Rubin's Gen Path Flashcards

Question

membrane lipids | (E) Progressive oxidation of bilirubin

Answer 1

formation and accumulation of lipofuscin granules. | Diagnosis: Lipofuscin, intracellular storage disorder

Answer 2

D: Hemosiderin. Hemosiderin is a partially denatured form of ferritin that aggregates easily and is recognized microscopically as yellow-brown granules in the cytoplasm, which turn blue with the Prussian blue reaction. In hereditary hemochromatosis, a genetic abnormality of iron absorption in the small intestine, excess iron is stored mostly in the form of hemosiderin, primarily in the liver. Hemoglobin (choice C) is the iron-containing pigment of RBCs. Bilirubin (choice A) is a product of heme catabolism that may accumulate in liver cells but does not stain with Prussian blue. Transferrin (choice E) binds serum iron. Diagnosis: Hereditary hemochromatosis

Answer 3

E: Metaplasia. Metaplasia of transitional epithelium to glandular epithelium is seen in patients with chronic inflammation of the bladder (cystitis glandularis). Metaplasia is considered to be a protective mechanism, but it is not necessarily a harmless process. For example, squamous metaplasia in a bronchus may protect against injury produced by tobacco smoke, but it also impairs the production of mucus and ciliary clearance of debris. Furthermore, neoplastic transformation may occur in metaplastic epithelium. Lack of cytologic evidence for atypia and neoplasia rules out dysplasia (choice B). Diagnosis: Chronic cystitis, metaplasia

Answer 4

E: Reactive oxygen species. Ischemia/reperfusion (I/R) injury is a common clinical problem that arises in the setting of occlusive cardiovascular disease, infection, transplantation, shock, and many other circumstances. The genesis of I/R injury relates to the interplay between transient ischemia and the re-establishment of blood flow (reperfusion). Initially, ischemia produces a type of cellular damage that leads to the generation of free radical species. Subsequently, reperfusion provides abundant molecular oxygen (O2) to combine with free radicals to form reactive oxygen species. Oxygen radicals are formed inside cells through the xanthine oxidase pathway and released from activated neutrophils. Diagnosis: Myocardial infarction

Answer 5

D: Phospholipids. During lipid peroxidation, hydroxyl radicals remove a hydrogen atom from the unsaturated fatty acids of membrane phospholipids. The lipid radicals so formed react with molecular oxygen and form a lipid peroxide radical. A chain reaction is initiated. Lipid peroxides are unstable and break down into smaller molecules. The destruction of the unsaturated fatty acids of phospholipids results in a loss of membrane integrity. The other choices represent targets for reactive oxygen species, but protein cross-linking (choices B and E) does not lead to rapid loss of membrane integrity in patients with myocardial infarction. Diagnosis: Myocardial infarction

Answer 6

E: Liquefactive necrosis. Polymorphonuclear leukocytes (segmented neutrophils) rapidly accumulate at sites of injury. They are loaded with acid hydrolases and are capable of digesting dead cells. A localized collection of these inflammatory cells may create an abscess with central lique faction (pus). Liquefactive necrosis is also commonly seen in the brain. Caseous necrosis (choice A) is seen in necrotizing granulomas. Fat necrosis (choice C) is typically encountered in patients with acute pancreatitis. Fibrinoid necrosis (choice D) is seen in patients with necrotizing vasculitis. Diagnosis: Abscess, acute inflammation

Answer 7

B: Apoptotic cell death. Apoptosis is a programmed pathway of cell death that is triggered by a variety of extracellular and intracellular signals. It is often a self defense mechanism, destroying cells that have been infected with pathogens or those in which genomic alterations have occurred. After staining with hematoxylin and eosin, apoptotic cells are visible under the light microscope as acidophilic (Councilman) bodies. These deeply eosinophilic structures represent membrane-bound cellular remnants that are extruded into the hepatic sinusoids. The other choices do not appear as acidophilic bodies. Diagnosis: Viral hepatitis

Answer 8

A: Fragmentation of DNA. Fragmentation of DNA is a hallmark of cells undergoing both necrosis and apoptosis, but apoptotic cells can be detected by demonstrating nucleosomal “laddering.” This pattern of DNA degradation is characteristic of apoptotic cell death. It results from the cleavage of chromosomal DNA at nucleosomes by endonucleases. Since nucleosomes are regularly spaced along the genome, a pattern of regular bands can be seen when fragments of cellular DNA are separated by electrophoresis. The other choices are associated with cell injury, but they do not serve as distinctive markers of programmed cell death. Diagnosis: Viral hepatitis

Answer 9

A: Atrophy. Interference with blood supply to tissues is known as ischemia. Total ischemia results in cell death. Partial ischemia occurs after incomplete occlusion of a blood vessel or in areas of inadequate collateral circulation. This results in a chronically reduced oxygen supply, a condition is often compatible with continued cell viability. Under such circumstances, cell atrophy is common. For example, it is frequently seen around the inadequately perfused margins of infarcts in the heart, brain, and kidneys. None of the other choices describe decreased organ size and function. Diagnosis: Renal artery stenosis

Answer 10

C: Metaplasia. Myositis ossifi cans is a disease characterized by formation of bony trabeculae within striated muscle. It represents a form of osseous metaplasia (i.e., replacement of one differentiated tissue with another type of normal differentiated tissue). Although dystrophic calcification (choice E) frequently occurs at sites of prior injury, it does not lead to the formation of bone trabeculae. Diagnosis: Myositis ossifi cans, metaplasia

Answer 11

B: Cytochrome c. The mitochondrial membrane is a key regulator of apoptosis. When mitochondrial pores open, cytochrome c leaks out and activates Apaf-1, which converts procaspase-9 to caspase-9, resulting in the activation of downstream caspases (cysteine proteases). These effector caspases cleave target proteins, including endonucleases nuclear proteins, and cytoskeletal proteins to mediate the varied morphological and biochemical changes that accompany apoptosis. Reactive oxygen species (related to choices A, D, and E) are triggers of apoptosis, but they do not mediate programmed cell death. Diagnosis: Apoptosis, squamous cell carcinoma of skin

Answer 12

A: Decreased stores of intracellular ATP. Hydropic swelling may result from many causes, including chemical and biological toxins, infections, and ischemia. Injurious agents cause hydropic swelling by (1) increasing the permeability of the plasma membrane to sodium; (2) damaging the membrane sodium-potassium ATPase (pump); or (3) interfering with the synthesis of ATP, thereby depriving the pump of its fuel. The other choices are incorrect because they do not regulate the concentration of intracellular sodium. Diagnosis: Hydropic swelling, hepatotoxicity

Answer 13

C: Decrease in intracellular pH. During periods of ischemia, anaerobic glycolysis leads to the overproduction of lactate and a decrease in intracellular pH. Lack of O2 during myocardial ischemia blocks the production of ATP. Pyruvate is reduced to lactate in the cytosol and lowers intracellular pH. The acidification of the cytosol initiates a downward spiral of events that propels the cell toward necrosis. The other choices point to changes in the opposite direction of what would be expected in irreversible cell injury. Diagnosis: Acute tubular necrosis

Answer 14

D: Fibrinoid necrosis. Fibrinoid necrosis is an alteration of injured blood vessels, in which the insudation and accumulation of plasma proteins cause the wall to stain intensely with eosin. The other choices are not typically associated directly with vascular injury. Diagnosis: Malignant hypertension, fi brinoid necrosis

Answer 15

B: Lamin. Hutchinson-Gilford progeria is a rare genetic disease characterized by early cataracts, hair loss, atrophy of the skin, osteoporosis, and atherosclerosis. This phenotype gives the impression of premature aging in children. Progeria is one of many diseases caused by mutations in the human lamin A gene (LMNA). Lamins are intermediate filament proteins that form a fibrous meshwork beneath the nuclear envelope. Defective lamin A is thought to make the nucleus unstable, leading to cell injury and death. Mutations in the other genes are not linked to Hutchinson-Gilford progeria syndrome. Diagnosis: Progeria

Answer 16

D: Lack of trophic signals. Atrophy of an organ may be caused by interruption of key trophic signals. Postpartum infarction of the anterior pituitary in this patient resulted in decreased production of adrenocorticotropic hor mone (ACTH, also termed corticotropin). Lack of corticotropin results in atrophy of the adrenal cortex, which leads to adrenal insufficiency. Symptoms of acute adrenal insufficiency (Addisonian crisis) include hypotension and shock, as well as weakness, vomiting, abdominal pain, and lethargy. The other choices are unlikely causes of postpartum adrenal insuf fi ciency. Diagnosis: Sheehan syndrome, adrenal insufficiency

Answer 17

E: Reversion to normal. Metaplasia is almost invariably a response to persistent injury and can be thought of as an adaptive mechanism. Prolonged exposure of the bronchi to tobacco smoke leads to squamous metaplasia of the bronchial epithelium. Unlike malignancy (choice B) and necrosis with scarring (choice C), metaplasia is usually fully reversible. If the source of injury in this patient is removed (the patient stops smoking), then the metaplastic epithelium will eventually return to normal. Diagnosis: Chronic bronchitis, metaplasia

Answer 18

B: Dysplasia. Actinic keratosis is a form of dysplasia in sun-exposed skin. Histologically, such lesions are composed of atypical squamous cells, which vary in size and shape. They show no signs of regular maturation as the cells move from the basal layer of the epidermis to the surface. Dysplasia is a preneoplastic lesion, in the sense that it is a necessary stage in the multistep evolution to cancer. However, unlike cancer cells, dysplastic cells are not entirely autonomous, and the histologic appearance of the tissue may still revert to normal. None of the other choices represent preneo plastic changes in sun-exposed skin. Diagnosis: Actinic keratosis, dysplasia

Answer 19

C: Hyperplasia. Renal cell carcinomas often secrete erythropoietin. This hormone stimulates the growth of erythrocyte precursors in the bone marrow by inhibiting programmed cell death. Increased hematocrit in this patient is the result of bone marrow hyperplasia affecting the erythroid lineage. The other choices do not represent physiologic responses to erythropoietin. Diagnosis: Renal cell carcinoma, hyperplasia

Answer 20

B: Dysplasia. The distinction between severe dysplasia and early cancer of the cervix is a common diagnostic problem for the pathologist. Both are associated with disordered growth and maturation of the tissue. Similar to the development of cancer, dysplasia is believed to result from mutations in a proliferating cell population. When a particular mutation confers a growth or survival advantage, the progeny of the affected cell will tend to predominate. In turn, their continued proliferation provides the opportunity for further mutations. The accumulation of such mutations progressively distances the cell from normal regulatory constraints and may lead to neoplasia. None of the other choices are associated with lack of normal tissue polarity. Diagnosis: Cervical intraepithelial neoplasia, dysplasia

Answer 21

D: Mixed function oxygenase. The metabolism of CCl4 is a model system for toxicologic studies. CCl4 is first metabolized via the mixed function oxygenase system (P450) of the liver to a chloride ion and a highly reactive trichlo methyl free radical. Like the hydroxyl radical, this radical is a potent initiator of lipid peroxidation, which damages the plasma membrane and leads to cell death. The other

Answer 22

choices are not involved in the formation of the trichloromethyl free radical in liver cells. Diagnosis: Hepatic failure, hepatotoxicity

Answer 23

Hyperplasia. Psoriasis is a disease of the dermis and epidermis that is characterized by persistent epidermal hyperplasia. It is a chronic, frequently familial disorder that features large, erythematous, scaly plaques, commonly on the dorsal extensor cutaneous surfaces. There is evidence to suggest that deregulation of epidermal proliferation and an abnormality in the microcirculation of the dermis are responsible for the development of psoriatic lesions. Abnormal proliferation of keratinocytes is thought to be related to defective epidermal cell surface receptors and altered intracellular signaling. The other choices do not describe increased numbers of otherwise normal epidermal cells. Diagnosis: Psoriasis, hyperplasia

Answer 24

E: Smooth endoplasmic reticulum. Carbon tetrachloride and acetaminophen are well studied hepatotoxins. Each is metabolized by cytochrome P450 of the mixed function oxidase system, located in the smooth endoplasmic reticulum. These hepatotoxins are metabolized differently, and it is possible to relate the subsequent evolution of lethal cell injury to the specific features of this metabolism. Acetaminophen, an important constituent of many analgesics, is innocuous in recommended doses, but when consumed to excess it is highly toxic to the liver. The metabolism of acetaminophen to yield highly reactive quinones is accelerated by alcohol consumption, an effect mediated by an ethanol-induced increase in cytochrome P450. Diagnosis: Hepatotoxicity, necrosis

Answer 25

B: Immune recognition of viral antigens on the cell surface. Viral cytotoxicity is either direct or indirect (immunologically mediated). Viruses may injure cells directly by subverting cellular enzymes and depleting the cell’s nutri ents, thereby disrupting the normal homeostatic mechanisms. Some viruses also encode proteins that induce apoptosis once daughter virions are mature. Viruses may also injure cells indirectly through activation of the immune system. Both humoral and cellular arms of the immune system protect against the harmful effects of viral infections by eliminating infected cells. In brief, the presentation of viral proteins to the immune system in the context of a self major histocompatibility complex on the cell surface immunizes the body against the invader and elicits both killer cells and antiviral antibodies. These arms of the immune system eliminate virus-infected cells by inducing apoptosis or by lysing the virally infected target cell with complement. None of the other choices describe mechanisms of indirect viral cytotoxicity. Diagnosis: Hepatitis, viral

Answer 26

C: α1-Antitrypsin deficiency. Several acquired and inherited diseases are characterized by intracellular accumulation of abnormal proteins. The deviant tertiary structure of the protein may result from an inherited mutation that alters the normal primary amino acid sequence, or may reflect an acquired defect in protein folding. α1-Antitrypsin deficiency is a heritable disorder in which mutations in the gene for α1-antitrypsin yield an insoluble protein. The mutant protein is not easily exported. It accumulates in liver cells, causing cell injury and cirrhosis. Pulmonary emphysema is another complication of α1-antitrypsin deficiency. Choices A and B are amyloidoses that represent extracellular deposits of fi brillar proteins arranged in β-pleated sheets. Choices D and E are lysosomal storage diseases that represent intracellular deposits of unmetabolized sphingolipids. Diagnosis: α1-Antitrypsin deficiency

