoma has grown far beyond the confines of the sella turcica and has distorted the overlying brain. Nonfunctioning adenomas tend to be larger at the time of diagnosis than those that secrete a hormone.
Figure 19–4 Pituitary adenoma. The monomorphism of these cells contrasts markedly with the admixture of cells seen in the normal anterior pituitary in Figure 19–1. Note also the absence of reticulin network.
Pathogenesis
Morphology
Summary
Hyperpituitarism
Prolactinomas
Growth Hormone–Producing (Somatotroph Cell) Adenomas
Adrenocorticotropic Hormone–Producing (Corticotroph Cell) Adenomas
Other Anterior Pituitary Neoplasms
Summary
Clinical Manifestations of Pituitary Adenomas
Hypopituitarism
Posterior Pituitary Syndromes
Thyroid
Figure 19–5 Homeostasis in the hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3 and T4) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels to rise. Elevated T3 and T4 levels, in turn, suppress the secretion of both TRH and TSH. This relationship is termed a negative-feedback loop. TSH binds to the TSH receptor on the thyroid follicular epithelium, which causes activation of G proteins, release of cyclic AMP (cAMP), and cAMP-mediated synthesis and release of thyroid hormones (i.e., T3 and T4). In the periphery, T3 and T4 interact with the thyroid hormone receptor (TR) and form a complex that translocates to the nucleus and binds to so-called thyroid response elements (TREs) on target genes, thereby initiating transcription.
Hyperthyroidism
Figure 19–6 Patient with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one of the classic features of this disorder. In Graves disease, one of the most important causes of hyperthyroidism, accumulation of loose connective tissue behind the orbits also adds to the protuberant appearance of the eyes.
Table 19–2 Causes of Thyrotoxicosis
Hypothyroidism
Table 19–3 Causes of Hypothyroidism
Thyroiditis
Chronic Lymphocytic (Hashimoto) Thyroiditis
Figure 19–7 Pathogenesis of Hashimoto thyroiditis. Breakdown of immune tolerance to thyroid autoantigens results in progressive autoimmune destruction of thyrocytes by infiltrating cytotoxic T cells, locally released cytokines, or antibody-dependent cytotoxicity.
Pathogenesis
Morphology
Clinical Features
Figure 19–8 Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hürthle cells also are seen.
Subacute Granulomatous (de Quervain) Thyroiditis
Morphology
Clinical Features
Subacute Lymphocytic Thyroiditis
Other Forms of Thyroiditis
Summary
Thyroiditis
Graves Disease
Pathogenesis
Figure 19–9 Graves disease. The thyroid is diffusely hyperplastic. The follicles are lined by tall columnar epithelial cells that project into the lumina. These cells actively resorb the colloid in the centers of the follicles, resulting in the “scalloped” appearance of the edges of the colloid.
Morphology
Clinical Features
Summary
Graves Disease
Diffuse and Multinodular Goiter
Morphology
Clinical Features
Neoplasms of the Thyroid
Figure 19–10 Multinodular goiter. A, Gross morphologic appearance. The coarsely nodular gland contains areas of fibrosis and cystic change. B, Photomicrograph of specimen from a hyperplastic nodule, with compressed residual thyroid parenchyma on the periphery. The hyperplastic follicles contain abundant pink “colloid” within their lumina. Note the absence of a prominent capsule, a feature distinguishing such lesions from neoplasms of the thyroid.
Adenomas
Figure 19–11 Follicular adenoma of the thyroid. A, A solitary, well-circumscribed nodule is visible in this gross specimen. B, The photomicrograph shows well-differentiated follicles resembling those of normal thyroid parenchyma.
Figure 19–12 Hürthle cell adenoma. On this high-power view, the tumor is composed of cells with abundant eosinophilic cytoplasm and small regular nuclei.
Pathogenesis
Morphology
Clinical Features
Carcinomas
Figure 19–13 Genetic alterations in follicular cell–derived malignancies of the thyroid gland.
Pathogenesis
Genetic Factors
Environmental Factors
Papillary Carcinoma
Figure 19–14 Papillary carcinoma of the thyroid. A–C, A papillary carcinoma with grossly discernible papillary structures. In this particular example, well-formed papillae (B) are lined by cells with characteristic empty-appearing nuclei, sometimes termed “Orphan Annie eye” nuclei (C). D, Cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear inclusions are visible in some of the aspirated cells (arrows).
Morphology
Clinical Features
Follicular Carcinoma
Figure 19–15 Follicular carcinoma of the thyroid. A few of the glandular lumina contain recognizable colloid.
Figure 19–16 Capsular invasion in follicular carcinoma. Evaluating the integrity of the capsule is critical in distinguishing follicular adenomas from follicular carcinomas. A, In adenomas, a fibrous capsule, usually thin but occasionally more prominent, surrounds the neoplastic follicles and no capsular invasion is seen (arrows); compressed normal thyroid parenchyma usually is present external to the capsule (top). B, By contrast, follicular carcinomas demonstrate capsular invasion (arrows) that may be minimal, as in this case, or widespread, with extension into local structures of the neck.
Morphology
Clinical Features
Anaplastic Carcinoma
Morphology
Clinical Features
Medullary Carcinoma
Morphology
Clinical Features
Figure 19–17 Medullary carcinoma of the thyroid. These tumors typically contain amyloid, visible here as homogeneous extracellular material, derived from calcitonin molecules secreted by the neoplastic cells.
Figure 19–18 Electron micrograph of medullary thyroid carcinoma. These cells contain membrane-bound secretory granules, which are the sites of storage of calcitonin and other peptides. (Original magnification ×30,000.)
Summary
Thyroid Neoplasms
Parathyroid Glands
Hyperparathyroidism
Primary Hyperparathyroidism
Figure 19–19 Technetium-99 radionuclide scan demonstrates an area of increased uptake corresponding to the left inferior parathyroid gland (arrow). This proved to be a parathyroid adenoma. Preoperative scintigraphy is useful in localizing and distinguishing adenomas from parathyroid hyperplasia, in which more than one gland will demonstrate increased uptake.
Figure 19–20 Chief cell parathyroid adenoma. A, On this low-power view, a solitary adenoma is clearly delineated from the residual gland below. B, High-power detail shows slight variation in nuclear size and tendency to follicular formation but no anaplasia.
