Ebook Robbins basic pathology (9/E): Part 2

Part 2 book “Robbins basic pathology” has contents: Hematopoietic and lymphoid systems, oral cavity and gastrointestinal tract, kidney and its collecting system, liver, gallbladder, and biliary tract, male genital system and lower urinary tract, endocrine system, central nervous system,… and other contents.

See Targeted Therapy available online at studentconsult.com Hematopoietic and Lymphoid Systems C H A P T E R 11 C H A P T E R CO N T E N T S RED CELL DISORDERS  408 Anemia of Blood Loss: Hemorrhage  409 Hemolytic Anemias  409 Hereditary Spherocytosis  410 Sickle Cell Anemia  411 Thalassemia  413 Glucose-6-Phosphate Dehydrogenase Deficiency  416 Paroxysmal Nocturnal Hemoglobinuria  417 Immunohemolytic Anemias  417 Hemolytic Anemias Resulting from Mechanical Trauma to Red Cells  418 Malaria  418 Anemias of Diminished Erythropoiesis  419 Iron Deficiency Anemia  420 Anemia of Chronic Disease  421 Megaloblastic Anemias  422 Aplastic Anemia  424 Myelophthisic Anemia  424 Polycythemia  425 WHITE CELL DISORDERS  425 Non-Neoplastic Disorders of White Cells  425 Leukopenia  425 Reactive Leukocytosis  426 Reactive Lymphadenitis  427 Neoplastic Proliferations of White Cells  428 Lymphoid Neoplasms  429 Myeloid Neoplasms  444 Histiocytic Neoplasms  449 Thrombocytopenia  452 Immune Thrombocytopenic Purpura  452 Heparin-Induced Thrombocytopenia  453 Thrombotic Microangiopathies: Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome  453 Coagulation Disorders  454 Deficiencies of Factor VIII–von Willebrand Factor Complex  454 DISORDERS THAT AFFECT THE SPLEEN AND THYMUS  456 Splenomegaly  456 Disorders of the Thymus  456 Thymic Hyperplasia  457 Thymoma  457 BLEEDING DISORDERS  449 Disseminated Intravascular Coagulation  450 The hematopoietic and lymphoid systems are affected by a wide spectrum of diseases One way to organize these disorders is based on whether they primarily affect red cells, white cells, or the hemostatic system, which includes platelets and clotting factors The most common red cell disorders are those that lead to anemia, a state of red cell deficiency White cell disorders, by contrast, are most often associated with excessive proliferation, as a result of malignant transformation Hemostatic derangements may result in hemorrhagic diatheses (bleeding disorders) Finally, splenomegaly, a feature of numerous diseases, is discussed at the end of the chapter, as are tumors of the thymus Although these divisions are useful, in reality the production, function, and destruction of red cells, white cells, and components of the hemostatic system are closely linked, and pathogenic derangements primarily affecting one cell type or component of the system often lead to alterations in others For example, in certain conditions B cells make autoantibodies against components of the red cell membrane The opsonized red cells are recognized and destroyed by phagocytes in the spleen, which becomes enlarged The increased red cell destruction causes anemia, which in turn drives a compensatory hyperplasia of red cell progenitors in the bone marrow Other levels of interplay and complexity stem from the anatomically dispersed nature of the hematolymphoid system, and the capacity of both normal and malignant white cells to “traffic” between various compartments Hence, a patient who is diagnosed with lymphoma by lymph node biopsy also may be found to have neoplastic lymphocytes in their bone marrow and blood The malignant lymphoid cells in the marrow may suppress hematopoiesis, giving rise to low blood cell counts (cytopenias), and the further seeding of tumor cells to the liver and spleen may lead to organomegaly Thus, in both benign and malignant hematolymphoid disorders, a single underlying abnormality can result in diverse systemic manifestations Keeping these complexities in mind, we will use the time-honored classification of hematolymphoid disorders based on predominant involvement of red cells, white cells, and the hemostatic system 408 C H A P T E R 11 Hematopoietic and Lymphoid Systems RED CELL DISORDERS Disorders of red cells can result in anemia or, less commonly, polycythemia (an increase in red cells also known as erythrocytosis) Anemia is defined as a reduction in the oxygen-transporting capacity of blood, which usually stems from a decrease in the red cell mass to subnormal levels Anemia can result from bleeding, increased red cell destruction, or decreased red cell production These mechanisms serve as one basis for classifying anemias (Table 11–1) In some entities overlap occurs, for example, in thalassemia where reduced red cell production and early destruction give rise to anemia With the exception of anemias caused by chronic renal failure or chronic inflammation (described later), the Table 11–1  Classification of Anemia According to Underlying Mechanism Blood Loss Acute: trauma Chronic: gastrointestinal tract lesions, gynecologic disturbances Increased Destruction (Hemolytic Anemias) Intrinsic (Intracorpuscular) Abnormalities Hereditary Membrane abnormalities Membrane skeleton proteins: spherocytosis, elliptocytosis Membrane lipids: abetalipoproteinemia Enzyme deficiencies Enzymes of hexose monophosphate shunt: glucose-6-phosphate dehydrogenase, glutathione synthetase Glycolytic enzymes: pyruvate kinase, hexokinase Disorders of hemoglobin synthesis Structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia, unstable hemoglobins Deficient globin synthesis: thalassemia syndromes Acquired Membrane defect: paroxysmal nocturnal hemoglobinuria Extrinsic (Extracorpuscular) Abnormalities Antibody-mediated Isohemagglutinins: transfusion reactions, immune hydrops (Rh disease of the newborn) Autoantibodies: idiopathic (primary), drug-associated, systemic lupus erythematosus Mechanical trauma to red cells Microangiopathic hemolytic anemias: thrombotic thrombocytopenic purpura, disseminated intravascular coagulation Defective cardiac valves Infections: malaria Impaired Red Cell Production Disturbed proliferation and differentiation of stem cells: aplastic anemia, pure red cell aplasia Disturbed proliferation and maturation of erythroblasts Defective DNA synthesis: deficiency or impaired utilization of vitamin B12 and folic acid (megaloblastic anemias) Anemia of renal failure (erythropoietin deficiency) Anemia of chronic disease (iron sequestration, relative erythropoietin deficiency) Anemia of endocrine disorders Defective hemoglobin synthesis Deficient heme synthesis: iron deficiency, sideroblastic anemias Deficient globin synthesis: thalassemias Marrow replacement: primary