Answer 27

B: Helicase. Werner syndrome is a rare auto somal recessive disease characterized by early cataracts, hair loss, atrophy of the skin, osteoporosis, and accelerated atherosclerosis. Affected persons are also at risk for development of a variety of cancers. Unlike Hutchinson-Gilford progeria, patients with Werner syndrome typically die in the fifth decade from either cancer or cardiovascular disease. Werner syndrome is caused by mutations in the WRN gene, which encodes a protein with multiple DNA-dependent enzymatic functions, including proteins with ATPase, helicase, and exonuclease activity. Hutchinson-Gilford progeria is caused by mutations in the human lamin A gene, which encodes an intermediate filament protein that forms a fibrous meshwork beneath the nuclear envelope. Mutations in the other choices are not associated with Werner syndrome. Diagnosis: Werner syndrome

Answer 28

E: p53. Apoptosis detects and destroys cells that harbor dangerous mutations, thereby maintaining genetic consistency and preventing the development of cancer. There are several means, the most important of which is probably p53, by which the cell recognizes genomic abnormalities and “assesses'' whether they can be repaired. If the damage to DNA is so severe that it cannot be repaired, the cascade of events leading to apoptosis is activated, and the cell dies. This process protects an organism from the consequences of a non functional cell or one that cannot control its own proliferation (e.g., a cancer cell). After it binds to areas of DNA damage, p53 activates proteins that arrest the cell in G1 of the cell cycle, allowing time for DNA repair to proceed. It also directs DNA repair enzymes to the site of injury. If the DNA damage cannot be repaired, p53 activates mechanisms that terminate in apoptosis. There are several pathways by which p53 induces apoptosis. This molecule downregulates transcription of the antiapoptotic protein Bcl-2, while it upregulates transcription of the proapoptotic genes bax and bak. Cytochrome P450 (choice A) is a member of the mixed function oxidase system. β-Catenin (choice B) is a membrane protein associated with cell adhesion molecules. Selectins (choices C and D) are cell adhesion molecules involved in leukocyte recirculation. Diagnosis: Apoptosis

Answer 29

D: Neutrophils. The thick, yellow fluid draining from the breast fissure in this patient represents a purulent exudate. Purulent exudates and effusions are associated with pathologic conditions such as pyogenic bacterial infections, in which the predominant cell type is the segmented neutrophil (polymorphonuclear leukocyte). Mast cells (choice C) are granulated cells that contain receptors for IgE on their cell surface. They are additional cellular sources of vasoactive mediators, particularly in response to allergens. B lymphocytes (choice A) and plasma cells (choice E) are mediators of chronic inflammation and provide antigen-specific immunity to infectious diseases. Diagnosis: Acute mastitis

Answer 30

A: Complement proteins. Complement proteins act upon one another in a cascade, generating biologically active fragments (e.g., C5a, C3b) or complexes (e.g., C567). These products of complement activation cause local edema by increasing the permeability of blood vessels. They also promote chemotaxis of leukocytes and lyse cells (membrane attack complex) and act as opsonins by coating bacteria. Although the other choices are mediators of inflammation, they have a more restricted set of functions. Kinins (choice D) are formed following tissue trauma and mediate pain transmission. None of the other choices are involved in opsonization or cytolysis. Diagnosis: Acute mastitis

Answer 31

D: N-formylated peptides. The most potent chemotactic factors for leukocytes at the site of injury are (1) complement proteins (e.g., C5a); (2) bacterial and mitochondrial products, particularly low molecular weight N formylated peptides; (3) products of arachidonic acid metabolism (especially LTB4); and (4) chemokines (e.g., interleukin-1 and interferon-γ). Plasmin (choice E) is a fibrinolytic enzyme generated by activated Hageman factor (clotting factor XII). Histamine (choice B) is one of the primary mediators of increased vascular permeability. None of the other choices are chemotactic agents. Diagnosis: Pneumonia

Answer 32

D: Neutrophils. During acute inflammation, neutrophils (PMNs) adhere to the vascular endothelium. They flatten and migrate from the vasculature, through the endothelial cell layer, and into the surrounding tissue. About 24 hours after the onset of infarction, PMNs are observed to infiltrate necrotic tissue at the periphery of the infarct. Their function is to clear debris and begin the process of wound healing. Lymphocytes (choice B) and plasma cells (choice E) are mediators of chronic inflammation and provide antigen specific immunity to infectious diseases. Fibroblasts (choice A) and macrophages (choice C) regulate scar tissue formation at the site of infarction. Diagnosis: Acute myocardial infarction

Answer 33

C: Increased capillary permeability. Forces that regulate the balance of vascular and tissue fluids include (1) hydrostatic pressure, (2) oncotic pressure, (3) osmotic pressure, and (4) lymph flow. During inflammation, an increase in the permeability of the endothelial cell barrier results in local edema. Vasodilation of arterioles exacerbates fluid leakage, and vasoconstriction of postcapillary venules increases the hydrostatic pressure in the capillary bed (thus, not choice A), potentiating the formation of edema. Vasodilation of venules decreases capillary hydrostatic pressure and inhibits the movement of fluid into the extravascular spaces. Acute inflammation is not associated with changes in plasma oncotic pressure (choices B and D). Diagnosis: Inflammatory edema

Answer 34

B: Hageman factor. Hageman factor (clotting factor XII) provides a key source of vasoactive mediators. Activation of this plasma protein at the site of tissue injury stimulates (1) conversion of plasminogen to plasmin, which induces fibrinolysis; (2) conversion of prekallikrein to kallikrein, which generates vasoactive peptides of low molecular weight referred to as kinins; (3) activation of the alternative complement pathway; and (4) activation of the

Answer 35

E: Tumor necrosis factor-α (TNF-α). Septicemia (bacteremia) denotes the clinical condition in which bacteria are found in the circulation. It can be suspected clinically, but the final diagnosis is made by culturing the organisms from the blood. In patients with endotoxic shock, lipopolysaccharide released from Gram-negative bacteria stimulates monocytes/ macrophages to secrete large quantities of TNF-α. This glycoprotein causes direct cytotoxic damage to capillary endothelial cells. The other choices do not cause direct vascular injury. Diagnosis: Septic shock

Answer 36

E: Suppurative inflammation. Suppurative inflammation describes a condition in which a purulent exudate is accompanied by significant liquefactive necrosis. It is the equivalent of pus. The photograph shows two encapsulated cavities in the brain. These abscesses are composed of a central cavity filled with pus, surrounded by a layer of granulation tissue. Chronic inflammation (choice A) is nonsuppurative. Fibrinoid necrosis (choice B) is observed in areas of necrotizing vasculitis. Granulomatous inflammation (choice C) is seen in patients with tuberculosis. Reactive gliosis (choice D) is a normal response of the brain to injury and infection but is not visible on the cut surface of the brain at autopsy. Diagnosis: Cerebral abscess

Answer 37

C: Purulent exudate. The pleural effusion encountered in this patient represents excess fluid in a body cavity. A transudate denotes edema fluid with low protein content, whereas an exudate denotes edema fluid with high protein content. A purulent exudate or effusion contains a prominent cellular component (PMNs). A serous exudate or effusion is characterized by the absence of a prominent cellular response and has a yellow, straw-like color. Fibrinous exudate (choice A) does not contain leukocytes. Serosanguineous exudate (choice D) contains RBCs and has a red tinge. Diagnosis: Bacterial pneumonia, pleural effusion

Answer 38

D: Parasitic infection. Eosinophils are particularly evident during allergic-type reactions and parasitic infestations. Infections with Trichinella are accompanied by eosinophilia, and skeletal muscle is typically infiltrated by eosinophils. Patients with muscular dystrophy (choice C) show elevated serum levels of creatine kinase, but eosinophils are not seen on muscle biopsy. Bacterial infections (choice B) are associated with neutrophilia, and affected tissues are infiltrated with PMNs. Viral infections (choice E) are associated with lymphocytosis, and affected tissues are infiltrated with B and T lymphocytes. Polymyositis, an autoimmune disease (choice A), does not feature eosinophils. Diagnosis: Trichinosis

Answer 39

D: NADPH oxidase. The importance of oxygen dependent mechanisms in the bacterial killing by phagocytic cells is exemplified in chronic granulomatous disease of childhood. Children with this disease suffer from a hereditary deficiency of NADPH oxidase, resulting in a failure to produce superoxide anion and hydrogen peroxide during phagocytosis. Persons with this disorder are susceptible to recurrent bacterial infections. Patients deficient in myeloperoxidase (choice C) cannot produce hypochlorous acid (HOCl) and experience an increased susceptibility to infections with the fungal pathogen Candida. Catalase (choice A) converts hydrogen peroxide to water and molecular oxygen. Diagnosis: Chronic granulomatous disease

Answer 40

B: Hereditary angioedema. Deficiency of C1 inhibitor, with excessive cleavage of C4 and C2

Answer 41

by C1s, is associated with the syndrome of hereditary angioedema. This disease is characterized by episodic, painless, nonpitting edema of soft tissues. It is the result of chronic complement activation, with the generation of a vasoactive peptide from C2, and may be life threatening because of the occurrence of laryngeal edema. Chronic granulomatous disease (choice A) is due to a hereditary deficiency of NADPH oxidase. Myeloperoxidase deficiency (choice C) increases susceptibility to infections with Candida. Selective IgA deficiency (choice D) and Wiskott Aldrich syndrome (choice E) are congenital immunodeficiency disorders associated with defects in lymphocyte function. Diagnosis: Hereditary angioedema

Answer 42

B: Eosinophils. Eosinophils are recruited in parasitic infestations and would be expected to predominate in the portal tracts of the liver in patients with schistosomiasis. Eosinophils contain leukotrienes and platelet-activating factors, as well as acid phosphatase and eosinophil major basic protein. Plasma cells (choice E) are differentiated B lymphocytes that secrete large amounts of monospecifi c immunoglobulin. Diagnosis: Schistosomiasis, eosinophils

Answer 43

B: Chronic inflammation. Inflammation has historically been referred to as either acute or chronic, depending on the persistence of the injury, clinical symptoms, and the nature of the inflammatory response. The cellular components of chronic inflammation are lymphocytes, antibody producing plasma cells (see arrows on photomicrograph), and macrophages. The chronic inflammatory response is often prolonged and may be associated with aberrant repair (i.e., fibrosis). Neutrophils are featured in acute inflammation (choice A) and menstruation (choice E). Choices C and D do not exhibit the histopathology shown in the image. Diagnosis: Chronic endometritis

Answer 44

B: Lymphocytes. This patient with viral myocarditis will show an accumulation of lymphocytes in the affected heart muscle. Naïve lymphocytes encounter antigen presenting cells (macrophages and dendritic cells) in the secondary lymphoid organs. In response to this cell-cell interaction, they become activated, circulate in the vascular system, and are recruited to peripheral tissues (e.g., heart). The other choices are not characteristic responders to viral infections, although acute inflammation may be observed in lytic infections. Diagnosis: Viral myocarditis

Answer 45

C: Injury and increased vascular permeability. Binding of vasoactive mediators to specific receptors on endothelial cells results in contraction and gap formation. This break in the endothelial barrier leads to the leakage of intravascular fluid into the extravascular space. Direct injury to endothelial cells also leads to leakage of intravascular fluid. A fibrinous exudate contains large amounts of fibrin as a result of activation of the coagulation system. When a fibrinous exudate occurs on a serosal surface, such as the pleura or pericardium, it is referred to as fibrinous pleuritis or fibrinous pericarditis. Although the other choices describe aspects of inflammation, they do not address the pathogenesis of edema formation with activation of the coagulation system. Diagnosis: End-stage kidney disease, fibrinous pericarditis

Answer 46

B: Interleukin-1. Release of exogenous pyrogens by bacteria, viruses, or injured cells stimulates the production of endogenous pyrogens such as IL 1α, IL-1β, and TNF-α. IL-1 is a 15-kDa protein that stimulates prostaglandin synthesis in the hypothalamic thermoregulatory centers, thereby altering the “thermostat” that controls body temperature. Inhibitors of cyclooxygenase (e.g., aspirin) block the fever response by inhibiting PGE2 synthesis in the hypothalamus. Chills, rigor (profound chills with shivering and piloerection), and sweats (to allow heat dissipation) are symptoms associated with fever. The other choices are mediators of inflammation, but they do not directly control body temperature. Diagnosis: Bacterial pneumonia

Answer 47

E: Phagocytosis. Many inflammatory cells are able to recognize, internalize, and digest foreign materials, microorganisms, and cellular debris. This process is termed phagocytosis, and the effector cells are known as phagocytes. Phagocytosis of most biologic agents is enhanced by their coating with specific plasma components (opsonins), particularly immunoglobulins or the C3b fragment of complement. The other functions are not enhanced by opsonization. Diagnosis: Bacterial pneumonia

Answer 48

E: Lysosomal enzymes. The primary role of neutrophils in inflammation is host defense and débridement of damaged tissue. However, when the response is extensive or unregulated, the chemical mediators of inflammation may prolong tissue damage. Thus, the same neutrophil-derived lysosomal enzymes that are beneficial when active intracellularly can be harmful when released to the extracellular environment. The other choices are less likely to cause direct injury to the lung in a patient with pneumonia. Diagnosis: Bacterial pneumonia

Answer 49

D: α2-Macroglobulin. Proteolytic enzymes that are released by phagocytic cells during inflammation are regulated by a family of protease inhibitors, including α1-antitrypsin and α2-macroglobulin. These plasma-derived proteins inhibit plasmin-activated fibrinolysis and activation of the complement system and help protect against nonspecific tissue injury during acute inflammation. Lysozyme (choice C) is a glycosidase that degrades the peptidoglycans of Gram positive bacterial cell walls. Myeloperoxidase (choice E) is contained within neutrophil granules. Diagnosis: Bacterial pneumonia