PathogEnesis
Morphology
Clinical Features
Table 19–4 Causes of Hypercalcemia
Secondary Hyperparathyroidism
Morphology
Clinical Features
Summary
Hyperparathyroidism
Hypoparathyroidism
Endocrine Pancreas
Diabetes Mellitus
Diagnosis
Classification
Normal Insulin Physiology and Glucose Homeostasis
Figure 19–21 Metabolic actions of insulin in striated muscle, adipose tissue, and liver.
Table 19–5 Classification of Diabetes Mellitus
Figure 19–22 Stages in the development of type 1 diabetes mellitus. The stages are listed from left to right, and hypothetical beta cell mass is plotted against age.
Pathogenesis
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Insulin Resistance
Figure 19–23 Pathogenesis of type 2 diabetes mellitus. Genetic predisposition and environmental influences converge to cause insulin resistance. Compensatory beta cell hyperplasia can maintain normoglycemia, but eventually beta cell secretory dysfunction sets in, leading to impaired glucose tolerance and, ultimately, frank diabetes. Rare instances of primary beta cell failure can lead directly to type 2 diabetes without an intervening state of insulin resistance.
Obesity and Insulin Resistance
Figure 19–24 Mechanisms of beta cell dysfunction and insulin resistance in type 2 diabetes. Free fatty acids directly cause beta cell dysfunction and induce insulin resistance in target tissues (such as striated muscle, shown here), and also induce the secretion of pro-inflammatory cytokines that cause more beta cell dysfunction and insulin resistance.
Beta Cell Dysfunction
Monogenic Forms of Diabetes
Complications of Diabetes
Figure 19–25 Long-term complications of diabetes.
Figure 19–26 A, Autoimmune insulitis in a rat (BB) model of autoimmune diabetes. This disorder also is seen in type 1 human diabetes. B, Amyloidosis of a pancreatic islet in type 2 diabetes. Amyloidosis typically is observed late in the natural history of this form of diabetes, with islet inflammation noted at earlier observations.
Figure 19–27 Severe renal hyaline arteriolosclerosis in a periodic acid–Schiff stained specimen. Note the markedly thickened, tortuous afferent arteriole. The amorphous nature of the thickened vascular wall is evident.
Figure 19–28 Renal cortex showing thickening of tubular basement membranes in a specimen from a diabetic patient. Periodic acid–Schiff stain.
Figure 19–29 Renal glomerulus showing markedly thickened glomerular basement membrane (B) in a diabetic. L, glomerular capillary lumen; U, urinary space.
Figure 19–30 Nodular glomerulosclerosis in a renal specimen from a patient with long-standing diabetes.
Figure 19–31 Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected to demonstrate both diffuse granular transformation of the surface (left) and marked thinning of the cortical tissue (right). Additional features include some irregular depressions, the result of pyelonephritis, and an incidental cortical cyst (far right).
Figure 19–32 Characteristic morphologic changes of diabetic retinopathy. Features include advanced proliferative retinopathy with retinal hemorrhages, exudates, neovascularization, and tractional retinal detachment (lower right corner).
Morphology
Diabetes and Its Late Complications
Pancreas
Diabetic Macrovascular Disease
Diabetic Microangiopathy
Diabetic Nephropathy
Ocular Complications of Diabetes
Diabetic Neuropathy
Clinical Features
Figure 19–33 Sequence of metabolic derangements leading to diabetic coma in type 1 diabetes mellitus. An absolute insulin deficiency leads to a catabolic state, eventuating in ketoacidosis and severe volume depletion. These derangements bring about sufficient central nervous system compromise to cause coma and, eventually, death if left untreated.
Table 19–6 Type 1 Versus Type 2 Diabetes Mellitus
Summary
Diabetes Mellitus: Pathogenesis and Long-Term Complications
Pancreatic Neuroendocrine Tumors
Insulinomas
Figure 19–34 Pancreatic neuroendocrine tumor (PanNET), also called islet cell tumor. A, The neoplastic cells are monotonous in appearance and demonstrate minimal pleomorphism or mitotic activity. There is abundant amyloid deposition, characteristic of an insulinoma. On clinical evaluation, the patient had episodic hypoglycemia. B, Electron micrograph of a normal beta cell shows the characteristic membrane-bound granules, each containing a dense, often rectangular core and distinct halo. Insulinomas contain comparable granules.
Morphology
Gastrinomas
Morphology
Adrenal Cortex
Adrenocortical Hyperfunction (Hyperadrenalism)
Hypercortisolism and Cushing Syndrome
Figure 19–35 Schematic representation of the various forms of Cushing syndrome: The three endogenous forms, as well as the more common exogenous (iatrogenic) form. ACTH, adrenocorticotropic hormone.
Figure 19–36 Diffuse hyperplasia of the adrenal (bottom) contrasted with normal adrenal gland (top). In cross-section, the adrenal cortex is yellow and thickened, and a subtle nodularity is evident. The abnormal gland was from a patient with ACTH-dependent Cushing syndrome, in whom both adrenals were diffusely hyperplastic. ACTH, adrenocorticotropic hormone.
Figure 19–37 Adrenocortical adenoma. A, The adenoma is distinguished from nodular hyperplasia by its solitary, circumscribed nature. The functional status of an adrenocortical adenoma cannot be predicted from its gross or microscopic appearance. B, Histologic features of an adrenal cortical adenoma. The neoplastic cells are vacuolated because of the presence of intracytoplasmic lipid. There is mild nuclear pleomorphism. Mitotic activity and necrosis are not seen.
Morphology
Clinical Features
Figure 19–38 A patient with Cushing syndrome. Characteristic features include central obesity, “moon facies,” and abdominal striae.
Summary
Hypercortisolism (Cushing Syndrome)
Hyperaldosteronism
Morphology
Clinical Features
Adrenogenital Syndromes
Morphology
Clinical Features
Summary
Adrenogenital Syndromes
Adrenal Insufficiency
Acute Adrenocortical Insufficiency
Table 19–7 Causes of Adrenal Insufficiency
Chronic Adrenocortical Insufficiency: Addison Disease
Figure 19–39 Waterhouse-Friderichsen syndrome. Bilateral adrenal hemorrhage in an infant with overwhelming sepsis, resulting in acute adrenal insufficiency. At autopsy, the adrenals were grossly hemorrhagic and shrunken; in this photomicrograph, little residual cortical architecture is discernible.
Secondary Adrenocortical Insufficiency
Morphology
Clinical Features
Figure 19–40 Autoimmune adrenalitis. In addition to loss of all but a subcapsular rim of cortical cells, there is an extensive mononuclear cell infiltrate.