hematopoietic neoplasms (acute leukemia, myelodysplastic syndromes) Marrow infiltration (myelophthisic anemia): metastatic neoplasms, granulomatous disease decrease in tissue oxygen tension that accompanies anemia triggers increased production of the growth factor erythropoietin from specialized cells in the kidney This in turn drives a compensatory hyperplasia of erythroid precursors in the bone marrow and, in severe anemias, the appearance of extramedullary hematopoiesis within the secondary hematopoietic organs (the liver, spleen, and lymph nodes) In well-nourished persons who become anemic because of acute bleeding or increased red cell destruction (hemolysis) the compensatory response can increase the production of red cells five- to eight-fold The rise in marrow output is signaled by the appearance of increased numbers of newly formed red cells (reticulocytes) in the peripheral blood By contrast, anemias caused by decreased red cell production (aregenerative anemias) are associated with subnormal reticulocyte counts (reticulocytopenia) Anemias also can be classified on the basis of red cell morphology, which often points to particular causes Specific features that provide etiologic clues include the size, color and shape of the red cells These features are judged subjectively by visual inspection of peripheral smears and also are expressed quantitatively using the following indices: • Mean cell volume (MCV): the average volume per red cell, expressed in femtoliters (cubic microns) • Mean cell hemoglobin (MCH): the average mass of hemoglobin per red cell, expressed in picograms • Mean cell hemoglobin concentration (MCHC): the average concentration of hemoglobin in a given volume of packed red cells, expressed in grams per deciliter • Red cell distribution width (RDW): the coefficient of variation of red cell volume Red cell indices are directly measured or automatically calculated by specialized instruments in clinical laboratories The same instruments also determine the reticulocyte count, a simple measure that distinguishes between hemolytic and aregenerative anemias Adult reference ranges for these tests are shown in Table 11–2 Depending on the differential diagnosis, a number of other blood tests also may be performed to evaluate anemia, including (1) iron indices (serum iron, serum iron-binding capacity, transferrin saturation, and serum ferritin concentrations), which help distinguish among anemias caused by iron deficiency, chronic disease, and thalassemia; (2) plasma unconjugated bilirubin, haptoglobin, and lactate dehydrogenase levels, which are abnormal in hemolytic anemias; (3) serum and red cell folate and vitamin B12 concentrations, which are low in megaloblastic anemias; (4) hemoglobin electrophoresis, which is used to detect abnormal hemoglobins; and (5) the Coombs test, which is used to detect antibodies or complement on red cells in suspected cases of immunohemolytic anemia In isolated anemia, tests performed on the peripheral blood usually suffice to establish the cause By contrast, when anemia occurs along with thrombocytopenia and/or granu­­locytopenia, it is much more likely to be associated with marrow aplasia or infiltration; in such instances, a marrow examination usually is warranted As discussed later, the clinical consequences of anemia are determined by its severity, rapidity of onset, and underlying pathogenic mechanism If the onset is slow, Hemolytic Anemias Table 11–2  Adult Reference Ranges for Red Blood Cells* Units Men Women 13.2–16.7 11.9–15.0 Hemoglobin (Hb) g/dL Hematocrit (Hct) % 3848 3544 Red cell count ì 106/àL 4.2–5.6 3.8–5.0 0.5–1.5 Reticulocyte count % 0.5–1.5 Mean cell volume (MCV) fL 81–97 81–97 Mean cell Hb (MCH) pg 28–34 28–34 Mean cell Hb concentration (MCHC) g/dL 33–35 33–35 Red cell distribution width (RDW) 11.5–14.8 *Reference ranges vary among laboratories The reference ranges for the laboratory providing the result should always be used in interpreting a laboratory test the deficit in O2-carrying capacity is partially compensated for by adaptations such as increases in plasma volume, cardiac output, respiratory rate, and levels of red cell 2,3diphosphoglycerate, a glycolytic pathway intermediate that enhances the release of O2 from hemoglobin These changes mitigate the effects of mild to moderate anemia in otherwise healthy persons but are less effective in those with compromised pulmonary or cardiac function Pallor, fatigue, and lassitude are common to all forms of anemia Anemias caused by the premature destruction of red cells (hemolytic anemias) are associated with hyperbilirubinemia, jaundice, and pigment gallstones, all related to increases in the turnover of hemoglobin Anemias that stem from ineffective hematopoiesis (the premature death of erythroid progenitors in the marrow) are associated with inappropriate increases in iron absorption from the gut, which can lead to iron overload (secondary hemochromatosis) with consequent damage to endocrine organs and the heart If left untreated, severe congenital anemias such as β-thalassemia major inevitably result in growth retardation, skeletal abnormalities, and cachexia SUMMARY Pathology of Anemias Causes • Blood loss (hemorrhage) • Increased red cell destruction (hemolysis) • Decreased red cell production Morphology • Microcytic (iron deficiency, thalassemia) • Macrocytic (folate or vitamin B12 deficiency) • Normocytic but with abnormal shapes (hereditary sphero­ cytosis, sickle cell disease) Clinical Manifestations • Acute: shortness of breath, organ failure, shock • Chronic  Pallor, fatigue, lassitude  With hemolysis: jaundice and gallstones  With ineffective erythropoiesis: iron overload, heart and endocrine failure  If severe and congenital: growth retardation, bone deformities due to reactive marrow hyperplasia ANEMIA OF BLOOD LOSS: HEMORRHAGE With acute blood loss exceeding 20% of blood volume, the immediate threat is hypovolemic shock rather than anemia If the patient survives, hemodilution begins at once and achieves its full effect within to days; only then is the full extent of the red cell loss revealed The anemia is normocytic and normochromic Recovery from blood loss anemia is enhanced by a compensatory rise in the erythropoietin level, which stimulates increased red cell production and reticulocytosis within a period of to days With chronic blood loss, iron stores are gradually depleted Iron is essential for hemoglobin synthesis and erythropoiesis, and its deficiency leads to a chronic anemia of underproduction Iron deficiency anemia can occur in other clinical settings as well; it is