Answer 50

E: Selectin. Selectins are sugar-binding glycoproteins that mediate the initial adhesion of leukocytes to endothelial cells at sites of inflammation. E-selectins are found on endothelial cells, P-selectins are found on platelets, and L-selectins are found on leukocytes. E-selectins are stored in Weibel Palade bodies of resting endothelial cells. Upon activation, E-selectins are redistributed along the luminal surface of the endothelial cells, where they mediate the initial adhesion (tethering) and rolling of leukocytes. After leukocytes have come to a rest, integrins (choice C) mediate transendothelial cell migration and chemotaxis. Cadherins (choice A) mediate cell-cell adhesion, but they are not involved in neutrophil adhesion to vascular endothelium. Entactin (choice B) and laminin (choice D) are basement membrane proteins.\ Diagnosis: Carbuncle

Answer 51

B: Constriction of precapillary arterioles. The initial response of arterioles to neurogenic and chemical stimuli is transient vasoconstriction. However, shortly thereafter, vasodilation (choice D) occurs, with an increase in blood flow to the inflamed area. This process is referred to as active hyperemia. None of the other choices cause transient skin blanching. Diagnosis: Laceration

Answer 52

D: Leukotrienes. Asthma is a chronic lung disease caused by increased responsiveness of the airways to a variety of stimuli. Chemical mediators released by chronic inflammatory cells in the lungs of these patients stimulate bronchial mucus production and bronchoconstriction. Among these mediators are leukotrienes, also known as slow-reacting substances of anaphylaxis. They are derived from arachidonic acid through the lipoxygenase pathway. Leukotrienes stimulate contraction of smooth muscle and enhance vascular permeability. They are responsible for the development of many of the clinical symptoms associated with asthma and other allergic reactions. Although the other choices are important mediators of inflammation, they do not play a leading role in the development of bronchoconstriction in patients with bronchial asthma. Diagnosis: Asthma

Answer 53

C: Histamine. When IgE-sensitized mast cells are stimulated by antigen, preformed mediators of inflammation are secreted into the extracellular tissues. Histamine binds to specific H1 receptors in the vascular wall, inducing endothelial cell contraction, gap formation, and edema. Massive release of histamine may cause circulatory collapse (anaphylactic shock). Bradykinin (choice A) and Hageman factor (choice B) are plasma-derived mediators. The other choices are not performed molecules but are synthesized de

Answer 54

C: Myeloperoxidase. Myeloperoxidase catalyzes the conversion of H2O2, in the presence of a halide (e.g., chloride ion), to form hypochlorous acid. This powerful oxidant is a major bactericidal agent produced by phagocytic cells. Patients deficient in myeloperoxidase cannot produce hypochlorous acid and have an increased susceptibility to recurrent infections. Catalase (choice A) catabolizes H2O2. Cyclooxygenase (choice B) mediates the conversion of arachidonic acid to prostaglandins. NADPH oxidase (choice D) is involved in oxygen-free radical formation during the neutrophil respiratory burst. Superoxide dismutase (choice E) reduces the superoxide radical to H2O2. Diagnosis: Bacterial pneumonia

Answer 55

B. Macrophages. The macrophage is the pivotal cell in regulating chronic inflammation. Macrophages, which are derived from circulating monocytes, regulate lymphocyte responses to antigens and secrete a variety of mediators that modulate the proliferation and function of fibroblasts and endothelial cells. None of the other cells have this wide spectrum of regulatory functions. Diagnosis: Laceration, wound healing

Answer 56

B: Leukopenia. Leukopenia is defined as an absolute decrease in the circulating WBC count. It is occasionally encountered under conditions of chronic inflammation, especially in patients who are malnourished or who suffer from a chronic debilitating disease. Leukopenia may also be caused by typhoid fever and certain viral and rickettsial infections. Leukocytosis (choice A) is defined as an absolute increase in the circulating WBC count. Neutrophilia (choice C) is defined as an absolute increase in the circulating neutrophil count. Pancytopenia (choice D) refers to decreased circulating levels of all formed elements in the blood. Diagnosis: Prostate cancer

Answer 57

E: Vasodilation. Vasodilation of precapillary arterioles increases blood flow at the site of tissue injury. This condition (active hyperemia) is caused by the release of specific mediators. Vasodilation and hyperemia are primarily responsible for the redness and warmth (rubor and calor) at sites of injury. The other choices do not regulate active hyperemia. Diagnosis: Acute inflammation

Answer 58

E. Thromboxane A2. Platelet adherence, aggregation, and degranulation occur when platelets come in contact with fi brillar collagen or thrombin (after activation of the coagulation system). Platelet degranulation is associated with the release of serotonin, which directly increases vascular permeability. In addition, the arachidonic acid metabolite thromboxane A2 plays a key role in the second wave of platelet aggregation and mediates smooth muscle constriction. Prostaglandins E2 and I2 (choices C and D) inhibit inflammatory cell functions. Leukotrienes C4 and D4 (choices A and B) induce smooth muscle contraction. Diagnosis: Acute inflammation

Answer 59

B: Prostaglandin (PGI2). PGI2 is a derivative of arachidonic acid that is formed in the cyclooxygenase enzyme pathway. It promotes vasodilation and bronchodilation and also inhibits platelet aggregation. It activates adenylyl cyclase and increases intracellular levels of cAMP. Its action is diametrically opposite to that of thromboxane A2 (choice E), which activates guanylyl cyclase and increases intracellular levels of cGMP. Plasmin (choice A) degrades fibrin. Serotonin (choice C) is a vasoactive amine. Thrombin (choice D) is a protease that mediates the conversion of fibrinogen to fibrin. Diagnosis: Acute inflammation

Answer 60

C: Macrophages. Granulomas are collections of epithelioid cells and multinucleated giant cells that are formed by cytoplasmic fusion of macrophages. When the nuclei are arranged around the periphery of the cell in a horseshoe pattern (see photomicrograph), the cell is termed a Langhans giant cell. Frequently, a foreign pathogenic agent is identified within

Answer 61

the cytoplasm of a multinucleated giant cell, in which case the label foreign body giant cell is used. The other cells do not form multinucleated giant cells in granulomas. Diagnosis: AIDS, granulomatous inflammation

Answer 62

C: Complement proteins. Activation of the complement cascade by the classical or alternative pathway leads to the cleavage of complement fragments and the formation of biologically active complexes. The C5b fragment aggregates with complement proteins C6, C7, C8, and C9, resulting in the polymerization of the membrane attack complex (MAC). MAC lyses cells by inserting into the lipid bilayer, forming a pore, and destroying the permeability barrier of the plasma membrane. Kallikrein and kinins (choice D) are formed following tissue trauma and mediate pain transmission. None of the other choices mediate hemolysis. Diagnosis: Hemolytic anemia, autoimmune disease

Answer 63

A: Arachidonic acid. Cellular sources of vasoactive mediators are (1) derived from the metabolism of arachidonic acid (prostaglandins, thromboxanes, leukotrienes, and platelet activating factor), (2) preformed and stored in cytoplasmic granules (histamine, serotonin, and lysosomal hydrolases), or (3) generated as normal regulators of vascular function (nitric oxide and neurokinins). The photomicrograph shows polymorphonuclear leukocytes responding to bacterial pneumonia. Free arachidonic acid in these acute inflammatory cells is derived from membrane phospholipids (primarily phosphatidylcholine) by stimulus induced activation of phospholipase A2. Phospholipase A2 activation does not generate the other inflammatory mediators listed. Diagnosis: Bacterial pneumonia

Answer 64

E: Transudate. According to the Starling principle, the interchange of fluid between vascular and extravascular compartments results from a balance of forces that draw fluid into the vascular space or out into tissues. These forces include (1) hydrostatic pressure, (2) oncotic pressure (reflects plasma protein concentration), (3) osmotic pressure, and (4) lymph flow. When the balance of these forces is altered, the net result is fluid accumulation in the interstitial spaces (i.e., edema). Although edema accompanies acute inflammation, a variety of noninflammatory conditions also lead to the formation of edema. For example, obstruction of venous outflow or decreased right ventricular function results in a back pressure in the vasculature, thereby increasing hydrostatic pressure. Loss of albumin (kidney disorders, this case) or decreased synthesis of plasma proteins (liver disease, malnutrition) reduces plasma oncotic pressure. NonInflammatory edema is referred to as a transudate. A transudate is edema fluid with a low protein content. An exudate (choice B) is edema fluid with a high protein and lipid concentration that frequently contains inflammatory cells. An effusion (choice A) represents excess fluid in a body cavity such as the peritoneum or pleura. Lymphedema (choice D) is usually associated with obstruction of lymphatic flow (e.g., surgery or infection). Diagnosis: Nephrotic syndrome, noninflammatory edema

Answer 65

D: Integrins. Chemokines and other proinflammatory molecules activate a family of cell adhesion molecules, namely the integrins. Molecules in this family participate in cell-cell and cell-substrate adhesions and cell signaling. Integrins are involved in leukocyte recruitment to sites of injury in acute inflammation. The other choices are extracellular matrix molecules that maintain tissue architecture and facilitate wound healing. Diagnosis: Gonococcal arthritis

Answer 66

A: Cyclooxygenase. Arachidonic acid is metabolized by cyclooxygenases (COX-1, COX-2) and lipoxygenases (5-LOX) to generate prostanoids and leukotrienes, respectively. The early inflammatory prostanoid response is COX 1 dependent. COX-2 becomes the major source of prostanoids as inflammation progresses. Inhibition of COX is one mechanism by which nonsteroidal anti-infl ammatory drugs (NSAIDs), including aspirin, indomethacin, and ibuprofen, exert their potent analgesic and anti-infl ammatory effects. NSAIDs block COX 2–induced formation of prostaglandins, thereby mitigating pain and inflammation. Myeloperoxidase (choice B) catalyzes the conversion of H2O2, in the presence of a halide (e.g., chloride ion) to form hypochlorous acid. This powerful oxidant is a major bactericidal agent produced by phagocytic cells. Superoxide dismutase (choice E) reduces the superoxide radical to H2O2. Diagnosis: Gonococcal arthritis

Answer 67

E: Neutropenia. The importance of protection afforded by acute inflammatory cells is emphasized by the frequency and severity of infections in persons with defective phagocytic cells. The most common defect is iatrogenic neutropenia secondary to cancer chemotherapy. Chemotherapy would not be expected to deplete serum levels of complement (choice A) or alter the respiratory burst within activated neutrophils (choice B). Diagnosis: Bacterial pneumonia

Answer 68

E: Granulomatous inflammation. The photograph shows a necrotizing granuloma due to M. tuberculosis. The necrotic center is surrounded

Answer 69

by histiocytes, giant cells, and fibrous tissue. Granulomatous inflammation is elicited by fungal infections, tuberculosis, leprosy, schistosomiasis, and the presence of foreign material. It is characteristically associated with caseous necrosis produced by M. tuberculosis. The other choices may be seen as secondary features in granulomatous inflammation. Diagnosis: Pulmonary tuberculosis

Answer 70

B: Endothelial cells. The vascular endothelium has the ability to promote or inhibit tissue perfusion and inflammatory cell influx through multiple mechanisms. For example, endothelial cells in the vicinity of the thrombus produce tissue-type plasminogen activators, which activate plasmin and initiate thrombolysis (fibrinolysis). None of the other cells produce significant quantities of plasminogen activators. Diagnosis: Myocardial infarction, hemostasis

Answer 71

D: Nitric oxide. Nitric oxide (NO), which was previously known as an endothelium-derived relaxing factor, leads to relaxation of vascular smooth muscle cells and vasodilation of arterioles. NO also inhibits platelet aggregation and mediates the killing of bacteria and tumor cells by macrophages. Histamine (choice B), leukotrienes (choice C), and thromboxane A2 (choice E) stimulate the contraction of smooth muscle cells. Diagnosis: Acute myocardial infarction

Answer 72

D: Macrophages. Coal workers’ pneumoconiosis reflects the inhalation of carbon particles. The characteristic pulmonary lesions of simple coal worker’s pneumoconiosis include nonpalpable coal-dust macules and palpable coal dust nodules, both of which are typically multiple and scattered throughout the lung as 1- to 4-mm black foci. Nodules consist of dust laden macrophages associated with a fibrotic stroma. Nodules occur when coal is admixed with fi brogenic dusts such as silica and are more properly classified as anthracosilicosis. Coal-dust macules and nodules appear on a chest radiograph as small nodular densities. The other choices are not phagocytic cells. Diagnosis: Anthracosilicosis, coal workers’ pneumoconiosis

Answer 73

A: Leukemoid reaction. Circulating levels of leukocytes and their precursors may occasionally reach very high levels (>50,000 WBC/µL). Such a situation, referred to as a leukemoid reaction, is sometimes difficult to differentiate from leukemia. In contrast to bacterial infections, viral infections (including infectious mononucleosis) are characterized by lymphocytosis, an absolute increase in the number of circulating lymphocytes. Parasitic infestations and certain allergic reactions cause eosinophilia, an increase in the number of circulating eosinophils. Leukopenia is defined as an absolute decrease in the circulating WBC count. Myeloid metaplasia (choice C) and myeloproliferative disease (choice D) are chronic disorders of the hematopoietic system. Although technically correct, neutrophilia (choice E) by itself does not demonstrate immature cells (band forms) and usually refers to lower levels of increased neutrophils. Diagnosis: Pulmonary abscess

Answer 74

C: Lymphocytosis. Peripheral blood lymphocytosis is defined as an increase in the absolute peripheral blood lymphocyte count above the normal range (<4,000/µL in children and 9,000/µL in infants). The principal causes of absolute peripheral blood lymphocytes are (1) acute viral infections (infectious mononucleosis, whooping cough, and acute infection lymphocytosis), (2) chronic bacterial infections (tuberculosis, brucellosis), and (3) lymphoproliferative diseases. The other choices are not features of acute viral infections. Diagnosis: Infectious mononucleosis