Summary
Adrenocortical Insufficiency (Hypoadrenalism)
Adrenocortical Neoplasms
Figure 19–41 Adrenal carcinoma. The tumor dwarfs the kidney and compresses the upper pole. It is largely hemorrhagic and necrotic.
Figure 19–42 Adrenal carcinoma with marked anaplasia.
Morphology
Adrenal Medulla
Tumors of the Adrenal Medulla
Pheochromocytoma
Figure 19–43 Pheochromocytoma. The tumor is enclosed within an attenuated cortex and demonstrates areas of hemorrhage. The comma-shaped residual adrenal is seen below.
Figure 19–44 Photomicrograph of pheochromocytoma, demonstrating characteristic nests of cells (Zellballen) with abundant cytoplasm. Granules containing catecholamine are not visible in this preparation. It is not uncommon to find bizarre cells even in pheochromocytomas that are biologically benign, and this criterion by itself should not be used to diagnose malignancy.
Morphology
Clinical Features
Neuroblastoma and Other Neuronal Neoplasms
Multiple Endocrine Neoplasia Syndromes
Multiple Endocrine Neoplasia Type 1
Multiple Endocrine Neoplasia Type 2
Multiple Endocrine Neoplasia Type 2A
Multiple Endocrine Neoplasia Type 2B
Bibliography
Chapter 20 Bones, Joints, and Soft Tissue Tumors
Bones
Figure 20–1 Cells of bone. A, Active osteoblasts synthesizing bone matrix proteins. The surrounding spindle cells are osteoprogenitor cells. B, Two osteoclasts resorbing bone. The smaller blue nuclei surrounded by a halo of clearing in the dense pink lamellar bone are osteocytes in their individual lacunae.
Figure 20–2 Paracrine mechanisms regulating osteoclast formation and function. Osteoclasts are derived from the same stem cells that produce macrophages. RANK (receptor activator for nuclear factor-κB) receptors on osteoclast precursors bind RANK ligand (RANKL) expressed by osteoblasts and marrow stromal cells. Along with macrophage colony-stimulating factor (M-CSF), the RANK-RANKL interaction drives the differentiation of functional osteoclasts. Stromal cells also secrete osteoprotegerin (OPG), which acts as a decoy receptor for RANKL, preventing it from binding the RANK receptor on osteoclast precursors. Consequently, OPG prevents bone resorption by inhibiting osteoclast differentiation.
Congenital Disorders of Bone and Cartilage
Osteogenesis Imperfecta
Achondroplasia and Thanatophoric Dwarfism
Osteopetrosis
Summary
Congenital Disorders of Bone and Cartilage
Acquired Diseases of Bone
Osteoporosis
Table 20–1 Categories of Generalized Osteoporosis
Figure 20–3 Osteoporotic vertebral body (right) shortened by compression fractures, compared with a normal vertebral body. The osteoporotic vertebra exhibits a characteristic loss of horizontal trabeculae and thickened vertical trabeculae.
Figure 20–4 Pathophysiology of postmenopausal and senile osteoporosis (see text).
Morphology
Pathogenesis
Clinical Course
Paget Disease (Osteitis Deformans)
Figure 20–5 Paget disease, showing a mosaic pattern of lamellar bone.
Morphology
Pathogenesis
Clinical Course
Rickets and Osteomalacia
Hyperparathyroidism
Figure 20–6 Bone manifestations of hyperparathyroidism. A, Osteoclasts gnawing into and disrupting lamellar bone. B, Resected rib, with expansile cystic mass (so-called brown tumor).
Morphology
Summary
Acquired Diseases of Bone Development and Mass
Fractures
Osteonecrosis (Avascular Necrosis)
Morphology
Clinical Course
Osteomyelitis
Pyogenic Osteomyelitis
Figure 20–7 Resected femur from a patient with chronic osteomyelitis. Necrotic bone (the sequestrum) visible in the center of a draining sinus tract is surrounded by a rim of new bone (the involucrum).
Morphology
Clinical Features
Tuberculous Osteomyelitis
Bone Tumors
Table 20–2 Tumors of Bone
Bone-Forming Tumors
Osteoma
Osteoid Osteoma and Osteoblastoma
Figure 20–8 Osteoid osteoma showing randomly oriented trabeculae of woven bone rimmed by prominent osteoblasts. The intertrabecular spaces are filled by vascular loose connective tissue.
Morphology
Osteosarcoma
Figure 20–9 Osteosarcoma. A, Mass involving the upper end of the tibia. The tan-white tumor fills most of the medullary cavity of the metaphysis and proximal diaphysis. It has infiltrated through the cortex, lifted the periosteum, and formed soft tissue masses on both sides of the bone. B, Histologic appearance, with coarse, lacelike pattern of neoplastic bone (arrow) produced by anaplastic tumor cells. Note the wildly aberrant mitotic figures (arrowheads).
Morphology
Pathogenesis
Clinical Features
Figure 20–10 The development of an osteochondroma, beginning with an outgrowth from the epiphyseal cartilage.
Cartilage-Forming Tumors
Osteochondroma
Morphology
Clinical Features
Chondroma
Pathogenesis
Morphology
Clinical Features
Chondrosarcoma
Morphology
Clinical Features
Figure 20–11 Chondrosarcoma. A, Islands of hyaline and myxoid cartilage expand the medullary cavity and grow through the cortex to form a sessile paracortical mass. B, Anaplastic chondrocytes within a chondroid matrix.
Fibrous and Fibroosseous Tumors
Fibrous Cortical Defect and Nonossifying Fibroma
Morphology
Clinical Features
Fibrous Dysplasia
Figure 20–12 Fibrous cortical defect or nonossifying fibroma. Characteristic storiform pattern of spindle cells interspersed with scattered osteoclast-type giant cells.
Morphology
Clinical Course
Figure 20–13 Fibrous dysplasia. Curved trabeculae of woven bone arising in a fibrous tissue. Note the absence of osteoblasts rimming the bones.
Miscellaneous Bone Tumors
Ewing Sarcoma and Primitive Neuroectodermal Tumor
Morphology
Clinical Features
Figure 20–14 Ewing sarcoma. Sheets of small round cells with scant, clear cytoplasm.
Giant Cell Tumor of Bone
Morphology
Clinical Course
Metastatic Disease
Figure 20–15 Benign giant cell tumor showing abundant multinucleate giant cells and a background of mononuclear cells.
Summary
Bone Tumors
Joints
Arthritis
Osteoarthritis
Figure 20–16 Osteoarthritis. A, Histologic demonstration of the characteristic fibrillation of the articular cartilage. B, Severe osteoarthritis, with eburnated articular surface exposing subchondral bone (1), subchondral cyst (2), and residual articular cartilage (3).