described later along with other anemias caused by decreased red cell production HEMOLYTIC ANEMIAS Normal red cells have a life span of about 120 days Anemias caused by accelerated red cell destruction are termed hemolytic anemias Destruction can stem from either intrinsic (intracorpuscular) red cell defects, which are usually inherited, or extrinsic (extracorpuscular) factors, which are usually acquired Examples of each type of hemolytic anemia are listed in Table 11–1 Features shared by all uncomplicated hemolytic anemias include (1) a decreased red cell life span, (2) a compensatory increase in erythropoiesis, and (3) the retention of the products of degraded red cells (including iron) by the body Because the recovered iron is efficiently recycled, red cell regeneration may almost keep pace with the hemolysis Consequently, hemolytic anemias are associated with erythroid hyperplasia in the marrow and increased numbers of reticulocytes in the peripheral blood In severe hemolytic anemias, extramedullary hematopoiesis may appear in the liver, spleen, and lymph nodes Destruction of red cells can occur within the vascular compartment (intravascular hemolysis) or within tissue macrophages (extravascular hemolysis) Intravascular hemolysis can result from mechanical forces (e.g., turbulence created by a defective heart valve) or biochemical or physical agents that damage the red cell membrane (e.g., fixation of complement, exposure to clostridial toxins, or heat) Regardless of cause, intravascular hemolysis leads to hemoglobinemia, hemoglobinuria, and hemosiderinuria The conversion of heme to bilirubin can result in unconjugated hyperbilirubinemia and jaundice Massive intravascular hemolysis sometimes leads to acute tubular necrosis (Chapter 13) Haptoglobin, a circulating protein that binds and clears free hemoglobin, is completely depleted from the plasma, which also usually contains high levels of lactate dehydrogenase (LDH) as a consequence of its release from hemolyzed red cells Extravascular hemolysis, the more common mode of red cell destruction, primarily takes place within the spleen and liver These organs contain large numbers of macrophages, the principal cells responsible for the removal of damaged or immunologically targeted red cells from the 409 410 C H A P T E R 11 Hematopoietic and Lymphoid Systems circulation Because extreme alterations of shape are necessary for red cells to navigate the splenic sinusoids, any reduction in red cell deformability makes this passage difficult and leads to splenic sequestration and phagocytosis As described later in the chapter, diminished deformability is a major cause of red cell destruction in several hemolytic anemias Extravascular hemolysis is not associated with hemoglobinemia and hemoglobinuria, but often produces jaundice and, if long-standing, leads to the formation of bilirubin-rich gallstones (pigment stones) Haptoglobin is decreased, as some hemoglobin invariably escapes from macrophages into the plasma, and LDH levels also are elevated In most forms of chronic extravascular hemolysis there is a reactive hyperplasia of mononuclear phagocytes that results in splenomegaly We now turn to some of the common hemolytic anemias Hereditary Spherocytosis This disorder stems from inherited (intrinsic) defects in the red cell membrane that lead to the formation of spherocytes, nondeformable cells that are highly vulnerable to sequestration and destruction in the spleen Hereditary spherocytosis is usually transmitted as an autosomal dominant trait; a more severe, autosomal recessive form of the disease affects a small minority of patients PATHOGENESIS Hereditary spherocytosis is caused by abnormalities in the membrane skeleton, a network of proteins that underlies lipid bilayer of the red cell (Fig 11–1) The major membrane skeleton protein is spectrin, a long, flexible heterodimer that self-associates at one end and binds short actin filaments at its other end These contacts create a twodimensional meshwork that is linked to the overlying membrane through ankyrin and band 4.2 to the intrinsic membrane protein called band 3, and through band 4.1 to glycophorin The mutations in hereditary spherocytosis most frequently involve ankyrin, band 3, and spectrin, but mutations in other components of the skeleton have also been described A shared feature of the pathogenic mutations is that they weaken the vertical interactions between the membrane skeleton and the intrinsic membrane proteins This defect somehow destabilizes the lipid bilayer of the red cells, which shed membrane vesicles into the circulation as they age Little cytoplasm is lost in the process and as a result the surface area to volume ratio decreases progressively over time until the cells become spherical (Fig 11–1) The spleen plays a major role in the destruction of spherocytes Red cells must undergo extreme degrees of deformation to pass through the splenic cords The floppy discoid shape of normal red cells allows considerable latitude for shape changes By contrast, spherocytes have limited deformability and are sequestered in the splenic cords, where they are destroyed by the plentiful resident macrophages The critical role of the spleen is illustrated by the beneficial effect of splenectomy; although the red cell defect and spherocytes persist, the anemia is corrected M O R P H O LO G Y On smears, spherocytes are dark red and lack central pallor (Fig 11–2) The excessive red cell destruction and resultant anemia lead to a compensatory hyperplasia of red cell progenitors in the marrow and an increase in red cell production marked by reticulocytosis Splenomegaly is more common and prominent in hereditary spherocytosis than in any other form of hemolytic anemia The splenic weight usually is between 500 and 1000 g The enlargement results from marked congestion of the splenic cords and increased numbers of tissue macrophages Phagocytosed red cells are seen within macrophages lining the sinusoids and, in particular, within the cords In long-standing cases there is prominent systemic hemosiderosis The other general features of hemolytic anemias also are present, including cholelithiasis, which occurs in 40% to 50% of patients with hereditary spherocytosis Spherocyte Band GP Lipid bilayer β Spectrin α 4.2 Ankyrin 4.1 α Actin β 4.1 Normal Splenic macrophage Figure 11–1  Pathogenesis of hereditary spherocytosis Left panel, Normal organization of the major red cell membrane skeleton proteins Mutations in α-spectrin, β-spectrin, ankyrin, band 4.2, and band that weaken the association of the membrane skeleton with the