Answer 75

C: T lymphocytes. Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease characterized by destruction of intrahepatic bile ducts (nonsuppurative destructive cholangitis). PBC occurs principally in middle aged women and is an autoimmune disease. Most patients with PBC have at least one other disease usually classed as autoimmune (e.g., thyroiditis, rheumatoid arthritis, scleroderma, Sjögren syndrome, or systemic lupus erythematosus). More than 95% of patients with PBC have circulating antimitochondrial antibodies. The cells surrounding and infiltrating the sites of bile duct damage are predominantly suppressor/cytotoxic (CD8+) T lymphocytes, suggesting that they mediate the destruction of the ductal epithelium. Macrophages and B lymphocytes (choice B) are associated with periductal inflammation but do not mediate epithelial cytotoxicity. Eosinophils (choice A) have no role in primary immune-related mechanisms. The other inflammatory cells (choices D and E) do not participate in the pathogenesis of PBC. Diagnosis: Primary biliary cirrhosis, chronic inflammation

Answer 76

C: Phospholipase A2. Corticosteroids are widely used to suppress the tissue destruction associated with many chronic inflammatory diseases, including rheumatoid arthritis and systemic lupus erythematosus. Corticosteroids induce the synthesis of an inhibitor of phospholipase A2 and block the release of arachidonic acid from the plasma membranes of inflammatory cells. Although corticosteroids are widely used to suppress inflammatory responses, the prolonged administration of these compounds can have deleterious effects, including atrophy of the adrenal glands. Myeloperoxidase (choice B) catalyzes the conversion of H2O2, in the presence of a

Answer 77

A: Acute phase proteins. These proteins are synthesized primarily by the liver and are released into the circulation in response to an acute inflammatory challenge. Changes in the plasma levels of acute phase proteins are mediated primarily by cytokines (IL-1, IL-6, and TNF-α). Increased plasma levels of some acute phase proteins are reflected in an accelerated erythrocyte sedimentation rate, which is an index used clinically to monitor the activity of many inflammatory diseases. None of the other choices describe the set of serum markers listed in this question. Diagnosis: Systemic lupus erythematosus

Answer 78

B: Collagen-rich scar tissue. Pathologic findings in congestive heart failure include microscopic signs of coagulative necrosis approximately 24 hours after the onset of vascular occlusion. Polymorphonuclear leukocytes and macrophages predominate during the next 2 to 5 days (choice D). Toward the end of the first week, the infarct is invaded by capillary rich granulation tissue (choice A). Ultimately, the necrotic myocardium is replaced by collagen rich scar tissue (weeks to months). Granulomatous inflammation (choice C) does not occur after an ischemic myocardial infarct. Vascular congestion and edema (choice E) are features of acute inflammation. Diagnosis: Myocardial infarction

Answer 79

D: Formation of a fibrin clot. The initial phase of the repair reaction, which typically begins with hemorrhage, involves the formation of a fibrin clot that fills the gap created by the wound. A thrombus (clot), referred to as a scab after drying out, forms on the wounded skin as a barrier to invading microorganisms. It also prevents the loss of plasma and tissue fluid. Formed primarily from plasma fibrin, the thrombus is rich in fibronectin. The thrombus also contains contracting platelets, which are an initial source of growth factors. Much later, the thrombus undergoes proteolysis, after which it is penetrated by regenerating epithelium. The scab then detaches. Accumulation of acute inflammatory cells (choice A) might occur after formation of the initial fibrin clot. Collagen formation (choice B) and macrophage activity (choice E) occur much later. Myofi broblasts (choice C) begin to accumulate in the wound around the 3rd day. Diagnosis: Wound healing

Answer 80

A: Type I collagen. A mature scar is composed primarily of type I collagen. By contrast, the early matrix of granulation tissue contains proteoglycans, glycoproteins, and type III collagen. Eventually, the temporary matrix is

Answer 81

removed by a combination of extracellular and intracellular digestion, and the definitive matrix is deposited. Extracellular cross linking of the newly synthesized type I collagen progressively increases wound strength. Collagen type II (choice B) is found in cartilage. Collagen type IV (choice C) is found in basement membranes. Collagen types V and VI (choices D and E) are found in various organs. Diagnosis: Myocardial infarction

Answer 82

D: Myofibroblasts. The myofibroblast is the cell responsible for wound contraction as well as the deform ing pathologic process termed wound contracture. These cells express α smooth muscle actin, desmin, and vimentin, and they respond to pharmacologic agents that cause smooth muscle to contract or relax. Myofi broblasts exert their contractile effects by forming syncytia, in which the myofibroblasts are bound together by tight junctions. By contrast, fibroblasts (choice B) tend to be solitary cells, surrounded by collagen fibers. Endothelial cells (choice A) respond to growth factors and form capillaries, which are necessary for the delivery of nutrients and inflammatory cells. Neither macrophages (choice C) nor smooth muscle cells (choice E) mediate wound contraction. Diagnosis: Wound contraction

Answer 83

D: Vitamin C. Vitamin C (ascorbic acid) is a powerful, biologic reducing agent that is necessary for the hydroxylation of proline residues in collagen. Most of the clinical features associated with vitamin C deficiency (scurvy) are caused by the formation of an abnormal collagen that lacks tensile strength. Patients with vitamin C deficiency exhibit poor wound healing. Dehiscence (bursting open) of previously healed wounds may also occur. None of the other choices are required for

Answer 84

A: Fibroblasts and endothelial cells. Granulation tissue has two major components: cells and proliferating capillaries. The cells are mostly fibroblasts, myofibroblasts, and macrophages. Fibroblasts and myofibroblasts derive from mesenchymal stem cells. Capillaries arise from adjacent blood vessels by division of endothelial cells in a process termed angiogenesis. Macrophages are a principal source of growth factors and are recognized for their phagocytic functions. Granulation tissue is fluid laden, and its cellular constitu ents supply antibacterial antibodies and growth factors. Once repair has been achieved, most of the newly formed capillaries are obliterated and then reabsorbed, leaving a pale avascular scar. Although the other inflammatory cells listed may be found in this healing wound, they do not constitute the principal components of granulation tissue. Diagnosis: Diabetic ulcer, granulation tissue

Answer 85

E: Metalloproteinase. Matrix metalloproteinases (MMPs) are crucial components in wound healing because they enable cells to migrate by degrading matrix proteins. Members of this protein family include collagenase, stromelysin, and gelatinase. In addition to enhancing cell migration, MMPs can disrupt cell-cell adhesions and release bioactive molecules stored in the matrix. MMP activity can be minimized by binding to specific proteinase inhibitors such as α1-antitrypsin (choice A) and α2-macroglobulin (choice D). Lysozyme (choice C) is a secretory product of neutrophils that degrades bacterial cell walls. Diagnosis: Diabetes mellitus

Answer 86

E: Scar formation. A large infarct of the kidney will heal by fibrosis (scar formation). In most renal diseases, there is destruction of the extracellular matrix framework. Repair and regeneration

Answer 87

(choice D) is then incomplete, and scar formation is the expected outcome. The regenerative capacity of renal tissue is maximal in cortical tubules, less in medullary tubules, and nonexistent in glomeruli. Recent data suggest that renal tubule repair occurs due to the proliferation of endogenous renal progenitor (stem) cells. Chronic inflammation (choice A) precedes scar formation. Granulomatous inflammation (choice B) is not a complication of renal corti cal infarction. Hemangiomas (choice C) are common benign tumors of endothelial cells that usually occur in the skin. Diagnosis: Infarction; embolism, atheroembolism

Answer 88

E: Maturation arrest of collagen assembly. Kel oid is an exuberant scar that tends to progress beyond the site of initial injury and recurs after excision. Dark-skinned persons are more frequently affected by keloids than light skinned people. Keloids are characterized by changes in the ratio of type III to type I collagen, suggesting a “maturation arrest” in the healing process. Further support for maturation arrest as an explanation for keloids and hypertrophic scars is the overexpression of fibronectin in these lesions. Keloids are unsightly, and attempts at surgical repair are always problematic. The other choices do not address the pathogenesis of keloids. Diagnosis: Keloid

Answer 89

B: Foreign material. Granulomatous inflammation is a subtype of chronic inflammation, which develops when acute inflammatory cells are unable to digest the injurious agent (e.g., suture or talc). Fusion of macrophages within the lesion results in the formation of multinucleated giant cells. None of the other choices elicit this type of granuloma tous reaction. Diagnosis: Granulomatous inflammation

Answer 90

B: Chronic viral hepatitis. Chronic liver injury (e.g., chronic viral hepatitis) is associated with the development of broad collagenous scars within the hepatic parenchyma. This is termed cirrhosis. Hepatocytes form regenerative nodules that lack central veins and expand to obstruct blood vessels and bile flow. Portal hypertension and jaundice ensue, despite ade quate numbers of regenerated but disconnected hepatocytes. Acute toxic liver injury (choice A) is generally reversible. Fulminant hepatic necrosis (choice C), if the patient survives, usually regenerates. Hepatocellular carcinoma (choice D) may be associated with tumor fibrosis but not with regeneration. Portal vein thrombosis (choice E) does not cause hepatic fibrosis but may be a complication of embolism. Diagnosis: Alcoholic liver disease, cirrhosis

Answer 91

D: Regeneration. Superficial abrasions of the skin heal by a process of regeneration. It is mediated by stem cells or stabile cells that are able to progress through the cell cycle and fully restore normal tissue organization and func tion. Cellular migration is the predominant means by which the wound surface is reepithelialized. Fibrosis (choice A) refers to aberrant healing with deposition of collagen rich scar tissue. Granulation tissue (choice B) forms during the repair of deep wounds. Primary and secondary intentions (choices C and E) are features of healing in deeper wounds. Diagnosis: Superficial abrasion

Answer 92

B: Contact inhibition of epithelial growth and motility. Maturation of the epidermis requires an intact layer of basal cells that are in direct contact with one another. If this contact is disrupted, basal epithelial cells at the wound margin become activated and eventually reestablish contact with other basal cells through extensive cell migration and mitosis. When epithelial continuity is reestablished, migration and cell division cease, and the epidermis resumes its normal cycle of maturation and shedding. This process of epithelial growth regulation is referred to as “contact inhibition of growth and motility.” The other choices describe responses to deep wound healing. Diagnosis: Superficial abrasion, regeneration

Answer 93

B: Fibronectins. Fibronectins are adhesive glycoproteins that are widely distributed in stromal connective tissue and deposited at the site of tissue injury. During the initial phase of healing, fibronectin in the extravasated plasma is cross-linked to fibrin, collagen, and other extracellular matrix components by the action of transglutaminases. This cross-linking provides a provisional stabilization of the wound during the first several hours. Fibronectin, cell debris, and bacterial products are chemoattractants for a variety of cells that are recruited to the wound site over the next several days. Selectins (choice E) are sugar-binding glycoproteins that mediate the initial adhesion of leukocytes to endothelial cells at sites of inflammation. They are found at the cell sur face and are not part of the extracellular matrix. Cadherins (choice A) and integrins (choice C) are cell adhesion molecules. Like the selectin family of cell adhesion proteins, they are found at the cell surface and are not part of the extracellular matrix. Diagnosis: Wound healing

Answer 94

C: Integrins. The locomotion of leukocytes is powered by membrane extensions called lamellipodia. Slower moving cells, such as fibroblasts, extend finger-like membrane protrusions called filopodia. The leading edge of the cell mem brane adheres to the extracellular matrix

Answer 95

through transmembrane adhesion receptors termed integrins. These cell surface glycoproteins transmit mechanical and chemical signals, thereby regulating cellular survival, proliferation, differentiation, and migration. The motility of epithelial cells is also regulated by integrin receptors. Cadherins (choice A) are cell-cell adhesion molecules. Fibrillins (choice B) are structural molecules that interact with elastic fibrils. Laminins (choice D) are basement membrane glycoproteins. Selectins (choice E) mediate the recruitment of neutrophils in acute inflammation but do not mediate directed cell migration at the site of tissue injury. Diagnosis: Wound healing

Answer 96

A: Apposition of edges. Healing by primary intention occurs in wounds with closely apposed edges and minimal tissue loss. Such a wound requires only minimal cell proliferation and neovascularization to heal, and the result is a small scar. Healing by secondary intention occurs in a gouge wound, in which the edges are far apart and in which there is substantial tissue loss. This wound requires wound contraction, extensive cell proliferation, and neovascularization (granulation tissue) to heal. Granulation tissue is eventually resorbed and replaced by a large scar that is functionally and esthetically unsatisfactory. The other choices are important determinants of the outcome of wound healing, but they do not provide a point of distinction between primary and sec ondary intentions healing. Diagnosis: Healing by primary intention

Answer 97

C: 3 to 5 days. Activated fibroblasts, myofi bro blasts, and capillary sprouts are abundant in healing wounds 3 to 5 days following injury. Activated fibroblasts change shape from oval to bipolar as they begin to form collagen and synthesize a variety of extracellular matrix proteins. Neutrophils accumulate in the wound 12 to 24 hours after injury (choice B). Mature scar tissue would be visible 2 weeks following injury (choice E). Diagnosis: Healing by primary intention

Answer 98

D: Phagocytosis. Macrophages arrive at the site of injury shortly after neutrophils, but they persist in the wound for days longer. Macrophages remove debris and orchestrate the formation of granulation tissue by releasing cytokines and chemoattractants. None of the other choices are functions of tissue macrophages. For example, plasma cells produce antibodies (choice A), and myofibroblasts mediate wound contraction (choice E). Diagnosis: Laceration

Answer 99

C: Type III. Concurrent with fibrinolysis, a temporary matrix composed of proteoglycans, glycoproteins, and type III collagen is deposited. The secretion of type III collagen is a forerunner to the formation of type I collagen (choice A), which will impart greater tensile strength to the wound. TGF-β enhances the synthesis of collagen and fibronectin and decreases metalloproteinase transcription and matrix degradation. Extracellular cross-linking of newly synthesized collagen further increases the mechanical strength of the wound. Type II collagen (choice B) is found in cartilage. Type IV collagen (choice D) is found in basement membranes. Diagnosis: Laceration