Figure 20–17 Comparison of the morphologic features of rheumatoid arthritis (RA) and osteoarthritis.
Morphology
Pathogenesis
Clinical Course
Rheumatoid Arthritis
Figure 20–18 Major processes involved in pathogenesis of rheumatoid arthritis.
Figure 20–19 Rheumatoid arthritis. A, A joint lesion. B, Synovium demonstrating papillary hyperplasia caused by dense inflammatory infiltrate. C, Hypertrophied synoviocytes with numerous underlying lymphocytes and plasma cells.
Pathogenesis
Morphology
Clinical Features
Figure 20–20 Rheumatoid nodule. Serpiginous area of necrobiotic collagen surrounded by palisading histiocytes.
Juvenile Rheumatoid Arthritis
Seronegative Spondyloarthropathies
Gout
Table 20–3 Classification of Gout
Figure 20–21 Gout. A, Amputated great toe with white tophi involving the joint and soft tissues. B, Photomicrograph of a gouty tophus. An aggregate of dissolved urate crystals is surrounded by reactive fibroblasts, mononuclear inflammatory cells, and giant cells.
Figure 20–22 Pathogenesis of acute gouty arthritis. IL, interleukin; LTB4, leukotriene B4; TNF, tumor necrosis factor.
Morphology
Pathogenesis
Clinical Features
Pseudogout
Infectious Arthritis
Suppurative Arthritis
Lyme Arthritis
Summary
Arthritis
Joint Tumors and Tumor-Like Lesions
Ganglion and Synovial Cysts
Tenosynovial Giant Cell Tumor
Figure 20–23 Tenosynovial giant cell tumor, diffuse type. A, Excised synovium with fronds and nodules typical of the diffuse variant (arrow). B, Sheets of proliferating cells in tenosynovial giant cell tumor bulging the synovial lining.
Morphology
Clinical Features
Soft Tissue
Table 20–4 Soft Tissue Tumors
Tumors of Adipose Tissue
Lipoma
Liposarcoma
Morphology
Fibrous Tumors and Tumor-Like Lesions
Figure 20–24 Myxoid liposarcoma. Adult-appearing fat cells and more primitive cells, with lipid vacuoles (lipoblasts), are scattered in abundant myxoid matrix and a rich, arborizing capillary network.
Reactive Proliferations
Nodular Fasciitis
Myositis Ossificans
Figure 20–25 Nodular fasciitis. A highly cellular lesion composed of plump, randomly oriented spindle cells surrounded by myxoid stroma. Note the prominent mitotic activity (arrowheads).
Fibromatoses
Morphology
Fibrosarcoma
Figure 20–26 Fibrosarcoma. Malignant spindle cells here are arranged in a herringbone pattern.
Morphology
Fibrohistiocytic Tumors
Benign Fibrous Histiocytoma (Dermatofibroma)
Pleomorphic Fibroblastic Sarcoma/Pleomorphic Undifferentiated Sarcoma
Skeletal Muscle Tumors
Rhabdomyosarcoma
Figure 20–27 Pleomorphic fibroblastic sarcoma. There are fascicles of plump spindle cells in a swirling (storiform) pattern.
Morphology
Smooth Muscle Tumors
Leiomyoma
Figure 20–28 Rhabdomyosarcoma. The rhabdomyoblasts are large and round and have abundant eosinophilic cytoplasm; no cross-striations are evident here.
Leiomyosarcoma
Synovial Sarcoma
Figure 20–29 Synovial sarcoma exhibiting a classic biphasic spindle cell and glandlike histologic appearance.
Morphology
Bibliography
Chapter 21 Peripheral Nerves and Muscles
Disorders of Peripheral Nerves
Patterns of Peripheral Nerve Injury
Figure 21–1 Patterns of peripheral nerve damage. A, In normal motor units, type I and type II myofibers are arranged in a “checkerboard” distribution, and the internodes along the motor axons are uniform in thickness and length. B, Acute axonal injury (left axon) results in degeneration of the distal axon and its associated myelin sheath, with atrophy of denervated myofibers. By contrast, acute demyelinating disease (right axon) produces random segmental degeneration of individual myelin internodes, while sparing the axon. C, Regeneration of axons after injury (left axon) allows connections with myofibers to re-form. The regenerated axon is myelinated by proliferating Schwann cells, but the new internodes are shorter and the myelin sheaths are thinner than the original ones. Remission of demyelinating disease (right axon) allows remyelination to take place, but the new internodes also are shorter and have thinner myelin sheaths than flanking normal undamaged internodes.
Disorders Associated with Peripheral Nerve Injury
Guillain-Barré Syndrome
Table 21–1 Peripheral Neuropathies
Chronic Inflammatory Demyelinating Polyneuropathy
Diabetic Peripheral Neuropathy
Toxic, Vasculitic, and Inherited Forms of Peripheral Neuropathy
Figure 21–2 Pathologic changes in peripheral neuropathies. A, Regeneration after segmental demyelination. Teased fiber preparations allow for examination of individual axons of peripheral nerves. A normal axon (left) has a myelin sheath of uniform thickness that is interrupted at the nodes of Ranvier (arrows). By contrast, the right axon contains a poorly myelinated segment with unevenly distributed nodes of Ranvier. The area of remyelination is segmental and therefore flanked by internodes with normal myelination. B and C, Vasculitic neuropathy. In B, the perineurial connective tissue contains a vasculocentric inflammatory infiltrate that has obliterated a small vessel. In C, a special stain that colors myelinated axons dark blue reveals that the nerve fascicle in the upper portion of this field (asterisk) has lost almost all of its large myelinated axons, in contrast with the other fascicle shown. Such interfascicular variation in axonal density often is seen in neuropathies resulting from vascular injury.
Summary
Peripheral Neuropathies
Disorders of Neuromuscular Junction
Myasthenia Gravis
Lambert-Eaton Syndrome
Miscellaneous Neuromuscular Junction Disorders
Summary
Neuromuscular Junction Disorders
Disorders of Skeletal Muscle
Patterns of Skeletal Muscle Injury
Figure 21–3 The dystrophin-glycoprotein complex (DGC). This complex of glycoproteins serves to couple the cell membrane (the sarcolemma) to the extracellular matrix proteins such as laminin-2 and the intracellular cytoskeleton. One key set of connections is made by dystrophin, a scaffolding protein that tethers the myofibrillar cytoskeleton to the transmembrane dystroglycans and sarcoglycans, and also binds complexes containing dystrobrevin, syntrophin, neuronal nitric oxide synthetase (nNOS), and caveolin, which participate in intracellular signaling pathways. Mutations in dystrophin are associated with X-linked Duchenne and Becker muscular dystrophies; mutations in caveolin and the sarcoglycan proteins, with autosomal limb-girdle muscular dystrophies; and mutations in α2-laminin (merosin), with a form of congenital muscular dystrophy.