overlying plasma membrane cause red cells to shed membrane vesicles and transform into spherocytes (right panel ) The nondeformable spherocytes are trapped in the splenic cords and phagocytosed by macrophages GP, glycophorin Hemolytic Anemias valine for glutamic acid at the sixth amino acid residue of β-globin In homozygotes, all HbA is replaced by HbS, whereas in heterozygotes, only about half is replaced Incidence Sickle cell anemia is the most common familial hemolytic anemia in the world In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a small but significant protective effect of HbS against Plasmodium falciparum malaria In the United States, approximately 8% of blacks are heterozygous for HbS, and about in 600 have sickle cell anemia Figure 11–2  Hereditary spherocytosis—peripheral blood smear Note the anisocytosis and several hyperchromic spherocytes Howell-Jolly bodies (small nuclear remnants) are also present in the red cells of this asplenic patient (Courtesy of Dr Robert W McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.) Clinical Features The characteristic clinical features are anemia, splenomegaly, and jaundice The anemia is highly variable in severity, ranging from subclinical to profound; most commonly it is of moderate degree Because of their spherical shape, red cells in hereditary spherocytosis have increased osmotic fragility when placed in hypotonic salt solutions, a characteristic that can help establish the diagnosis The clinical course often is stable but may be punctuated by aplastic crises The most severe crises are triggered by parvovirus B19, which infects and destroys erythroblasts in the bone marrow Because red cells in hereditary spherocytosis have a shortened life span, a lack of red cell production for even a few days results in a rapid worsening of the anemia Such episodes are self-limited, but some patients need supportive blood transfusions during the period of red cell aplasia There is no specific treatment for hereditary spherocytosis Splenectomy provides relief for symptomatic patients by removing the major site of red cell destruction The benefits of splenectomy must be weighed against the risk of increased susceptibility to infections, particularly in children Partial splenectomy is gaining favor, because this approach may produce hematologic improvement while maintaining protection against sepsis Sickle Cell Anemia The hemoglobinopathies are a group of hereditary disorders caused by inherited mutations that lead to structural abnormalities in hemoglobin Sickle cell anemia, the prototypical (and most prevalent) hemoglobinopathy, stems from a mutation in the β-globin gene that creates sickle hemoglobin (HbS) Other hemoglobinopathies are infrequent and beyond the scope of this discussion Normal hemoglobins are tetramers composed of two pairs of similar chains On average, the normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2) HbS is produced by the substitution of PAT H O G E N E S I S On deoxygenation, HbS molecules form long polymers by means of intermolecular contacts that involve the abnormal valine residue at position These polymers distort the red cell, which assumes an elongated crescentic, or sickle, shape (Fig 11–3) The sickling of red cells initially is reversible upon reoxygenation However, the distortion of the membrane that is produced by each sickling episode leads to an influx of calcium, which causes the loss of potassium and water and also damages the membrane skeleton Over time, this cumulative damage creates irreversibly sickled cells, which are rapidly hemolyzed Many variables influence the sickling of red cells in vivo The three most important factors are • The presence of hemoglobins other than HbS In heterozygotes approximately 40% of Hb is HbS and the remainder is HbA, which interacts only weakly with deoxygenated HbS Because the presence of HbA greatly retards the polymerization of HbS, the red cells of heterozygotes have little tendency to sickle in vivo Such persons are said to have sickle cell trait HbC, another mutant β-globin, has a lysine residue instead of the normal glutamic acid residue at position About 2.3% of American blacks are heterozygous carriers of HbC; as a result, about in 1250 newborns are compound heterozygotes for HbC and HbS Because HbC has a greater tendency to aggregate with HbS than does HbA, HbS/HbC compound heterozygotes have a symptomatic sickling disorder called HbSC disease HbF interacts weakly with HbS, so newborns with sickle cell anemia not manifest the disease until HbF falls to adult levels, generally around the age of to months • The intracellular concentration of HbS The poly­ merization of deoxygenated HbS is strongly concentrationdependent Thus, red cell dehydration, which increases the Hb concentration, facilitates sickling Conversely, the coexistence of α-thalassemia (described later), which decreases the Hb concentration, reduces sickling The relatively low concentration of HbS also contributes to the absence of sickling in heterozygotes with sickle cell trait • The transit time for red cells through the microvasculature The normal transit times of red cells through capillaries are too short for significant polymerization of deoxygenated HbS to occur Hence, sickling in microvascular beds is confined to areas of the body in which blood flow is sluggish This is the normal situation 411 412 C H A P T E R 11 Hematopoietic and Lymphoid Systems A B Figure 11–3  Sickle cell anemia—peripheral blood smear A, Low magnification shows sickle cells, anisocytosis, poikilocytosis, and target cells B, Higher magnification shows an irreversibly sickled cell in the center (Courtesy of Dr Robert W McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.) in the spleen and the bone marrow, two tissues prominently affected by sickle cell disease Sickling also can be triggered in other microvascular beds by acquired factors that retard the passage of red cells As described previously, inflammation slows the flow of blood by increasing the adhesion of leukocytes and red cells to endothelium and by inducing the exudation of fluid through leaky vessels In addition, sickle red cells have a greater tendency than normal red cells to adhere to endothelial cells, apparently because repeated bouts of sickling causes membrane damage that make them sticky These factors conspire to prolong the transit times of sickle red cells, increasing the probability of clinically significant sickling Two major consequences arise from the sickling of red cells (Fig 11–4) First, the red cell membrane damage and dehydration caused by