Answer 100

B: Glial cells. Damage to the brain or spinal cord is followed by growth of capillaries and gliosis (i.e., the proliferation of astrocytes and microglia). Gliosis in the central nervous system is the equivalent of scar formation elsewhere; once established, it remains permanently. In spinal cord injuries, axonal regeneration can be seen up to 2 weeks after injury. After 2 weeks, gliosis has taken place and attempts at axonal regeneration end. In the central nervous system, axonal regeneration occurs only in the hypothalamohypophysial region, where glial and capillary barriers do not interfere with axonal regeneration. Axonal regeneration seems to require contact with extracellular fluid containing plasma proteins. The other cells listed do not proliferate significantly in response to brain or spinal cord injury. Diagnosis: Cerebral contusion, gliosis

Answer 101

A: Contracture. A mechanical reduction in the size of a wound depends on the presence of myofibroblasts and sustained cell contraction. An exaggeration of these processes is termed contracture and results in severe deformity of the wound and surrounding tissues. Contractures are particularly conspicuous in the healing of serious burns and can be severe enough to compromise the movement of joints. Diagnosis: Contracture

Answer 102

E: Neuroma. Neurons in the peripheral nervous system can regenerate their axons, and under ideal circumstances, interruption in the continuity of a peripheral nerve results in complete functional recovery. However, if the cut ends are not in perfect alignment or are prevented from establishing continuity by inflammation, a traumatic neu roma results. This bullous lesion consists of disorganized axons and proliferating Schwann cells and fibroblasts. In this patient’s biopsy, the original nerve (lower left) enters the neu roma. The nerve is surrounded by dense collagenous tissue, which appears dark blue in this trichrome stain. Ganglioma (choice A), ganglioneuroma (choice B), and hamartoma (choice C) are benign neoplasms. Diagnosis: Traumatic neuroma

Answer 103

B: Postcapillary venules. One of the earliest responses following tissue injury occurs within the microvasculature at the level of the capillary and postcapillary venule. Within this vascular network are the major components of the inflammatory response, including plasma, platelets, erythrocytes, and circulating leukocytes. Following injury, changes in the structure of the vascular wall lead to activation of endothelial cells, loss of vascular integrity, leakage of fluid and plasma components from the intravascular compartment, and emigration of erythrocytes and leukocytes from the vascular space into the extravascular

Answer 104

E: Ulcer. Incidental findings are frequently encountered at autopsy. In this case, a peptic ulcer is identified in the distal stomach. Histologic examination shows focal destruction of the mucosa and full-thickness replacement of the muscularis with collagen-rich connective tissue (see photomicrograph). Gastric ulcers are usually single and less than 2 cm in diameter. Ulcers on the lesser curvature are commonly associated with chronic gastritis (this patient), whereas those on the greater curvature are often related to NSAIDs. Grossly, chronic peptic ulcers may closely resemble gastric carcinoma (choice A). Thus, the endoscopist must take multiple biopsies from the edges and bed of any gastric ulcer. Although contraction and scarring of gastric ulcers (choice B) may occur and may cause pyloric stenosis, the histopathologic findings do not suggest this complication. Diverticula of the stomach (choice C) are rare and, if present, are usually lined by a normal gastric mucosa. Granuloma (choice D) features inflammatory cells that are not observed. Diagnosis: Gastric ulcer, peptic ulcer disease

Answer 105

The answer is D: Hypersensitivity. Although the incorrect choices may cause eye irritation, seasonal conjunctivitis is typi- cally caused by allergies to pollens that are released during a particular time of the year. Allergic rhinitis (hay fever) is the most common type I hypersensitivity disease in adults. It may be caused by pollen, house dust, animal dandruff, and many other allergens. Antigens inhaled react with the IgE attached to basophils in the nasal mucosa, thereby triggering the release of vasoactive substances stored in cytoplasmic granules. Hista mine, the main mediator released from mast cells, increases the permeability of mucosal vessels, causing edema and sneezing. Diagnosis: Conjunctivitis, hypersensitivity reaction

Answer 106

The answer is B: Deposition of circulating immune complexes. Type III hypersensitivity reactions are characterized by immune complex deposition, complement fixation, and localized inflammation. Antibody directed against either a circulating antigen or an antigen that is deposited in a tissue can give rise to a type III response. Diseases that seem to be most clearly attributable to the deposition of immune complexes are systemic lupus erythematosus, rheumatoid arthritis, and varieties of glomerulonephritis. Streptococcal infection in this case led to the deposition of antigens and antibodies in glomerular basement membranes, resulting in clinical features of nephritic syndrome (e.g., hematuria, oliguria, and hypertension). Post- streptococcal illnesses do not include any of the other choices. Diagnosis: Postinfectious glomerulonephritis

Answer 107

The answer is B: Double-stranded DNA. Systemic lupus erythematosus (SLE) is an autoimmune, inflammatory disease that may involve almost any organ but characteristically affects the kidneys, joints, serous membranes, and skin. Auto antibodies are formed against a variety of self-antigens. The most important diagnostic autoantibodies are those against nuclear antigens—in particular, antibodies to double-stranded DNA and to a soluble nuclear antigen complex that is part of the spliceosome and is termed Sm (Smith) antigen. High titers of these two autoantibodies (termed antinuclear antibodies) are nearly pathognomonic for SLE. Antibodies to rheumatoid factor (choice D) are seen in patients with rheumatoid arthritis. Antineutrophil cytoplasmic antibodies (choices A and C) are seen in patients with small-vessel vasculitis (e.g., Wegener granulomatosis). Diagnosis: Systemic lupus erythematosus

Answer 108

The answer is A: Binding of complement to immune complexes. Acquired deficiencies of early complement components occur in patients with autoimmune diseases, especially those associ- ated with circulating immune complexes (e.g., systemic lupus erythematosus [SLE]). Antigen-antibody complexes formed in the circulation during the active stage of these diseases lead to a marked reduction in circulating levels of complement proteins (hypocomplementemia). None of the other choices mediates hypocomplementemia in patients with SLE. Diagnosis: Systemic lupus erythematosus

Answer 109

The answer is D: Scl-70 (anti-topoisomerase I). Scleroderma is an autoimmune disease of connective tissue. Circulating male fetal cells have been demonstrated in blood and blood vessel walls of many women with scleroderma who bore male children many years before the disease began. Accordingly, it has been suggested that scleroderma in these patients is similar to graft-versus-host disease. Antinuclear antibodies are common but are usually present in a lower titer than in patients with SLE. Antibodies virtually specific for scleroderma include (1) nucleolar autoantibodies (primarily against RNA polymerase); (2) antibodies to Scl-70, a nonhistone nuclear protein topoisomerase; and (3) anticentromere antibodies, which are associated with the “CREST” variant of the disease. The Scl-70 autoantibody is most common and specific for the diffuse form of scleroderma and is seen in 70% of patients. Autoantibodies to double-stranded DNA (choice B) are seen in patients with SLE. Autoantibodies to SS-A/SS-B (choice E) are seen in patients with Sjögren syndrome. Diagnosis: Scleroderma

Answer 110

The answer is A: Collagen. Scleroderma is characterized by vasculopathy and excessive collagen deposition in the skin and internal organs, such as the lung, gastrointestinal tract, heart, and kidney. The disease occurs four times as often in women as in men and mostly in persons aged 25 to 50 years. Progressive systemic sclerosis is characterized by widespread excessive collagen deposition. There is emerging evidence for the expansion of fibrogenic clones of fibroblasts. These clones display augmented procollagen synthesis, including increased circulating levels of type III collagen amino propeptide. Tissue levels of the other proteins are not significantly altered in patients with scleroderma. Diagnosis: Scleroderma