Inherited Disorders of Skeletal Muscle
Dystrophinopathies: Duchenne and Becker Muscular Dystrophy
Figure 21–4 Patterns of skeletal muscle injury. A, Normal skeletal muscle has relatively uniform polygonal myofibers with peripherally placed nuclei that are tightly packed together into fascicles separated by scant connective tissue. A perimysial interfascicular septum containing a blood vessel is present (top center). B, Myopathic conditions often are associated with segmental necrosis and regeneration of individual myofibers. Necrotic cells (B1-B3) are infiltrated by variable numbers of inflammatory cells. Regenerative myofibers (B4, arrow) are characterized by cytoplasmic basophilia and enlarged nucleoli (not visible at this power). C and D, Clusters of both atrophic myofibers (C) (grouped atrophy) and fiber-type grouping (D), patchy areas in which myofibers share the same fiber type, are features of neurogenic remodeling. The ATPase reaction shown in D is one method of distinguishing between fiber types, as type I fibers stain more lightly than type II fibers. Note loss of the “checkerboard” pattern (Fig 21–1, A).
Morphology
Pathogenesis
Clinical Features
Figure 21–5 Duchenne muscular dystrophy. Histologic images of muscle biopsy specimens from two brothers. A and B, Specimens from a 3-year-old boy. C, Specimen from his brother, 9 years of age. As seen in A, at a younger age fascicular muscle architecture is maintained, but myofibers show variation in size. Additionally, there is a cluster of basophilic regenerating myofibers (left side) and slight endomysial fibrosis, seen as focal pink-staining connective tissue between myofibers. In B, immunohistochemical staining shows a complete absence of membrane-associated dystrophin, seen as a brown stain in normal muscle (inset). In C, the biopsy from the older brother illustrates disease progression, which is marked by extensive variation in myofiber size, fatty replacement, and endomysial fibrosis.
Other X-Linked and Autosomal Muscular Dystrophies
Channelopathies, Metabolic Myopathies, and Mitochondrial Myopathies
Acquired Disorders of Skeletal Muscle
Inflammatory Myopathies
Toxic Myopathies
Figure 21–6 Inflammatory myopathies. A, Polymyositis is characterized by endomysial inflammatory infiltrates and myofiber necrosis (arrow). B, Dermatomyositis often shows prominent perifascicular and paraseptal atrophy. C, Inclusion body myositis, showing myofibers containing rimmed vacuoles (arrows).
Summary
Disorders of Skeletal Muscle
Peripheral Nerve Sheath Tumors
Schwannomas and Neurofibromatosis Type 2
Figure 21–7 Schwannoma and plexiform neurofibroma. A and B, Schwannoma. As seen in A, schwannomas often contain dense pink Antoni A areas (left) and loose, pale Antoni B areas (right), as well as hyalinized blood vessels (right). B, Antoni A area with the nuclei of tumor cells aligned in palisading rows. C and D, Plexiform neurofibroma. Multiple nerve fascicles are expanded by infiltrating tumor cells (C), which at higher power (D) are seen to consist of bland spindle cells admixed with wavy collagen bundles likened to carrot shavings.
Morphology
Neurofibromas
Morphology
Malignant Peripheral Nerve Sheath Tumors
Morphology
Neurofibromatosis Type 1
Traumatic Neuroma
Summary
Peripheral Nerve Sheath Tumors
Bibliography
Chapter 22 Central Nervous System
Patterns of Injury in The Nervous System
Figure 22–1 Patterns of neuronal injury. A, Acute hypoxic-ischemic injury in cerebral cortex, where the individual cell bodies are shrunken, along with the nuclei. They also are prominently stained by eosin (“red neurons”). B, Axonal spheroids are visible as bulbous swellings at points of disruption, or altered axonal transport. C, With axonal injury there can be swelling of the cell body and peripheral dispersal of the Nissl substance, termed chromatolysis.
Morphology
Features of Neuronal Injury
Astrocytes in Injury and Repair
Changes in Other Cell Types
Edema, Herniation, and Hydrocephalus
Cerebral Edema
Hydrocephalus
Figure 22–2 Cerebral edema. The surfaces of the gyri are flattened as a result of compression of the expanding brain by the dura mater and inner surface of the skull. Such changes are associated with a dangerous increase in intracranial pressure.
Herniation
Figure 22–3 Hydrocephalus. Dilated lateral ventricles seen in a coronal section through the midthalamus.
Figure 22–4 Herniation syndromes. Displacement of brain parenchyma across fixed barriers can be subfalcine, transtentorial, or tonsillar (into the foramen magnum).
Figure 22–5 Duret hemorrhage. As mass effect displaces the brain downward, there is disruption of the vessels that enter the pons along the midline, leading to hemorrhage.
Summary
Edema, Herniation, and Hydrocephalus
Cerebrovascular Diseases
Hypoxia, Ischemia, and Infarction
Global Cerebral Ischemia
Morphology
Focal Cerebral Ischemia
Figure 22–6 Cerebral infarction. A, Infiltration of a cerebral infarction by neutrophils begins at the edges of the lesion where the vascular supply is intact. B, By day 10, an area of infarction shows the presence of macrophages and surrounding reactive gliosis. C, Old intracortical infarcts are seen as areas of tissue loss with a modest amount of residual gliosis.
Figure 22–7 Cerebral infarction. A, Section of the brain showing a large, discolored, focally hemorrhagic region in the left middle cerebral artery distribution (hemorrhagic, or red, infarction). B, An infarct with punctate hemorrhages, consistent with ischemia-reperfusion injury, is present in the temporal lobe. C, Old cystic infarct shows destruction of cortex and surrounding gliosis.
Morphology
Intracranial Hemorrhage
Primary Brain Parenchymal Hemorrhage
Morphology
Cerebral Amyloid Angiopathy
Figure 22–8 Cerebral hemorrhage. Massive hypertensive hemorrhage rupturing into a lateral ventricle.
Subarachnoid Hemorrhage and Saccular Aneurysms
Figure 22–9 Common sites of saccular aneurysms.