repeated episodes of sickling produce a chronic hemolytic anemia The mean life span of red cells in sickle cell anemia is only 20 days (one sixth of normal) Second, red cell sickling produces widespread microvascular obstructions, which result in ischemic tissue damage and pain crises Vaso-occlusion does not correlate with the number of irreversibly sickled cells and therefore appears to result from factors such as infection, inflammation, dehydration, and acidosis that enhance the sickling of reversibly sickled cells resorption and secondary new bone formation, resulting in prominent cheekbones and changes in the skull resembling a “crewcut” in radiographs Extramedullary hematopoiesis may appear in the liver and spleen In children there is moderate splenomegaly (splenic weight up to 500 g) due to red pulp congestion caused by entrapment of sickled red cells However, the chronic splenic erythrostasis produces hypoxic damage and infarcts, which over time reduce the spleen to a useless nubbin of fibrous A G T C T Point C G mutation C HbA G C A HbS RBC Deoxygenation Irreversibly sickled cell Hemolysis MORPHOLOGY The anatomic alterations in sickle cell anemia stem from (1) the severe chronic hemolytic anemia, (2) the increased breakdown of heme to bilirubin, and (3) microvascular obstructions, which provoke tissue ischemia and infarction In peripheral smears, elongated, spindled, or boat-shaped irreversibly sickled red cells are evident (Fig 11–3) Both the anemia and the vascular stasis lead to hypoxia-induced fatty changes in the heart, liver, and renal tubules There is a compensatory hyperplasia of erythroid progenitors in the marrow The cellular proliferation in the marrow often causes bone G Reversibly sickled cell Microvascular occlusion Ca2+ Extensive membrane damage Deoxygenation, prolonged transit times K+, H2O Oxygenation Additional cycles of deoxygenation Cell with dehydration and membrane damage Figure 11–4  Pathophysiology of sickle cell disease Hemolytic Anemias tissue This process, referred to as autosplenectomy, is complete by adulthood Vascular congestion, thrombosis, and infarction can affect any organ, including the bones, liver, kidney, retina, brain, lung, and skin The bone marrow is particularly prone to ischemia because of its sluggish blood flow and high rate of metabolism Priapism, another frequent problem, can lead to penile fibrosis and erectile dysfunction As with the other hemolytic anemias, hemosiderosis and gallstones are common Clinical Course Homozygous sickle cell disease usually is asymptomatic until months of age when the shift from HbF to HbS is complete The anemia is moderate to severe; most patients have hematocrits 18% to 30% (normal range, 36% to 48%) The chronic hemolysis is associated with hyperbilirubinemia and compensatory reticulocytosis From its onset, the disease runs an unremitting course punctuated by sudden crises The most serious of these are the vaso-occlusive, or pain, crises The vaso-occlusion in these episodes can involve many sites but occurs most commonly in the bone marrow, where it often progresses to infarction A feared complication is the acute chest syndrome, which can be triggered by pulmonary infections or fat emboli from infarcted marrow The blood flow in the inflamed, ischemic lung becomes sluggish and “spleenlike,” leading to sickling within hypoxemic pulmonary beds This exacerbates the underlying pulmonary dysfunction, creating a vicious circle of worsening pulmonary and systemic hypoxemia, sickling, and vaso-occlusion Another major complication is stroke, which sometimes occurs in the setting of the acute chest syndrome Although virtually any organ can be damaged by ischemic injury, the acute chest syndrome and stroke are the two leading causes of ischemia-related death A second acute event, aplastic crisis, is caused by a sudden decrease in red cell production As in hereditary spherocytosis, this usually is triggered by the infection of erythroblasts by parvovirus B19 and, while severe, is self-limited In addition to these crises, patients with sickle cell disease are prone to infections Both children and adults with sickle cell disease are functionally asplenic, making them susceptible to infections caused by encapsulated bacteria, such as pneumococci In adults the basis for “hyposplenism” is autoinfarction In the earlier childhood phase of splenic enlargement, congestion caused by trapped sickled red cells apparently interferes with bacterial sequestration and killing; hence, even children with enlarged spleens are at risk for development of fatal septicemia Patients with sickle cell disease also are predisposed to Salmonella osteomyelitis, possibly in part because of poorly understood acquired defects in complement function In homozygous sickle cell disease, irreversibly sickled red cells are seen in routine peripheral blood smears In sickle cell trait, sickling can be induced in vitro by exposing cells to marked hypoxia The diagnosis is confirmed by electrophoretic demonstration of HbS Prenatal diagnosis of sickle cell anemia can be performed by analyzing fetal DNA obtained by amniocentesis or biopsy of chorionic villi The clinical course is highly variable As a result of improvements in supportive care, an increasing number of patients are surviving into adulthood and producing offspring Of particular importance is prophylactic treatment with penicillin to prevent pneumococcal infections Approximately 50% of patients survive beyond the fifth decade By contrast, sickle cell trait causes symptoms rarely and only under extreme conditions, such as after vigorous exertion at high altitudes A mainstay of therapy is hydroxyurea, a “gentle” inhibitor of DNA synthesis Hydroxyurea reduces pain crises and lessens the anemia through several beneficial intracorpuscular and extracorpuscular effects, including (1) an increase in red cell levels of HbF; (2) an anti-inflammatory effect due to the inhibition of white cell production; (3) an increase in red cell size, which lowers the mean cell hemoglobin concentration; and (4) its metabolism to NO, a potent vasodilator and inhibitor of platelet aggregation Encouraging results also have been obtained with allogeneic bone marrow transplantation, which has the potential to be curative Thalassemia The thalassemias are inherited disorders caused by mutations that decrease the synthesis of α- or β-globin chains As a result, there is a deficiency of Hb and additional red cell changes due to the relative excess of the unaffected globin chain The mutations that cause thalassemia are particularly common among populations