Answer 111

``` The answer is D: Class II HLA molecules Delayed-type hyper- sensitivity is defined as a tissue reaction involving lymphocytes and mononuclear phagocytes, which occurs in response to a soluble protein antigen and reaches greatest intensity 24 to 48 hours after initiation. In the initial phase, foreign protein anti- gens or chemical ligands interact with accessory cells bearing class II HLA molecules. Protein antigens are actively processed into short peptides within phagolysosomes and are presented on the cell surface in conjunction with the class II HLA mol- ecules. The latter are recognized by CD4+ T cells (choice A), which become activated to synthesize an array of cytokines. The cytokines recruit and activate lymphocytes, monocytes, fibroblasts, and other inflammatory cells. Suppressor T cells are CD8+ (choice B). Class I HLA molecules (choice C) provide targets for cell-mediated cytotoxicity. GlyCAM-1 (choice E) isa cell adhesion molecule involved in lymphocyte trafficking. Diagnosis: Delayed-type hypersensitivity ```

Answer 112

The answer is B: Antibody-mediated complement fixation. Type II hypersensitivity reactions are mediated by antibodies directed against fixed antigens. In this case, preformed antibod- ies in the patient’s blood attached to foreign antigens (oligosac- charides) on the membranes of the transfused erythrocytes. At sufficient density, bound immunoglobulins fix complement. Once activated, the complement cascade leads to the destruc- tion of the target cell through formation of a membrane attack complex. This type of complement-mediated cell lysis occurs in autoimmune hemolytic anemia. Antibody dependent cell- mediated cytotoxicity (ADCC, choice A) involves cytolytic leukocytes that attack antibody-coated target cells. ADCC may be involved in the pathogenesis of some autoimmune diseases (e.g., autoimmune thyroiditis). Delayed-type hypersensitivity (choice C) occurs over a period of days and does not involve preformed antibodies.

Answer 113

The answer is E: Membrane immunoglobulin (mIg). The clinicopathologic findings presented here indicate that this patient is a chronic HBV carrier with active hepatitis. Humoral immune responses to specific viral antigens in this patient involve the activation and differentiation of B lymphocytes into antibody-secreting plasma cells. Analogous to T cells, B cells express an antigen-binding receptor, namely mIg. This immunoglobulin bears the same antigen specificity as the soluble immunoglobulin that is ultimately secreted. Class I HLA molecules (choice C) provide targets for CD8+ T cells in cell-mediated cytotoxicity. Class II HLA molecules (choice D) are recognized by CD4+ T cells, which become activated to synthesize an array of cytokines. Diagnosis: Humoral immunity, chronic hepatitis

Answer 114

The answer is C: Class I HLA molecules. Class I molecules of the major histocompatibility complex present foreign peptides and are recognized by cytotoxic T lymphocytes during graft rejection or during cell-mediated killing of virus infected cells. All tissues express class I molecules, whereas class II molecules (choice D) are displayed primarily on macrophages and B lymphocytes. CD4 and CD8 (choices A and B) are cell surface markers of helper and killer T lymphocytes, respectively. GlyCAM 1 (choice E) facilitates lymphocyte recirculation by providing a receptor for leukocyte attachment to high endothelial venules. Diagnosis: Chronic hepatitis B

Answer 115

The answer is C: Nucleus. Sjögren syndrome (SS) is an autoimmune disorder characterized by keratoconjunctivitis sicca and xerostomia in the absence of other connective tissue disease. The production of autoantibodies, particularly antinuclear antibodies directed against DNA or nonhistone proteins, typically occurs in patients with SS. Autoantibodies to soluble nuclear nonhistone proteins, especially the antigens SS-A and SS-B, are found in half of patients with primary SS and are associated with more severe glandular and extraglandular manifestations. Autoantibodies to DNA or histones are rare. Organ-specific autoantibodies, such as those directed against salivary gland antigens, are distinctly uncommon. Autoantibodies to centromere proteins (choice A) are seen in the CREST variant of progressive systemic sclerosis. Diagnosis: Sjögren syndrome

Answer 116

The answer is E: X-linked agammaglobulinemia of Bruton. The congenital disorder Bruton X-linked agammaglobulinemia appears in male infants at 5 to 8 months of age, the period during which maternal antibody levels begin to decline. The infant suffers from recurrent pyogenic infections and severe hypogammaglobulinemia. There is an absence of both mature B cells in peripheral blood and plasma cells in lymphoid tissues. The genetic defect, located on the long arm of the X chromosome, is an inactivating mutation of the gene for B-cell tyrosine kinase, an enzyme critical to B-lymphocyte maturation. Wiskott-Aldrich syndrome (choice D) is also an X-linked genetic disease but is characterized by defects in both B-cell and T-cell functions (i.e., humeral and cellular immunity). DiGeorge syndrome (choice A) is a developmental disorder characterized by thymic and parathyroid aplasia. Diagnosis: X-linked agammaglobulinemia of Bruton

Answer 117

The answer is E: Preformed antibodies. Hyperacute rejection occurs within minutes to hours after transplantation. It is manifested clinically as a sudden cessation of urine output, along with fever and pain in the area of the graft site. This immediate rejection is mediated by preformed antibodies and complement activation products. Lymphocytes and macrophages (choices A, B, and C) are associated with acute and chronic graft rejection. Diagnosis: Hyperacute graft rejection

Answer 118

The answer is A: Acetylcholine receptor. Myasthenia gravis is a type II hypersensitivity disorder caused by antibodies that bind to the acetylcholine receptor. These antibodies interfere with the transmission of neural impulses at the neuromuscular junction, causing muscle weakness and easy fatigability. External ocular and eyelid muscles are most often affected, but the disease is often progressive and may cause death by respiratory muscle paralysis. Autoantibodies to desmoglein-3 (choice C) are found in patients with pemphigus vulgaris, an autoimmune blistering skin disorder. Antibodies to the TSH receptor (choice E) are seen in patients with Graves hyperthyroidism. Antibodies to calcium channels (choice B) are found in patients with Eaton-Lambert syndrome. This paraneoplastic syndrome also manifests as muscle weakness but is usually associated with small cell carcinoma of the lung. Rheumatoid factor (choice D) represents multiple antibodies directed against the Fc portion of

Answer 119

The answer is B: Helper T lymphocytes. The relentless progression of HIV infection is now recognized as a continuum that extends from an initial asymptomatic state to the immune depletion that characterizes patients with overt AIDS. The fundamental lesion is infection of CD4+ (helper) T lymphocytes, which leads to the depletion of this cell population and impaired immune function. As a result, patients with AIDS usually die of opportunistic infections. HIV does infect the monocyte/macrophage lineage (choice D), but infected cells exhibit little if any cytotoxicity. NK cell activity (choice E) is also decreased in AIDS. This defect may contribute to the appearance of malignant tumors and the viral infections that plague these patients. The suppression of NK cell activity has been related to a decrease in the number of NK cells and to a reduction in IL-2 levels due to the loss of CD4+ cells. Diagnosis: AIDS

Answer 120

The answer is D: Reverse transcriptase. The primary etiologic agent of AIDS is HIV-1, an enveloped RNA retrovirus that contains a reverse transcriptase (RNA-dependent DNA polymerase). After it enters into the cytoplasm of a T lymphocyte, the virus is uncoated, and its RNA is copied into double-stranded DNA by retroviral reverse transcriptase. The DNA derived from the virus is integrated into the host genome by the viral integrase protein (choice C), thereby producing the latent proviral form of HIV-1. Viral genes are replicated along with host chromosomes and, therefore, persist for the life of the cell. Diagnosis: AIDS

Answer 121

The answer is C: IgE. Immediate-type hypersensitivity is manifested by a localized or generalized reaction that occurs within minutes after exposure to an antigen or “allergen” to which the person has previously been sensitized. In its generalized and most severe form, immediate hypersensitivity reactions are associated with bronchoconstriction, airway obstruction, and circulatory collapse, as seen in anaphylactic shock. Type I hypersensitivity reactions feature the formation of IgE antibodies that bind avidly to Fc-epsilon (Fc-ε) receptors on mast cells and basophils. The high-avidity binding of IgE accounts for the term cytophilic antibody. Once exposed to a specific allergen that has resulted in the formation of IgE, a person is

Answer 122

The answer is B: Cytopathic auto antibiotics. Graves disease is a type II hypersensitivity disorder caused by antibodies to the TSH receptor on follicular cells of the thyroid. Antibody binding to the TSH receptor stimulates a release of tetraiodothyronine (T4) and triiodothyronine (T3) from the thyroid into the circulation. Circulating T4 and T3 suppress TSH production in the pituitary. Sweating, weight loss, and tachycardia are evidence of the hypermetabolism typical of hyperthyroidism. Graves disease also causes exophthalmos. Delayed-type hypersensitivity (choice C) is seen in patients with poison ivy and graft rejection. Immune complex disease (choice E) is caused by deposition of immune complexes and complement activation. Diagnosis: Graves disease

Answer 123

The answer is D: Wiskott-Aldrich syndrome. This rare syndrome is characterized by (1) recurrent infections, (2) hemorrhages secondary to thrombocytopenia, and (3) eczema. It typically manifests in boys within the first few months of life as petechiae and recurrent infections (e.g., diarrhea). It is caused by numerous distinct mutations in a gene on the X chromosome that encodes a protein called WASP (Wiskott- Aldrich syndrome protein), which is expressed at high levels in lymphocytes and megakaryocytes. WASP binds members of the Rho family of GTPases. WASP itself controls the assembly of actin filaments that are required to form microvesicles. X-linked agammaglobulinemia of Bruton (choice E) is not associated with thrombocytopenia and eczema. Choices A, B, and C are not X-linked genetic diseases. Diagnosis: Wiskott-Aldrich syndrome

Answer 124

The answer is A: Donor lymphocytes. The advent of transplantation of bone marrow into patients whose immune system has been ablated or into otherwise immunodeficient patients has resulted in the complication of graft-versus-host disease (GVHD). GVHD occurs when lymphocytes in the grafted tissue recognize and react to the recipient. GVHD can also occur when an immunodeficient patient is transfused with blood containing HLA incompatible lymphocytes. The major organs affected in GVHD include the skin, gastrointestinal tract, and liver. Clinically, GVHD manifests as rash, diarrhea, abdominal cramps, anemia, and liver dysfunction. None of the other cells mediates GVHD. Diagnosis: Graft-versus-host disease

Answer 125

The answer is B: Delayed-type hypersensitivity. “Poison ivy” is a type IV hypersensitivity reaction to plants of the Rhus genus. This T-lymphocyte–mediated allergic contact dermatitis presents as urticaria and bullous eruption. Blisters rupture and heal with crusts, usually without scarring. Deposition of antigluten antibodies (choice C) occurs in patients with dermatitis herpetiformis. IgE mediated mast cell degranulation (choice E) is part of the response to poison ivy (hypersensitivity reactions overlap), but this immediate response does not explain the pathogenesis of delayed hypersensitivity in this patient. Diagnosis: Allergic contact dermatitis

Answer 126

The answer is D: Severe combined immunodeficiency (SCID). SCID is a group of disorders of T and B lymphocytes that are characterized by recurrent viral, bacterial, fungal, and protozoal infections. Many infants with SCID have severely reduced volumes of lymphoid tissue and an immature thymus that lacks lymphocytes. In some patients, lymphocytes fail to develop beyond pre-B cells and pre-T cells. About one half of these severely immunodeficient children lack adenosine deaminase (ADA). ADA deficiency causes the accumulation of intermediate products that are toxic to lymphocytes. These children cannot survive beyond early infancy unless they are raised in a sterile environment (“bubble children”). None of the other choices are associated with ADA deficiency. Diagnosis: Severe combined immunodeficiency

Answer 127

The answer is E: Immune complex disease. Immune complex (type III) hypersensitivity reactions cause vasculitis. Antigen- antibody complexes are either formed in the circulation and deposited in the tissues or formed in situ. Immune complexes induce a localized inflammatory response by fixing complement, which leads to the recruitment of neutrophils and monocytes. The vasculitis in patients with polyarteritis nodosa involves small to medium sized muscular arteries. The diagnosis is usually made by biopsy of the skin, muscle, peripheral nerves, or the most affected internal organ (the kidney in this case). The most prominent morphologic feature of the affected artery is an area of fibrinoid necrosis (see photomicrograph). Other examples of type III hypersensitivity reactions include Henoch-Schönlein purpura (vascular IgA deposits) and vasculitis associated with hepatitis C infection. The other choices are uncommon mediators of vasculitis in patients with polyarteritis nodosa. Diagnosis: Polyarteritis nodosa

Answer 128

The answer is C: DiGeorge syndrome. DiGeorge syndrome is a chromosomal defect that results in developmental anomalies of the branchial (pharyngeal) pouches and organs that develop from these embryonic structures (thymus, parathyroids, and aortic arch). These children present with tetany caused by hypoparathyroidism and deficiency of cellular immunity. They also have characteristic facial features (“angry look”). In the absence of a thymus, T cell maturation is interrupted at the pre-T stage. DiGeorge syndrome has been corrected by transplanting thymic tissue. None of the other choices are associated with thymic aplasia. Diagnosis: DiGeorge syndrome

Answer 129

The answer is B: Mixed connective tissue disease (MCTD). MCTD has features of other common autoimmune diseases (e.g., SLE and scleroderma) but appears to be distinct. Patients typically have autoantibodies to ribonucleoproteins, but unlike SLE, they do not have antibodies to Sm antigen or double-stranded DNA. Some patients with MCTD develop symptoms of scleroderma or rheumatoid arthritis, suggesting that MCTD may be an intermediate stage in a genetically determined progression. Whether MCTD represents a distinct entity or simply an overlap of symptoms in patients with other types of collagen vascular diseases remains an open question. Intermittent episodes of ischemia of the fingers, marked by pallor,

Answer 130

The answer is E: Phospholipids. One third of patients with systemic lupus erythematosus (SLE) possess elevated concentrations of antiphospholipid antibodies. This phenomenon predisposes these patients to thromboembolic complications, including stroke, pulmonary embolism, deep venous thrombosis, and portal vein thrombosis. The clinical course of SLE is highly variable and typically exhibits exacerbations and remissions. With the recognition of mild forms of the disease, improved antihypertensive medications, and the use of immunosuppressive agents, the overall 10-year survival rate approaches 90%. Antibodies against clotting factors (choice C) or fibrinolytic enzymes (choice D) are not involved in the clotting tendency associated with SLE. Diagnosis: Systemic lupus erythematosus

Answer 131

The answer is D: Selective IgA deficiency. Selective IgA deficiency is the most common primary immunodeficiency syndrome, with an incidence of 1:700 among Europeans. Although patients are often asymptomatic, they occasionally present with respiratory or gastrointestinal infections of varying severity. They also display a strong predilection for allergies and collagen vascular diseases. Patients with IgA deficiency have normal numbers of IgA-bearing B cells, and their varied defects result in an inability to synthesize and secrete IgA subclasses. Patients with chronic mucocutaneous candidiasis (choice B) show an increased susceptibility to Candida infections and also may exhibit various endocrine disorders (e.g., hypoparathyroidism and Addison disease). The other choices are associated with severe immunodeficiency. Diagnosis: Selective IgA deficiency

Answer 132

The answer is C: Interstitial infiltrates of lymphocytes and macrophages. Transplant rejection reactions have been traditionally categorized into hyperacute, acute, and chronic rejection based on the clinical tempo of the response and on the mechanisms involved. Acute rejection is characterized by an abrupt onset of azotemia and oliguria, which may be associated with fever and graft tenderness. A needle biopsy would be expected to show (1) interstitial infiltrates of lymphocytes and macrophages, (2) edema, (3) lymphocytic tubulitis, and (4) tubular necrosis. Neutrophilic vasculitis and fibrinoid necrosis (choice D) are seen in hyperacute rejection. Arterial intimal thickening (choice A),

Answer 133

The answer is D: High endothelial venules (HEVs) B and T lymphocytes circulate via the vascular system to secondary lymphoid organs and tissues. Included among these tissues are lymph nodes, mucosa associated lymphoid tissues, and spleen. In the case of lymph nodes, lymphocyte trafficking occurs through specialized postcapillary venules termed high endothelial venules (HEVs). HEVs express an array of specific cell adhesion molecules (e.g., CD31) that allow lymphocyte binding and diapedesis. The cuboidal shape of HEV cells reduces flow-mediated shear forces and specialized intercellular connections facilitate egress of lymphocytes out of the vascular space. Afferent and efferent lymphatic channels (choices A and B) do not possess HEVs. Hassall corpuscles (choice C) are found in the medulla of the thymus. Peyer patches (choice E) are organized lymphoid tissues found in the small intestine. Diagnosis: Lymphadenopathy, streptococcal pharyngitis