Morphology
Vascular Malformations
Figure 22–10 Saccular aneurysms. A, View of the base of the brain, dissected to show the circle of Willis with an aneurysm of the anterior cerebral artery (arrow). B, Circle of Willis dissected to show large aneurysm. C, Section through a saccular aneurysm showing the hyalinized fibrous vessel wall. Hematoxylin-eosin stain.
Figure 22–11 Arteriovenous malformation.
Morphology
Other Vascular Diseases
Hypertensive Cerebrovascular Disease
Vasculitis
Summary
Cerebrovascular Diseases
Central Nervous System Trauma
Traumatic Parenchymal Injuries
Figure 22–12 Cerebral trauma. A, Acute contusions are present in both temporal lobes, with areas of hemorrhage and tissue disruption. B, Remote contusions, seen as discolored yellow areas, are present on the inferior frontal surface of this brain.
Morphology
Traumatic Vascular Injury
Epidural Hematoma
Figure 22–13 Traumatic intracranial hemorrhages. A, Epidural hematoma (left) in which rupture of a meningeal artery, usually associated with a skull fracture, has led to accumulation of arterial blood between the dura and the skull. In a subdural hematoma (right), damage to bridging veins between the brain and the superior sagittal sinus has led to the accumulation of blood between the dura and the arachnoid. B, Epidural hematoma covering a portion of the dura. C, Large organizing subdural hematoma attached to the dura.
Subdural Hematoma
Morphology
Summary
Central Nervous System Trauma
Congenital Malformations and Perinatal Brain Injury
Malformations
Neural Tube Defects
Figure 22–14 Myelomeningocele. Both meninges and spinal cord parenchyma are included in the cystlike structure visible just above the buttocks.
Forebrain Malformations
Posterior Fossa Anomalies
Spinal Cord Abnormalities
Figure 22–15 Perinatal brain injury. This specimen from a patient with periventricular leukomalacia contains a central focus of white matter necrosis with a peripheral rim of mineralized axonal processes.
Perinatal Brain Injury
Summary
Congenital Malformations and Perinatal Brain Injury
Infections of the Nervous System
Epidural and Subdural Infections
Meningitis
Acute Pyogenic Meningitis (Bacterial Meningitis)
Figure 22–16 Bacterial infections. A, Pyogenic meningitis. A thick layer of suppurative exudate covers the brain stem and cerebellum and thickens the leptomeninges. B, Cerebral abscesses in the frontal lobe white matter (arrows).
Morphology
Aseptic Meningitis (Viral Meningitis)
Chronic Meningitis
Tuberculous Meningitis
Morphology
Spirochetal Infections
Parenchymal Infections
Brain Abscesses
Morphology
Viral Encephalitis
Figure 22–17 Viral infections. A and B, Characteristic findings in many forms of viral meningitis include perivascular cuffing of lymphocytes (A) and microglial nodules (B). C, Herpes encephalitis showing extensive destruction of inferior frontal and anterior temporal lobes. D, Human immunodeficiency virus (HIV) encephalitis. Note the accumulation of microglia forming a microglial nodule and multinucleate giant cell.
Arboviruses
Morphology
Herpesviruses
Morphology
Cytomegalovirus
Poliovirus
Rabies Virus
Human Immunodeficiency Virus
Morphology
Polyomavirus and Progressive Multifocal Leukoencephalopathy
Morphology
Fungal Encephalitis
Figure 22–18 Progressive multifocal leukoencephalopathy. A, Section stained for myelin showing irregular, poorly defined areas of demyelination, which become confluent in places. B, Enlarged oligodendrocyte nuclei stained for viral antigens surround an area of early myelin loss.
Other Meningoencephalitides
Cerebral Toxoplasmosis
Figure 22–19 Cryptococcal infection. A, Whole-brain section showing the numerous areas of tissue destruction associated with the spread of organisms in the perivascular spaces. B, At higher magnification, it is possible to see the cryptococci in the lesions.
Morphology
Cysticercosis
Figure 22–20 Toxoplasma infection. A, Abscesses are present in the putamen and thalamus. B, Free tachyzoites are demonstrated by immunohistochemical staining. Inset, Bradyzoites are present as a pseudocyst, again highlighted by immunohistochemical staining.
Amebiasis
Prion Diseases
Figure 22–21 Pathogenesis of prion disease. α-Helical PrPc may spontaneously shift to the β-sheet PrPsc conformation, an event that occurs at a much higher rate in familial disease associated with germ line PrP mutations. PrPsc may also be from exogenous sources, such as contaminated food, medical instrumentation, or medicines. Once present, PrPsc converts additional molecules of PrPc into PrPsc through physical interaction, eventually leading to the formation of pathogenic PrPsc aggregates.
Creutzfeldt-Jakob Disease
Morphology
Variant Creutzfeldt-Jakob Disease
Figure 22–22 Prion disease. A, Histologic features of Creutzfeldt-Jakob disease (CJD) include spongiform change in the cerebral cortex. Inset, High magnification of neuron with vacuoles. B, Variant CJD (vCJD) is characterized by amyloid plaques (see inset) that sit in the regions of greatest spongiform change.
Summary
Infections of the Nervous System
Primary Diseases of Myelin
Multiple Sclerosis
Figure 22–23 Multiple sclerosis (MS). A, Section of fresh brain showing a plaque around occipital horn of the lateral ventricle. B, Unstained regions of demyelination (MS plaques) around the fourth ventricle. Luxol fast blue–periodic acid–Schiff stain for myelin.
Pathogenesis
Morphology
Clinical Features
Other Acquired Demyelinating Diseases
Leukodystrophies
Morphology
Clinical Features
Table 22–1 Selected Leukodystrophies
Summary
Primary Diseases of Myelin
Acquired Metabolic and Toxic Disturbances
Nutritional Diseases
Thiamine Deficiency
Morphology
Vitamin B12 Deficiency
Metabolic Disorders
Hypoglycemia
Hyperglycemia
Hepatic Encephalopathy
Toxic Disorders
Neurodegenerative Diseases
Table 22–2 Protein Inclusions in Degenerative Diseases
Table 22–3 Some Causes of Dementia or Cognitive Impairment
Alzheimer Disease
Figure 22–24 Aβ peptide genesis and consequences in Alzheimer disease. Amyloid precursor protein cleavage by α-secretase and γ-secretase produces a harmless soluble peptide, whereas amyloid precursor protein cleavage by β-amyloid–converting enzyme (BACE) and γ-secretase releases Aβ peptides, which form pathogenic aggregates and contribute to the characteristic plaques and tangles of Alzheimer disease.