in Mediterranean, African, and Asian regions in which malaria is endemic As with HbS, it is hypothesized that globin mutations associated with thalassemia are protective against falciparum malaria PAT H O G E N E S I S A diverse collection of α-globin and β-globin mutations underlies the thalassemias, which are autosomal codominant conditions As described previously, adult hemoglobin, or HbA, is a tetramer composed of two α chains and two β chains The α chains are encoded by two α-globin genes, which lie in tandem on chromosome 11, while the β chains are encoded by a single β-globin gene located on chromosome 16 The clinical features vary widely depending on the specific combination of mutated alleles that are inherited by the patient (Table 11–3), as described next β-Thalassemia The mutations associated with β-thalassemia fall into two categories: (1) β0, in which no β-globin chains are produced; and (2) β+, in which there is reduced (but detectable) β-globin synthesis Sequencing of β-thalassemia genes has revealed more than 100 different causative mutations, a majority consisting of single-base changes Persons inheriting one abnormal allele have β-thalassemia minor (also known as β-thalassemia trait), which is asymptomatic or mildly symptomatic Most people inheriting any two β0 and β+ alleles have β-thalassemia major; occasionally, persons inheriting two β+ alleles have a milder disease termed β-thalassemia intermedia In contrast with α-thalassemias (described 413 414 C H A P T E R 11 Hematopoietic and Lymphoid Systems Table 11–3  Clinical and Genetic Classification of Thalassemias Clinical Syndrome Genotype Clinical Features Molecular Genetics β-Thalassemia major Homozygous β-thalassemia (β0/β0, β+/β+, β0/β+) Severe anemia; regular blood transfusions required Mainly point mutations that lead to defects in the transcription, splicing, or translation of β-globin mRNA β-Thalassemia intermedia Variable (β0/β+, β+/β+, β0/β, β+/β) Severe anemia, but regular blood transfusions not required β-Thalassemia minor Heterozygous β-thalassemia (β0/β, β+/β) Asymptomatic with mild or absent anemia; red cell abnormalities seen Silent carrier −/α, α/α Asymptomatic; no red cell abnormality α-Thalassemia trait −/−, α/α (Asian) −/α, −/α (black African, Asian) Asymptomatic, like β-thalassemia minor HbH disease −/−, −/α Severe; resembles β-thalassemia intermedia Hydrops fetalis −/−, −/− Lethal in utero without transfusions β-Thalassemias α-Thalassemias Mainly gene deletions HgH, hemoglobin H; mRNA, messenger ribonucleic acid later), gene deletions rarely underlie β-thalassemias (Table 11–3) The mutations responsible for β-thalassemia disrupt β-globin synthesis in several different ways (Fig 11–5): • Mutations leading to aberrant RNA splicing are the most common cause of β-thalassemia Some of these mutations disrupt the normal RNA splice junctions; as a result, no mature mRNA is made and there is a complete failure of β-globin production, creating β0 Other mutations create new splice junctions in abnormal positions—within an intron, for example Because the normal splice sites are intact, both normal and abnormal splicing occurs, and some normal β-globin mRNA is made These alleles are designated β+ • Some mutations lie within the β-globin promoter and lower the rate of β-globin gene transcription Because some normal β-globin is synthesized, these are β+ alleles • Other mutations involve the coding regions of the βglobin gene, usually with severe consequences For example, some single-nucleotide changes create termination (“stop”) codons that interrupt the translation of β-globin mRNA and completely prevent the synthesis of β-globin Two mechanisms contribute to the anemia in β-thalassemia The reduced synthesis of β-globin leads to inadequate HbA formation and results in the production of poorly hemoglobinized red cells that are pale (hypochromic) and small in size (microcytic) Even more important is the imbalance in β-globin and α-globin chain synthesis, as this creates an excess of unpaired α chains that aggregate into insoluble precipitates, which bind and severely damage the membranes of both red cells and erythroid precursors A high fraction of the damaged erythroid precursors die by apoptosis (Fig 11–6), a phenomenon termed ineffective erythropoiesis, and the few red cells that are produced have a shortened life span due to extravascular hemolysis Ineffective hematopoiesis has another untoward effect: It is associated with an inappropriate increase in the absorption of dietary iron, which without medical intervention inevitably leads to iron overload The increased iron absorption is caused by inappropriately low levels of hepcidin, which is a negative regulator of iron absorption (see later) 5´ 3´ Exon-1 Promoter sequence b+Thal Exon-2 b0Thal Exon-3 b0Thal b+Thal Transcription defect RNA splicing defect Translation defect Figure 11–5  Distribution of β-globin gene mutations associated with β-thalassemia Arrows denote sites at which point mutations giving rise to β+ or β0 thalassemia have been identified Hemolytic Anemias b-THALASSEMIA NORMAL Reduced b-globin synthesis, with relative excess of a-globin HbA (a2b2) Insoluble a-globin aggregate HbA Normal erythroblast Abnormal erythroblast Few abnormal red cells leave a-globin aggregate Normal HbA Hypochromic red cell Normal red blood cells Ineffective erythropoiesis Most erythroblasts die in bone marrow Dietary iron Extravascular hemolysis Destruction of aggregate-containing red cells in spleen ANEMIA Increased iron absorption Blood transfusions Tissue hypoxia Reduce Heart Liver Erythropoietin increase Marrow expansion Systemic iron overload (secondary hemochromatosis) Skeletal deformities Figure 11–6  Pathogenesis of β-thalassemia major Note that aggregates of excess α-globin are not visible on routine blood smears Blood transfusions constitute a double-edged sword, diminishing the anemia and its attendant complications but also adding to the systemic iron overload α-Thalassemia Unlike β-thalassemia, α-thalassemia is caused mainly by deletions involving one or more of the α-globin genes The severity of the disease is proportional to the number of α-globin genes that are missing (Table 11–3) For example, the loss of a single α-globin gene produces a silentcarrier state, whereas the deletion of all four α-globin genes is lethal in utero because the red cells have virtually no oxygen-delivering capacity With loss of three α-globin genes there is a relative excess of β-globin or (early in life) γ-globin chains Excess β-globin and γ-globin chains form relatively stable β4 and γ4 