Answer 134

The answer is A: CD4. The HIV-1 genome consists of two identical 9.7-kb single strands of RNA enclosed within a core of viral proteins. The core is enveloped by a phospholipid bilayer derived from the host cell membrane, in which are found virally encoded glycoproteins (gp120 and gp41). In addition to the gag, pol, and env genes— characteristic of all replication-competent RNA viruses—HIV-1 contains six other genes that code for proteins involved in replication. The specific target cells for HIV-1 are CD4+ helper T lymphocytes and mononuclear phagocytes, although infection of other cells occurs. The HIV envelope glycoprotein gp120 (either on the free virus or on the surface of an infected cell) binds CD4 on the surface of helper T lymphocytes. The binding of gp120 to CD4 allows gp41 to insert into the cell membrane of the lymphocyte, thereby promoting fusion of the viral envelope with the lymphocyte. Entry of HIV-1 into a target cell in vivo also requires viral binding to a coreceptor, β-chemokine receptor 5 (CCR-5). Choices C and D (gp41 and gp120) are involved in viral replication, but they are present on the viral envelope. Choice E (LFA-1) is a member of the leukocyte integrin family that is involved in cell-cell adhesion. Diagnosis: Acquired immunodeficiency

Answer 135

The answer is E: Telomerase. Somatic cells do not normally express telomerase, which is an enzyme that adds repetitive sequences to maintain the length of the telomere. Thus, with each round of somatic cell replication, the telomere shortens. The length of telomeres may act as a “molecular clock” and govern the lifespan of replicating cells. Because cancer cells and embryonic cells express high levels of telomerase, the reactivation of this enzyme may be important for maintaining stem cell proliferation. Most human cancers show activation of the gene for the catalytic subunit of telomerase: human telomerase reverse transcriptase. P selectin (choice D) is a cell adhesion molecule that mediates the margination of neutrophils during acute inflammation. The other choices are not involved in malignant transformation. Diagnosis: Embryonal carcinoma

Answer 136

The answer is D: Inactivation of tumor suppressor proteins. Unlike RNA tumor viruses, whose oncogenes have normal cellular counterparts, the transforming genes of DNA viruses are not homologous with any cellular genes. This conundrum was resolved with the discovery that the gene products of oncogenic DNA viruses inactivate tumor suppressor proteins. For example, proteins encoded by the E6 and E7 genes of HPV16 bind p53 and pRb. The other choices are involved in the pathogenesis of neoplasia, but they are not specific for HPV. Diagnosis: Cervical intraepithelial neoplasia, HPV infection

Answer 137

The answer is B: Carcinoma in situ. Most carcinomas begin as localized growths confined to the epithelium in which they arise. As long as these early cancers do not penetrate the basement membrane on which the epithelium rests, such tumors are labeled carcinoma in situ. When the in situ tumor acquires invasive potential and extends directly through the underlying basement membrane, it is in a position to compromise neighboring tissues and metastasize. Carcinomatosis (choice C) is a clinical term used to describe widespread dissemination of cancer. Koilocytosis (choice E) implies the presence of squamous cells with perinuclear halos and nuclear changes. It is indicative of human papillomavirus infection and carries an increased risk of carcinoma. Atypical and complex hyperplasia (choices A and D) refer to proliferative lesions of the glands within the uterine endometrium. Diagnosis: Cervical carcinoma, carcinoma in situ

Answer 138

The answer is B: E-cadherin. Cadherins are Ca2+- dependent transmembrane glycoproteins that mediated cell–cell adhesion. E-cadherin is expressed on the surface of all epithelia and mediates cell adhesion by “zipper-like” interactions. Overall, cadherins suppress invasion and metastasis. Thus, it is perhaps not surprising that the expression of E cadherin is reduced in most carcinomas. Desmin (choice A) is an intermediate filament protein found in cells of mesenchymal origin. Lysyl hydroxylase (choice C) is involved in the posttranslational modification of collagen. P selectin is a cell adhesion molecule that mediates the margination of neutrophils during acute inflammation. Telomerase (choice E) is increased in certain malignancies. Diagnosis: Breast cancer

Answer 139

The answer is D: Resemblance to normal tissue of origin. To establish criteria for therapy, many cancers are classified according to histologic grading schemes or by staging protocols that describe the extent of spread. Cancer grading reflects cellular characteristics. Low-grade tumors are well differentiated, whereas high-grade tumors lack differentiated features (anaplasia). The general correlation between cytologic grade and the behavior of a neoplasm is not invariable. Indeed, there are many examples of tumors of low cytologic grades that exhibit substantial malignant properties. The other choices pertain to cancer staging. Diagnosis: Prostate cancer

Answer 140

The answer is C: Desmoplastic change. Secondary descriptors are used to refer to a tumor’s morphologic

Answer 141

and functional characteristics. Papillomatosis (choice E) describes frond-like structures. Medullary (choice D) signifies a soft cellular tumor, whereas scirrhous or desmoplastic implies dense fibrous stroma. Colloid carcinomas (choice A) secrete abundant mucus. Comedocarcinoma (choice B) is an intraductal neoplasm in which necrotic material can be expressed from the ducts. Diagnosis: Breast cancer

Answer 142

The answer is B: Paraneoplastic syndrome. Cancers may produce remote effects, collectively termed paraneoplastic syndromes. For example, the secretion of corticotropin (ACTH) by a tumor leads to clinical features of Cushing syndrome, including hyperglycemia and hypertension. Corticotropin production is most commonly seen with cancers of the lung, particularly small cell carcinoma. Adrenal and pituitary metastases (choices A and D) would lead to loss of adrenal function (Addison disease). Although pituitary adenoma (choice C) is a possible cause of Cushing syndrome, this choice would be unlikely in a patient with lung cancer. Diagnosis: Small cell carcinoma of lung, paraneoplastic syndrome

Answer 143

The answer is D: Cytokeratins. Tumor markers are products of malignant neoplasms that can be detected in cells or body fluids. Useful tumor markers include immunoglobulins, fetal proteins, enzymes, hormones, and cytoskeletal proteins. Carcinomas uniformly express cytokeratins, which are intermediate filaments. Alpha-fetoprotein (choice A) is a marker for yolk sac carcinoma and hepatocellular carcinoma. Calretinin (choice B) provides a marker for mesothelioma. Carcinoembryonic antigen (choice C) is a marker for colon carcinoma and many other malignancies. Synaptophysin (choice E) is a marker for

Answer 144

neuroendocrine tumors, including small cell carcinoma of the lung. Diagnosis: Squamous cell carcinoma of lung

Answer 145

The answer is D: Polycyclic aromatic hydrocarbons. Polycyclic aromatic hydrocarbons, originally derived from coal tar, are among the most extensively studied carcinogens. These compounds produce cancers at the site of application. Since polycyclic hydrocarbons have been identified in cigarette smoke, it has been suggested (but not proved) that they are involved in the pathogenesis of lung cancer. Aflatoxin B1 (choice A), a natural product of the fungus Aspergillus fl avus, is among the most potent liver carcinogens. Asbestos (choice B), a mineral, is associated with mesothelioma and adenocarcinoma of the lung. Industrial workers exposed to high levels of vinyl chloride (choice E) in the ambient atmosphere developed angiosarcomas of the liver. Diagnosis: Squamous cell carcinoma of lung

Answer 146

The answer is C: DNA repair. Breast (BR) cancer (CA) susceptibility genes (BRCA1 and BRCA2) encode tumor suppressor proteins involved in checkpoint functions related to progression of the cell cycle into S phase. BRCA1 and BRCA2 proteins also promote DNA repair by binding to RAD51, a molecule that mediates DNA double-strand repair breaks. The other choices may be abnormal in neoplasia, but they are not primarily affected by BRCA1. Diagnosis: Breast cancer

Answer 147

The answer is A: Aniline dyes. Transitional cell carcinoma is the most common malignant tumor of the urinary bladder, and the incidence of bladder cancer is increased in aniline dye workers. These azo dyes are converted to water-soluble carcinogens in the liver. They are excreted in the urine, where they primarily affect the transitional epithelium of the bladder. Benzene exposure (choice C) is associated with leukemia. Vinyl chloride exposure (choice E) has been associated with hepatic angiosarcomas. Diagnosis: Transitional cell carcinoma of bladder

Answer 148

The answer is E: Plasminogen activator. Malignant cells and stromal cells associated with cancers elaborate a variety of proteases that degrade basement membrane components. Such enzymes include the urokinase-type plasminogen activator (u-PA) and matrix metalloproteinases. u-PA converts serum plasminogen to plasmin, a serine protease that degrades laminin and activates type IV procollagenase. Changes in the expression of u-PA, the u-PA receptor, and PA inhibitors have been reported in different cancers. Metastatic cells would be expected to show reduced expression of collagens (choice A) and cadherins (choice C). Desmin (choice B) is found in cells of mesenchymal origin. Diagnosis: Squamous cell carcinoma of skin

Answer 149

The answer is A: Acquired immunodeficiency. Kaposi sarcoma is the most common neoplasm associated with acquired immunodeficiency syndrome (AIDS). The neoplastic cells contain sequences of a novel virus, HHV-8, which is also known as Kaposi sarcoma– associated herpesvirus. In addition to infecting the spindle cells of Kaposi sarcoma, HHV-8 is lymphotropic and has been implicated in two uncommon B-cell lymphoid malignancies, namely, primary effusion lymphoma and multicentric Castleman disease. Like other DNA viruses, the HHV-8 genome encodes proteins that interfere with the p53 and pRb tumor suppressor pathways. The other choices are hereditary conditions associated with cancer; however, these patients do not typically acquire Kaposi sarcoma. The predominant malignancy seen

Answer 150

The answer is B: Metastases to regional lymph nodes. The choice of surgical approach or treatment modalities is influenced more by the stage of a cancer than by its cytologic grade. The significant criteria used for staging vary with different organs. Commonly used criteria include (1) tumor size, (2) extent of local growth, (3) presence of lymph node metastases, and (4) presence of distant metastases. The other choices reflect the grade of the tumor. Diagnosis: Renal cell carcinoma

Answer 151

The answer is B: Asbestos. The characteristic tumor associated with asbestos exposure is mesothelioma of the pleural and peritoneal cavities. This cancer has been reported to occur in 2% to 3% of heavily exposed workers. The pipe fitters in shipyards were the most exposed workers. Many of these workers developed mesotheliomas 20 to 40 years after exposure. It is reasonable to surmise that mesotheliomas of both the pleura and the peritoneum reflect the close contact of these membranes with asbestos fibers transported to them by lymphatic channels. Like the polycyclic aromatic hydrocarbons, aflatoxin B1 (choice A) can bind covalently to DNA and is among the most potent liver carcinogens recognized. Beryllium (choice C) and silica (choice E) cause lung disease, but they are not carcinogenic. Diagnosis: Mesothelioma

Answer 152

The answer is C: Invasion of the underlying basement membrane. The first event in tumor cell invasion is breach of the basement membrane that separates an epithelium from the underlying mesenchyme. After invading the interstitial tissue, malignant cells penetrate lymphatic or vascular channels (choice D). In the lymph nodes, communications between the lymphatics and venous tributaries allow malignant cells access to the systemic circulation. The other choices are important for tumor metastases, but they occur later than basement membrane invasion. Diagnosis: Adenocarcinoma of colon

Answer 153

The answer is E: Loss of cell cycle restriction point control. Cancer cells often display loss of cell cycle restriction point control through mechanisms such as overexpression of cyclin D1, loss of Cdk inhibitors, or inactivation of the pRb or p53 proteins. The p53 gene is deleted or mutated in 75% of cases of colorectal cancer and frequently mutated in numerous other tumors. The p53 protein is a negative regulator of cell division. Inactivating mutations of p53 cause loss of cell cycle restriction point control and allow cells with damaged DNA to progress through the cell cycle. Malignant cells have increased cellular motility (see choice A), reduced stem cell differentiation (see choice B), decreased cell adhesion (see choice C), and decreased susceptibility to apoptosis (see choice D). Diagnosis: Adenocarcinoma of colon

Answer 154

The answer is A: Adenoma. Benign tumors arising from a glandular epithelium are termed adenomas. Patients with a prolactin-secreting pituitary adenoma present with amenorrhea and galactorrhea. Ectopic islands of normal tissue are called choristomas (choice B). Localized, disordered differentiation during development results in a hamartoma (choice C). Papillomas (choice D) do not occur in the pituitary. Benign tumors that arise from germ cells and contain all three germ layers are termed teratomas (choice E). Diagnosis: Pituitary adenoma, prolactinoma

Answer 155

The answer is E: Neuroendocrine granules. Neuroendocrine tumors may synthesize a number of hormones. The presence of small, membrane-bound granules with a dense core is a feature of these neoplasms. Dense granules are visible by electron microscopy. In this way, electron microscopy may aid in the diagnosis of poorly differentiated cancers, whose classification is problematic by light microscopy. Carcinomas often exhibit desmosomes and specialized junctional complexes, which are structures that are not typical of sarcomas or lymphomas. Myelin figures (choice D) are seen in patients with inherited lysosomal storage disease.

Answer 156

The answer is A: Apoptosis. Many human cancers show abnormalities in the control of apoptosis. For example, follicular B-cell lymphomas display a characteristic chromosomal translocation in which the bcl-2 gene is brought under the transcriptional control of the immunoglobulin light-chain gene promoter, thereby causing overexpression of bcl-2. As a result of the antiapoptotic properties of bcl-2, the neoplastic clone accumulates in lymph nodes. Since its demonstration in follicular lymphomas, bcl-2 expression has been observed in a variety of other human cancers. None of the other choices describes the function of bcl-2. Diagnosis: Follicular lymphoma

Answer 157

The answer is D: Pancreas. Radiologic evidence of “canon ball” lesions in the liver or lung suggests metastatic cancer. The liver is involved in a third of all metastatic cancers, including half of those of the gastrointestinal tract, breast, and lung. Other tumors that characteristically metastasize to the liver are pancreatic carcinoma and malignant melanoma. Liver metastases are the most common cause of massive hepatomegaly. Visible secretions of tumor cells, such as mucin or serous fluid, provide important clues for tumor diagnosis. Mucin-secreting glandular epithelium and mucin-secreting adenocarcinoma are expected in the pancreas. None of the other organs are composed of glandular epithelial cells or produce mucin. Diagnosis: Metastatic cancer

Answer 158

The answer is E: Stomach. Acanthosis nigricans is a cutaneous disorder marked by hyperkeratosis and pigmentation of the axilla, neck, flexures, and anogenital region. It is of particular interest because more than half of patients with acanthosis nigricans have cancer. Over 90% of cases occur in association with gastrointestinal carcinomas (primarily stomach cancer). The other tumors are uncommon causes of acanthosis nigricans. Diagnosis: Paraneoplastic syndrome, acanthosis nigricans

Answer 159

The answer is D: Ischemia and infarction. Angiogenesis is a requirement for the continued growth of cancers, whether primary or metastatic. In the absence of new vessels to supply the nutrients and remove waste products, malignant tumors do not grow larger than 1 to 2 mm in diameter. In general, causes of tumor cell death in situ include (1) programmed cell death (apoptosis); (2) inadequate blood supply, with consequent ischemia; (3) a paucity of nutrients; and (4) vulnerability to specific and nonspecific host defenses. The CT scan provided for Question 21 shows central necrosis (umbilication) in most of the metastatic tumor nodules. None of the other choices are likely causes of tumor necrosis. Diagnosis: Metastatic cancer

Answer 160

The answer is B: Carcinoembryonic antigen (CEA). Colorectal cancer is asymptomatic in its initial stages. As the tumor grows, the most common sign is occult blood in feces, especially when the tumor is in the proximal portion of the colon. Chronic, symptomatic bleeding typically causes iron- deficiency anemia. Adenocarcinomas of the colon usually express CEA, a glycoprotein that is released into the circulation and serves as a serologic marker for these tumors. CEA is also found in association with malignant tumors of the pancreas, lung, and ovary. AFP (choice A) is expressed by hepatocellular carcinoma and yolk sac tumors. Chromogranin (choice D) is expressed by neuroendocrine tumors. Chorionic gonadotropin (choice C) is secreted by choriocarcinoma. Diagnosis: Colon cancer