Figure 22–25 Alzheimer disease. A, Plaques (arrow) contain a central core of amyloid and a surrounding region of dystrophic neurites (Bielschowsky stain). B, Immunohistochemical stain for Aβ. Peptide is present in the core of the plaques as well as in the surrounding region. C, Neurons containing tangles stained with an antibody specific for tau.
Pathogenesis
Morphology
Frontotemporal Lobar Degeneration
Parkinson Disease
Figure 22–26 Parkinson disease. A, Normal substantia nigra. B, Depigmented substantia nigra in idiopathic Parkinson disease. C, Lewy body in a neuron from the substantia nigra stains pink.
Pathogenesis
Morphology
Clinical Features
Huntington Disease
Figure 22–27 Huntington disease. Normal hemisphere on the left compared with the hemisphere with Huntington disease on the right showing atrophy of the striatum and ventricular dilation. Inset, An intranuclear inclusion in a cortical neuron is strongly immunoreactive for ubiquitin.
Pathogenesis
Morphology
Spinocerebellar Ataxias
Amyotrophic Lateral Sclerosis
Pathogenesis
Morphology
Summary
Neurodegenerative Diseases
Tumors
Gliomas
Astrocytoma
Diffuse Astrocytoma
Morphology
Pilocytic Astrocytoma
Figure 22–28 Astrocytomas. A, Low-grade astrocytoma is seen as expanded white matter of the left cerebral hemisphere and thickened corpus callosum and fornices. B, Glioblastoma appearing as a necrotic, hemorrhagic, infiltrating mass. C, Glioblastoma is a densely cellular tumor with necrosis and pseudopalisading of tumor cell nuclei.
Morphology
Oligodendroglioma
Figure 22–29 Other gliomas. A, In oligodendroglioma tumor cells have round nuclei, often with a cytoplasmic halo. Blood vessels in the background are thin and can form an interlacing pattern. B, Microscopic appearance of ependymoma.
Morphology
Ependymoma
Morphology
Neuronal Tumors
Embryonal (Primitive) Neoplasms
Medulloblastoma
Figure 22–30 Medulloblastoma. A, Sagittal section of brain showing medulloblastoma with destruction of the superior midline cerebellum. B, Microscopic appearance of medulloblastoma.
Morphology
Other Parenchymal Tumors
Primary Central Nervous System Lymphoma
Morphology
Germ Cell Tumors
Figure 22–31 Meningioma. A, Parasagittal multilobular meningioma attached to the dura with compression of underlying brain. B, Meningioma with a whorled pattern of cell growth and psammoma bodies.
Meningiomas
Morphology
Metastatic Tumors
Figure 22–32 Metastatic melanoma. Metastatic lesions are distinguished grossly from most primary central nervous system tumors by their multicentricity and well-demarcated margins. The dark color of the tumor nodules in this specimen is due to the presence of melanin.
Familial Tumor Syndromes
Tuberous Sclerosis
Morphology
von Hippel–Lindau Disease
Morphology
Summary
Tumors of the Central Nervous System
Bibliography
Central Nervous System Trauma
Congenital Malformations and Perinatal Brain Injury
Infections of the Nervous System
Primary Diseases of Myelin
NEURODegenerative Diseases
Tumors
Chapter 23 Skin
Terms for Macroscopic Lesions
Microscopic Terms
Acute Inflammatory Dermatoses
Urticaria
Pathogenesis
Morphology
Clinical Features
Acute Eczematous Dermatitis
Morphology
Clinical Features
Erythema Multiforme
Figure 23–1 Eczematous dermatitis. A, The patterned erythema and scale stems from a nickel-induced contact dermatitis produced by this woman’s necklace. B, Microscopically, there is fluid accumulation (spongiosis) between epidermal cells that can progress to small vesicles if intercellular connections are stretched until broken.
Figure 23–2 Erythema multiforme. A, The target-like lesions consist of a pale central blister or zone of epidermal necrosis surrounded by macular erythema. B, Early lesions show a collection of lymphocytes along the dermoepidermal junction (interface dermatitis) associated with scattered keratinocytes with dark shrunken nuclei and eosinophilic cytoplasm that are undergoing apoptosis.
Morphology
Clinical Features
Chronic Inflammatory Dermatoses
Psoriasis
Pathogenesis
Morphology
Clinical Features
Figure 23–3 Psoriasis. A, Chronic plaques of psoriasis show silvery-white scale on the surface of erythematous plaques. B, Microscopic examination reveals marked epidermal hyperplasia, uniform downward extension of rete ridges (psoriasiform hyperplasia), and prominent parakeratotic scale that is focally infiltrated by neutrophils.
Lichen Planus
Figure 23–4 Lichen planus. A, This flat-topped pink-purple polygonal papule has white lacelike markings referred to as Wickham striae. B, Microscopic features include a bandlike infiltrate of lymphocytes along the dermoepidermal junction, hyperkeratosis, hypergranulosis, and pointed rete ridges (“sawtoothing”), which results from chronic injury of the basal cell layer.
Morphology
Clinical Features
Lichen Simplex Chronicus
Figure 23–5 Lichen simplex chronicus. Acanthosis with hyperkeratosis and hypergranulosis are distinctive. Superficial dermal fibrosis and vascular ectasia, both common features, also are present.
Morphology
Clinical Features
Summary
Inflammatory Dermatoses
Infectious Dermatoses
Bacterial Infections
Morphology
Clinical Features
Figure 23–6 Impetigo. This child’s arm is involved by a superficial bacterial infection producing the characteristic erythematous scablike lesions crusted with dried serum.
Fungal Infections
Morphology
Clinical Features
Verrucae (Warts)
Pathogenesis
Morphology
Blistering (Bullous) Disorders
Figure 23–7 Verruca vulgaris. A, Multiple warts, with characteristic rough, pebble-like surfaces. B, Microscopically, common warts contain zones of papillary epidermal proliferation that often radiate symmetrically like the points of a crown (top). Nuclear pallor, prominent keratohyalin granules, and related cytopathic changes are seen at higher magnification (bottom).
Pemphigus (Vulgaris and Foliaceus)
Figure 23–8 Levels of blister formation. A, Subcorneal (as in pemphigus foliaceus). B, Suprabasal (as in pemphigus vulgaris). C, Subepidermal (as in bullous pemphigoid or dermatitis herpetiformis). The level of epidermal separation forms the basis of the differential diagnosis for blistering disorders.