tetramers known as HbH and Hb Bart, respectively, which cause less membrane damage than the free α-globin chains that are found in β-thalassemia; as a result, ineffective erythropoiesis is less pronounced in α-thalassemia Unfortunately, both HbH and Hb Bart have an abnormally high affinity for oxygen, which renders them ineffective at delivering oxygen to the tissues M O R P H O LO G Y A range of pathologic features are seen, depending on the specific underlying molecular lesion On one end of the spectrum is β-thalassemia minor and α-thalassemia trait, in which the abnormalities are confined to the peripheral blood In smears the red cells are small (microcytic) and pale (hypochromic), but regular in shape Often seen are target cells, cells with an increased surface area-to-volume ratio that allows the cytoplasm to collect in a central, dark-red “puddle.” On the other end of the spectrum, in β-thalassemia major, peripheral blood smears show marked microcytosis, hypochromia, poikilocytosis (variation in cell size), and anisocytosis (variation in cell shape) Nucleated red cells (normoblasts) are also seen that reflect the underlying erythropoietic drive β-Thalassemia intermedia and HbH disease are associated with peripheral smear findings that lie between these two extremes 415 416 C H A P T E R 11 Hematopoietic and Lymphoid Systems The anatomic changes in β-thalassemia major are similar in kind to those seen in other hemolytic anemias but profound in degree The ineffective erythropoiesis and hemolysis result in a striking hyperplasia of erythroid progenitors, with a shift toward early forms The expanded erythropoietic marrow may completely fill the intramedullary space of the skeleton, invade the bony cortex, impair bone growth, and produce skeletal deformities Extramedullary hematopoiesis and hyperplasia of mononuclear phagocytes result in prominent splenomegaly, hepatomegaly, and lymphadenopathy The ineffective erythropoietic precursors consume nutrients and produce growth retardation and a degree of cachexia reminiscent of that seen in cancer patients Unless steps are taken to prevent iron overload, over the span of years severe hemosiderosis develops (Fig 11–6) HbH disease and β-thalassemia intermedia are also associated with splenomegaly, erythroid hyperplasia, and growth retardation related to anemia, but these are less severe than in β-thalassemia major Clinical Course β-Thalassemia minor and α-thalassemia trait (caused by deletion of two α-globin genes) are often asymptomatic There is usually only a mild microcytic hypochromic anemia; generally, these patients have a normal life expectancy Iron deficiency anemia is associated with a similar red cell appearance and must be excluded by appropriate laboratory tests (described later) β-Thalassemia major manifests postnatally as HbF synthesis diminishes Affected children suffer from growth retardation that commences in infancy They are sustained by repeated blood transfusions, which improve the anemia and reduce the skeletal deformities associated with excessive erythropoiesis With transfusions alone, survival into the second or third decade is possible, but systemic iron overload gradually develops owing to inappropriate uptake of iron from the gut and the iron load in transfused red cells Unless patients are treated aggressively with iron chelators, cardiac dysfunction from secondary hemochromatosis inevitably develops and often is fatal in the second or third decade of life When feasible, bone marrow transplantation at an early age is the treatment of choice HbH disease (caused by deletion of three α-globin genes) and β-thalassemia intermedia are not as severe as β-thalassemia major, since the imbalance in α- and β-globin chain synthesis is not as great and hematopoiesis is more effective Anemia is of moderate severity and patients usually not require transfusions Thus, the iron overload that is so common in β-thalassemia major is rarely seen The diagnosis of β-thalassemia major can be strongly suspected on clinical grounds Hb electrophoresis shows profound reduction or absence of HbA and increased levels of HbF The HbA2 level may be normal or increased Similar but less profound changes are noted in patients affected by β-thalassemia intermedia Prenatal diagnosis of β-thalassemia is challenging due to the diversity of causative mutations, but can be made in specialized centers by DNA analysis In fact, thalassemia was the first disease diagnosed by DNA-based tests, opening the way for the field of molecular diagnostics The diagnosis of β-thalassemia minor is made by Hb electrophoresis, which typically reveals a reduced level of HbA (α2β2) and an increased level of HbA2 (α2δ2) HbH disease can be diagnosed by detection of β4 tetramers by electrophoresis Glucose-6-Phosphate Dehydrogenase Deficiency Red cells are constantly exposed to both endogenous and exogenous oxidants, which are normally inactivated by reduced glutathione (GSH) Abnormalities affecting the enzymes responsible for the synthesis of GSH leave red cells vulnerable to oxidative injury and lead to hemolytic anemias By far the most common of these anemias is that caused by glucose-6-phosphate dehydrogenase (G6PD) deficiency The G6PD gene is on the X chromosome More than 400 G6PD variants have been identified, but only a few are associated with disease One of the most important variants is G6PD A−, which is carried by approximately 10% of black males in the United States G6PD A− has a normal enzymatic activity but a decreased half-life Because red cells not synthesize proteins, older G6PD A− red cells become progressively deficient in enzyme activity and the reduced form of glutathione This in turn renders older red cells more sensitive to oxidant stress PAT H O G E N E S I S G6PD deficiency produces no symptoms until the patient is exposed to an environmental factor (most commonly infectious agents or drugs) that produces oxidants The drugs incriminated include antimalarials (e.g., primaquine), sulfonamides, nitrofurantoin, phenacetin, aspirin (in large doses), and vitamin K derivatives More commonly, episodes of hemolysis are triggered by infections, which induce phagocytes to generate oxidants as part of the normal host response These oxidants, such as hydrogen peroxide, are normally sopped up by GSH, which is converted to oxidized glutathione in the process Because regeneration of GSH is impaired in G6PD-deficient cells, oxidants are free to “attack” other red cell components including globin chains, which have sulfhydryl groups that are susceptible to oxidation Oxidized hemoglobin denatures and