Answer 161

The answer is A: Epigenetic modification. Hypermethylation of many tumor suppressor and DNA repair genes has been demonstrated in human tumors. The pathways controlled by these genes are, therefore, suppressed. For example, the normal p53 gene can be inactivated by hypermethylation. Thus, aberrant methylation of tumor suppressor genes may be an epigenetic mechanism for a “second hit,” leading to loss of heterozygosity. Unlike genetic changes in cancer, epigenetic changes are reversible, and a search for drugs that infl uence DNA methylation is under way. The other choices are unrelated to DNA methylation. Diagnosis: Colon cancer

Answer 162

The answer is E: Teratoma. Teratomas are benign tumors composed of tissues derived from all three primary germ layers: ectoderm, mesoderm, and endoderm. They are most common in the ovary but also occur in the testis and extragonadal sites. Teratocarcinomas (choice D) are malignant tumors that harbor embryonal carcinoma stem cells. Adenoma (choice A) is a benign tumor of epithelial origin. Chondroma (choice B) is a benign cartilaginous tumor. Hamartoma (choice C) is disorganized normal tissue. Diagnosis: Mature teratoma

Answer 163

The answer is C: Japan. The highest incidence of stomach cancer occurs in Japan, where the disease is almost ten times as frequent as it is among American whites. A study of Japanese residents of Hawaii found that emigrants from Japanese regions with the highest risk of stomach cancer continued to exhibit an excess risk in Hawaii. By contrast, their offspring who were born in Hawaii had the same incidence of this cancer as American whites. The highest incidence of colorectal cancer is found in the United States (choice E). Diagnosis: Gastric cancer

Answer 164

The answer is E: Xeroderma pigmentosum. Xeroderma pigmentosum is an autosomal recessive disease in which increased sensitivity to sunlight is accompanied by a high incidence of skin cancers, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Several xeroderma pigmentosum genes are involved in nucleotide excision of ultraviolet-damaged DNA. Li Fraumeni syndrome (choice C) refers to an inherited predisposition to develop cancers in many organs due to germline mutations of p53. Ataxia telangiectasia (choice A) features cerebellar degeneration, immunologic abnormalities, and a predisposition to cancer. The mutated gene codes for a nuclear phosphoprotein involved in regulation of the cell cycle and DNA repair. Patients with hereditary albinism (choice B) are also at high risk for development of squamous cell carcinoma of the skin,

Answer 165

The answer is D: Lung. Lung carcinoma is the cause of most cancer-related deaths in the United States and Western Europe in men and women. The second most common cause of death from cancer in women is breast cancer (choice B). One of the most common findings in patients with cancer is anemia, but the mechanism for this paraneoplastic syndrome is not clear. The anemia is usually normocytic and normochromic, although iron defi ciency anemia is common in cancers that bleed into the gastrointestinal tract. Diagnosis: Lung cancer

Answer 166

The answer is E: Gene amplification. Chromosomal alterations that result in an increased number of copies of a gene have been found primarily in solid tumors. Such aberrations are recognized as (1) homogeneous staining regions (HSRs); (2) abnormal banding regions on chromosomes; or (3) double minutes, which are visualized as small, paired cytoplasmic bodies. In some cases, gene amplification has been shown to involve protooncogenes. For example, HSRs may be seen in neuroblastomas and are all derived from the N-myc protooncogene. The presence of N-myc HSRs is associated with up to 700-fold amplification of this gene and is a marker of advanced disease with a poor prognosis. Although the other choices are mechanisms for protooncogene activation, they do not cause upregulation of N-myc in patients with neuroblastoma. Diagnosis: Neuroblastoma

Answer 167

The answer is C: Lymphocytes. Four DNA viruses (human papillomavirus, Epstein-Barr virus [EBV], hepatitis B virus, and herpesvirus-8) are incriminated in the development of human cancers. EBV was the first virus to be unequivocally linked to the development of a human tumor. In 1958, Burkitt described a form of childhood lymphoma in a geographical belt across equatorial Africa, which he suggested might have a viral etiology. A few years later, Epstein and Barr discovered viral particles in cell lines cultured from patients with Burkitt lymphoma. African Burkitt lymphoma is a B-cell tumor, in which the neoplastic lymphocytes invariably contain EBV in their DNA and manifest EBV-related antigens. EBV does not infect the other choices. Diagnosis: Burkitt lymphoma, EBV

Answer 168

The answer is B: Flushing and wheezing. Carcinoid syndrome is a systemic paraneoplastic disease caused by the release of hormones from carcinoid tumors (via neuroendocrine granules) into venous blood. Symptoms of flushing, bronchial wheezing, watery diarrhea, and abdominal colic are caused by the release of serotonin, bradykinin, and histamine. Carcinoids are neuroendocrine tumors of low malignancy that are most commonly located in the submucosa of the intestines (e.g., appendix, terminal ileum, and rectum). The other choices are not associated with this paraneoplastic syndrome. Diagnosis: Carcinoid tumor, paraneoplastic syndrome

Answer 169

The answer is B: Melanoma. The photograph shows pigmented cells in the vertebral bodies of a person who died of malignant melanoma. This autopsy finding illustrates the point that accurate tumor identification depends on morphologic resemblance to normal tissue. Tumor emboli in this case probably reached bone after surviving passage through the pulmonary microcirculation. None of the other tumors show pigmentation. Diagnosis: Melanoma

Answer 170

The answer is B: Leiomyoma. Leiomyoma is the most common benign tumor of the uterus, usually arising in women of reproductive age. It originates from smooth muscle cells of the myometrium. None of the other choices are benign tumors of smooth muscle. Diagnosis: Leiomyoma of stroma

Answer 171

The answer is E: Protooncogene activation. The best known example of an acquired chromosomal translocation in a human cancer is the Philadelphia chromosome, which is found in 95% of patients with CML. The c-abl protooncogene on chromosome 9 is translocated to chromosome 22, it is placed in juxtaposition to the breakpoint cluster region (bcr). The c-abl gene and bcr region unite to produce a hybrid oncogene that codes for an aberrant protein with very high levels of tyrosine kinase activity, which generates mitogenic and antiapoptotic signals. Diagnosis: Chronic myelogenous leukemia, Philadelphia chromosome

Answer 172

The answer is B: CD4. CD4 is a cluster-differentiation antigeno f helper T lymphocytes. HMB-45 and S-100 (choices D and E) are markers for malignant melanoma, among other tumors. Calcitonin (choice A) is a peptide hormone. Desmin (choice C) is an intermediate filament protein found in cells of mesenchymal origin. Diagnosis: Mycosis fungoides

Answer 173

The answer is B: Disorganized normal tissue. Localized, disordered differentiation during embryonic development results in a hamartoma, a disorganized caricature of normal tissue components. Such tumors, which are not strictly neoplasms, contain varying combinations of cartilage, ducts or bronchi, connective tissue, blood vessels, and lymphoid tissue. Ectopic islands of normal tissue (choice C), called choristoma, may also be mistaken for true neoplasms. These small lesions are represented by pancreatic tissue in the wall of the stomach or intestine, adrenal rests under the renal capsule, and nodules of splenic tissue in the peritoneal cavity. Diagnosis: Hamartoma

Answer 174

The answer is D: Seeding of the body cavity. The photograph shows a loop of small bowel and mesentery studded with small nodules of metastatic cancer. Malignant tumors that arise in organs adjacent to body cavities (e.g., ovaries, gastrointestinal tract, or lung) may shed malignant cells into these spaces. Such body cavities include principally the peritoneal and pleural cavities, although occasional seeding of the pericardial cavity, joint space, and subarachnoid space is observed. Tumor cells in these sites grow in masses and often produce fluid (e.g., ascites or pleural fluid), sometimes in massive quantities. Although the other choices provide routes for tumor metastasis, they do not lead to peritoneal carcinomatosis in patients with ovarian cancer. Diagnosis: Ovarian cancer, carcinomatosis

Answer 175

The answer is D: Loss of heterozygosity. Retinoblastomas are malignant ocular tumors of young children. In cases of hereditary retinoblastoma, an affected child inherits one defective Rb allele together with one normal gene. This heterozygous state is not associated with any observable changes in the retina because 50% of the Rb gene product is sufficient to prevent the development of retinoblastoma. However, if the remaining normal Rb allele is inactivated by deletion or mutation, the loss of its suppressor function leads to the appearance of a neoplasm. This genetic process is referred to as loss of heterozygosity. The other choices have not been associated with the loss of tumor suppressor genes in somatic cells. Diagnosis: Retinoblastoma

Answer 176

The answer is C: Hyperplasia. The cellular and molecular mechanisms of hyperplasia are related to the control of cell proliferation and provide a basis for further genetic changes that can lead to neoplasia. Endometrial hyperplasia refers to a spectrum that ranges from simple glandular crowding to conspicuous proliferation of atypical glands. These changes are often difficult to distinguish from carcinoma. The risk of developing endometrial cancer increases with higher degrees of endometrial hyperplasia. Estrogen exposure is thought to be a risk factor for both endometrial hyperplasia and endometrial carcinoma. Neoplastic transformation may occur in the setting of a metaplastic epithelium (e.g., cancers of the lung, cervix, stomach, and bladder); however, metaplasia (choice E) does not precede the development of uterine adenocarcinoma. The other choices do not represent risk factors for cancer. Diagnosis: Endometrial adenocarcinoma

Answer 177

The answer is C: Metastatic carcinoma of the lung. This patient’s lung shows numerous nodules of metastatic carcinoma corresponding to “cannonball” metastases seen radiologically. Pulmonary metastases are more common than primary lung tumors, and the histologic appearance of most metastases resembles that of the primary tumor. Persons with ulcerative colitis (such as this patient) have a higher risk of colorectal cancer than the general population. The risk is related to the extent of colorectal involvement and the duration of the inflammatory disease. Carcinoid tumor of the lung (choice A) and primary lung cancer (choice B) would not typically show multiple, circumscribed nodules. Miliary tuberculosis (choice D) and sarcoidosis (choice E) feature mm-sized inflammatory nodules (minute granulomas). Diagnosis: Metastatic cancer, metastatic carcinoma of the lung

Answer 178

The answer is A: Adenoma. The patient shows signs and symptoms of Cushing syndrome (upper truncal obesity and hypercortisolism). The surgical specimen reveals a circumscribed tumor of the adrenal cortex that produces cortisol. Histologic examination of this tumor reveals nests of clear, lipid-laden epithelial cells. None of the other choices describe a benign tumor of glandular epithelial origin. Diagnosis: Adrenal adenoma, Cushing syndrome

Answer 179

The answer is E: Sunlight. Basal cell carcinoma (BCC) is the most common malignant tumor in persons with pale skin. BCC usually develops on the sun-damaged skin of people with fair skin and freckles. There is a direct correlation between total exposure to sunlight and the incidence of BCC, as well as squamous cell carcinoma and melanoma. The deleterious effects of sunlight (UV radiation) include enzyme inactivation, mutagenesis, and cell death. Divalent metal cations

Answer 180

such as nickel, lead, cadmium, cobalt, and beryllium (choice B) can react with biomolecules and induce cancer. Most metal induced cancers occur in an occupational setting; however the carcinogenic mechanisms are unknown. Diagnosis: Basal cell carcinoma

Answer 181

The answer is C: Cell cycle. The surgical specimen reveals thousands of small adenomatous polyps on the mucosal surface of the colon. Patients with adenomatous polyposis coli have mutations in the APC tumor suppressor gene. Most cases are familial, but 30% to 50% represent new mutations. The mean age for occurrence of symptoms is 36 years. Without the APC protooncogene, cells are unable to downregulate signals from E-cadherin to b-catenin to nuclear transcription factors (myc and cyclin D) that regulate cell cycle progression. Autophagy (choice B) is a normal catabolic process in which cellular components and organelles are degraded in lysosomes. Autophagy is often a response to cell injury. It is also believed to protect cells from intracellular pathogens and slow the progression of various chronic diseases, including cancer. Diagnosis: Adenomatous polyposis coli

Answer 182

The answer is A: Alcohol abuse. Fetal alcohol syndrome refers to a complex of abnormalities induced by the maternal consumption of alcoholic beverages while pregnant that includes (1) growth retardation, (2) dysfunction of the central nervous system, and (3) characteristic facial dysmorphology (e.g., small head circumference and thin upper lip). One fifth of children with fetal alcohol syndrome have IQs below 70, and 40% have IQs between 70 and 85. Even with a normal IQ, these children tend to have short memory spans, impulsiveness, and emotional instability. The children of mothers who smoke (choice B) or who have inadequate nutrition (choice D) may also exhibit deficiencies in physical growth and intellectual development; however, there is no association with the pattern of facial dysmorphology and emotional instability seen in this case. Congenital syphilis (choice C) may also cause mental retardation, but it would show protean manifestations not illustrated in this case. Gestational diabetes (choice E) does not cause mental retardation. Diagnosis: Fetal alcohol syndrome

Answer 183

The answer is A: Collagen. Osteogenesis imperfecta (OI), or brittle bone disease, is a group of inherited disorders expressed principally as fragility of bone. The genetic defects in the four types of OI are heterogeneous, but all affect the synthesis of type I collagen. Type I OI is characterized by a normal appearance at birth, but fractures of many bones occur during infancy and at the time the child learns to walk. Such patients have been described as being as “fragile as a China doll.” Children with type I OI typically have blue sclerae as a result of the deficiency in collagen fibers, which imparts translucence to the sclera. A high incidence of hearing loss occurs because fractures and fusion of bones of the middle ear restrict their mobility. Fibrillin gene mutations (choice B) are found in patients with Marfan syndrome. Keratin gene mutations (choice C) are found in patients with epidermolytic hyperkeratosis. Diagnosis: Osteogenesis imperfecta

Answer 184

The answer is B: 20 to 40 days. Anencephaly refers to the congenital absence of the cranial vault, with cerebral hemispheres either missing or reduced to small masses. It is a dysraphic anomaly of neural tube closure that results from an injury to the fetus between the 23rd and 26th day of gestation. During fetal development, the neural plate is transformed into the neural tube by fusion of the posterior surfaces. Failure of the neural tube to close results in the lack of closure of the overlying bony structures of the cranium and an absence of the calvarium, skin, and subcutaneous tissues of this region. The exposed brain is incompletely formed or absent. Blastocyst formation and implantation occur on days 1 to 10 after fertilization (choice A). Diagnosis: Acrania, neural tube defect

Answer 185

The answer is B: GTPase activating protein. Neurofibromatosis type 1 (NF1) is characterized by (1) disfiguring neurofibromas, (2) areas of dark pigmentation of the skin (café au lait spots), and (3) pigmented lesions of the iris (Lisch nodules). It is one of the more common autosomal dominant disorders. The NF1 gene has a high rate of mutation, and half of cases are sporadic rather than familial. The protein product, termed neurofibromin, is expressed in many tissues and belongs to a family of GTPase-activating proteins (GAPs), which inactivate ras protein (choice E). Thus, NF1 is a classic tumor suppressor gene. Loss of GAP activity (in cells acquiring a second hit mutation) permits uncontrolled ras p21 activation, an effect that predisposes to the formation of benign neurofibromas. None of the other choices (A, C, and D) are associated with the pathogenesis of neurofibromatosis. Diagnosis: Neurofibromatosis, type 1

Answer 186

The answer is C: Neurofibrosarcoma. One of the major complications of neurofibromatosis type 1 (NF1), occurring in 3% to 5% of patients, is the appearance of a neurofibrosarcoma in a neurofibroma. NF1 is also associated with an increased incidence of other neurogenic tumors, including meningioma, optic glioma, and pheochromocytoma. The other tumors listed are not associated with NF1. Diagnosis: Neurofibromatosis, type 1

Answer 187

The answer is B: Alpha-fetoprotein (AFP). Screening of pregnant women for serum AFP and examination by ultrasonography allow detection of virtually all anencephalic fetuses. Levels of the other proteins are not significantly affected by a neural tube defect in the fetus. Diagnosis: Neural tube defect, spina bifida

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