Figure 23–9 Direct immunofluorescence findings in pemphigus. A, Pemphigus vulgaris. There is uniform deposition of immunoglobulin and complement (green) along the cell membranes of keratinocytes in a characteristic “fishnet” pattern. B, Pemphigus foliaceus. Immunoglobulin deposits are confined to superficial layers of the epidermis.
Pathogenesis
Morphology
Clinical Features
Bullous Pemphigoid
Figure 23–10 Pemphigus vulgaris. A, This erosion on the leg represents a group of confluent, “unroofed” blisters. B, Suprabasal acantholysis results in an intraepidermal blister in which rounded, dissociated (acantholytic) keratinocytes are plentiful (inset).
Figure 23–11 Pemphigus foliaceus. A, Gross appearance of a typical blister, which is less severely eroded than those seen in pemphigus vulgaris. B, Microscopic appearance of a characteristic subcorneal blister.
Figure 23–12 Bullous pemphigoid. A, Deposition of IgG antibody detected by direct immunofluorescence as a linear band outlining the subepidermal basement membrane zone (epidermis is on the left side of the fluorescent band). B, Gross appearance of characteristic tense, fluid-filled blisters. C, A subepidermal vesicle with an inflammatory infiltrate rich in eosinophils.
Pathogenesis
Morphology
Clinical Features
Dermatitis Herpetiformis
Figure 23–13 Dermatitis herpetiformis. A, Selective deposition of IgA autoantibody at the tips of dermal papillae is characteristic. B, Lesions consist of intact and eroded (usually scratched) erythematous blisters, often grouped (seen here on elbows and arms). C, The blisters are associated with basal cell layer injury, initially caused by accumulation of neutrophils (microabscesses) at the tips of dermal papillae.
Pathogenesis
Morphology
Summary
Blistering Disorders
Benign and Premalignant Tumors
Benign and Premalignant Epithelial Lesions
Seborrheic Keratosis
Figure 23–14 Seborrheic keratosis. This roughened, brown, waxy lesion almost appears to be “stuck on” the skin (inset). Microscopic examination shows the lesion to consist of an orderly proliferation of uniform, basaloid keratinocytes that tend to form keratin microcysts (horn cysts).
Morphology
Actinic Keratosis
Figure 23–15 Actinic keratosis. A, Most lesions are red and rough (sandpaper-like), owing to excessive scale, as seen in the lesions on the cheek, nose, and chin of this female patient. B, Basal cell layer atypia (dysplasia) with epithelial buds, and associated with marked hyperkeratosis, parakeratosis, and dermal solar elastosis (asterisk). C, More advanced lesions show full-thickness atypia, qualifying as squamous carcinoma in situ.
Morphology
Clinical Features
Summary
Benign and Premalignant Epithelial Lesions
Malignant Epidermal Tumors
Squamous Cell Carcinoma
Pathogenesis
Morphology
Clinical Features
Figure 23–16 Invasive squamous cell carcinoma. A, A nodular, hyperkeratotic lesion occurring on the ear, associated with metastasis to a prominent postauricular lymph node (arrow). B, The tumor invades the dermis infiltrating collagen as irregular projections of atypical squamous cells, which in this case exhibit acantholysis.
Basal Cell Carcinoma
Pathogenesis
Morphology
Clinical Features
Figure 23–17 Basal cell carcinoma. A, A prototypical pearly, smooth-surfaced papule with associated telangiectatic vessels. B, The tumor is composed of nests of basaloid cells infiltrating a fibrotic stroma. C, The tumor cells have scant cytoplasm and small hyperchromatic nuclei that palisade on the outside of the nest. The cleft between the tumor cells and the stroma is a highly characteristic artifact of sectioning.
Summary
Malignant Epidermal Tumors
Melanocytic Proliferations
Melanocytic Nevi
Pathogenesis
Morphology
Clinical Features
Dysplastic Nevus
Figure 23–18 Possible steps in development of melanocytic nevi. A, Normal skin shows only scattered melanocytes. B, Junctional nevus. C, Compound nevus. D, Intradermal nevus. E, Intradermal nevus with extensive cellular senescence.
Figure 23–19 Melanocytic nevus. A, Melanocytic nevi are relatively small, symmetric, and uniformly pigmented. B, This nevus shows rounded melanocytes that lose their pigmentation and become smaller and more separated as they extend into the dermis—all signs of cellular senescence that speak to the benign nature of the proliferation.
Morphology
Clinical Features
Figure 23–20 Dysplastic nevus. A, Numerous irregular nevi on the back of a patient with the dysplastic nevus syndrome. The lesions usually are greater than 5mm in diameter and have irregular borders and variable pigmentation (inset). B, Compound dysplastic nevi feature a central dermal component with an asymmetric “shoulder” of exclusively junctional melanocytes (lentiginous hyperplasia). The former corresponds to the more pigmented and raised central zone (see A, inset), and the latter, to the less pigmented flat peripheral rim. C, Other important features are cytologic atypia (irregular, dark-staining nuclei) and characteristic parallel bands of fibrosis—part of the host response to these lesions.
Melanoma
Figure 23–21 Possible steps in development of melanoma. A, Normal skin shows only scattered melanocytes. B, Lentiginous melanocytic hyperplasia. C, Lentiginous compound nevus with abnormal architecture and cytologic features (dysplastic nevus). D, Early or radial growth phase melanoma (large dark cells in epidermis) arising in a nevus. E, Melanoma in vertical growth phase with metastatic potential. Note that no melanocytic nevus precursor is identified in most cases of melanoma. They are believed to arise de novo, perhaps all using the same pathway.
Pathogenesis
Morphology
Clinical Features
Figure 23–22 Melanoma. A, On clinical evaluation, lesions tend to be larger than nevi, with irregular contours and pigmentation. Macular areas indicate early superficial (radial) growth, while elevated areas often indicate dermal invasion (vertical growth). B, Radial growth phase, with spread of nested and single-cell melanoma cells within the epidermis. C, Vertical growth phase, with nodular aggregates of infiltrating tumor cells within the dermis (epidermis is on the right). D, Melanoma cells have hyperchromatic nuclei of irregular size and shape with prominent nucleoli. Mitoses, including atypical forms such as seen in the center of this field, often are encountered. The inset shows a sentinel lymph node containing a tiny cluster of metastatic melanoma cells (arrow), detected by staining for the melanocytic marker HMB-45.
Summary
Melanocytic Lesions, Benign and Malignant
Bibliography
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
R
S
T
U
V
W
X
Y
Z
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