precipitates, forming intracellular inclusions called Heinz bodies, which can damage the cell membrane sufficiently to cause intravascular hemolysis Other, less severely damaged cells lose their deformability and suffer further injury when splenic phagocytes attempt to “pluck out” the Heinz bodies, creating so-called bite cells (Fig 11–7) Such cells become trapped upon recirculation to the spleen and are destroyed by phagocytes (extravascular hemolysis) Clinical Features Drug-induced hemolysis is acute and of variable severity Typically, patients develop hemolysis after a lag of or days Since G6PD is X-linked, the red cells of affected males are uniformly deficient and vulnerable to oxidant injury By contrast, random inactivation of one X chromosome in heterozygous females (Chapter 6) creates two populations of red cells, one normal and the other G6PD-deficient Most carrier females are unaffected except for those with a large proportion of deficient red cells (a chance situation known as unfavorable lyonization) In the case of the G6PD 896 Index Myxomatous mitral valve clinical features of  390–391 degenerative valve disease as  390–391 morphology of  390b, 390f pathogenesis of  390b N Nasopharyngeal carcinoma  513 Natural killer (NK) cell  105, 125–131 as antitumor effector mechanisms  206 Necrosis clinicopathologic correlation examples for  16–18 morphology of  6f, 9b morphology of cell and tissue injury and  patterns of  9–11 morphology of  10b–11b, 10f–11f Necrotizing arteriolitis  333b–334b Necrotizing enterocolitis (NEC) discussion of  252, 252f premature infants and  249 preterm birth complications and  251 Necrotizing glomerulonephritis, focal and segmental  353b–354b Necrotizing granulomatous vasculitis  353b–354b, 353f Necrotizing vasculitis  117b Necrotizing vasculitis, acute  128 Necrotizing vasculitis, noninfectious  135 Neoplasia See also Tumor, benign; Tumor, malignant cancer and etiology of  198–204 genetic lesions in  173–176 molecular basis of cancer and  173 process of carcinogenesis and  177 tumor immunity and  204–207 characteristics of  164–169, 169f clinical aspects of  207–213 effects of tumor on host and  207–208 grading/staging of  207–208 laboratory diagnosis of  210–213 summary for  209b–210b discussion of  161–162 epidemiology of  169–172 nomenclature for  162–163, 164t Neoplasm characteristics of differentiation/anaplasia and  164–166 local invasion and  167–168 metastasis and  168–169 rate of growth and  166–167 summary for  169b of the penis  657–658, 658f summary of  658b of the salivary glands  555–557, 556t mucoepidermoid carcinoma as  557 pleomorphic adenoma as  556 Neoplasm, benign differentiation and anaplasia of  164 local invasion and  167f–168f metastasis and  168–169 nomenclature for  162 rate of growth of  166–167 summary for  169b, 169f Neoplasm, embryonal  844–845 medulloblastoma as  844–845 neuroectodermal tumors and  844–845 Neoplasm, malignant differentiation and anaplasia of  164–165, 165f local invasion and  167–168, 167f–168f metastasis and  168–169 nomenclature for  162–163 rate of growth of  166 summary for  169b, 169f Neovascularization  251 Nephritic syndrome acute postinfectious glomerulonephritis as  529 glomerular disease and  529–531 hereditary nephritis as  531 IgA nephropathy as  530–531 renal syndromes and  517–518 summary for  531b Nephritis, hereditary clinical course of  531 morphology of  531b nephritic syndromes and  531 pathogenesis of  531b summary for  531 Nephrolithiasis  518 Nephron loss  523 Nephrosclerosis  333b–334b Nephrotic syndrome amyloidosis and  158 focal segmental glomerulosclerosis as  525–526 and glomerular disease  523–528, 524t membranoproliferative glomerulonephritis and dense deposit disease as  527–528 membranous nephropathy as  526–527 minimal-change disease as  524–525 renal diseases and  518 summary for  528b–529b Nervous system infections of  824–831 epidural and subdural infections of  824–825 meningitis as  825–826 parenchymal infections and  826–831 prion diseases and  831 summary for  832b patterns of injury in morphology of  811b–812b, 812f Neural tube defect  822–823, 823f Neuroblastic  258–259 Neuroblastoma of the adrenal medulla  761 clinical course and prognosis for  259–260, 260t discussion of  258–260 morphology of  259b, 259f summary for  260b Neuroborreliosis  826 Neurodegenerative disease Alzheimer disease as  836–837 amyotrophic lateral sclerosis as  841 of the central nervous system  836–841, 836t frontotemporal lobar degeneration as  838 Huntington disease as  840 Parkinson disease as  839–840 spinocerebellar ataxias as  840–841 summary of  841b–842b Neurofibroma morphology of  808b of peripheral nerve sheath  807–808 Neurofibroma, diffuse  807, 808b Neurofibroma, localized cutaneous  807 Neurofibromatosis type 1  808 Neurofibromatosis type 1, familial  179–180 Neurofibromatosis type (NF2)  806–807 Neurohypophysis See Posterior pituitary syndrome Index Neuromuscular junction, disorders of introduction to  800–801 Lambert-Eaton syndrome as  801 miscellaneous disorders of  801 myasthenia gravis as  800–801 summary for  801b Neuromyelitis optica (NMO)  834 Neuropeptides  49 Neurosyphilis  826 Neutropenia  425–426 Neutrophil extracellular trap (NET)  39, 40f Nevus flammeus  357 Newborn, hemolytic disease in  254 NextGen sequencing  265–266, 267f NF2  187–188 Niemann-Pick disease types A and B  230–231, 230f Niemann-Pick disease types C (NPC)  231 Night blindness  297 Nitric oxide (NO)  49–50 Nodular fasciitis  793 Nomenclature benign tumors and  162 malignant tumors and  162–163 for neoplasia  162–163 Nonalcoholic fatty liver disease (NAFLD) introduction to  625 pathogenesis of  625b summary for  625b Nonbacterial thrombotic endocarditis (NBTE)  394–395, 395f Non-coding RNA (ncRNA)  217–218, 217f Nongonococcal urethritis (NGU)  676 summary for  676b Non-infected vegetation Libman-Sacks endocarditis as  395 nonbacterial thrombotic endocarditis as  394–395 Noninfectious vasculitis anti-endothelial cell antibodies as  350 anti-neutrophil cytoplasmic antibodies as  349–350 immune complex-associated vasculitis as  348–350 Nonspecific interstitial pneumonia (NSIP)  473 Nontuberculous mycobacterial disease as chronic pneumonia  499 Norovirus  585 Noxious stimuli, cellular responses to  1–3, 2f Nuclear transcription factor  180 Numeric abnormality, cytogenetic disorders and  235 Nutmeg liver  368 Nutritional disease anorexia nervosa/bulimia as  295–296 diet and cancer as  306 diet and systemic diseases as  306 discussion of  293–306 malnutrition as  293–294 neurologic illnesses and  835 obesity as  302–305 protein-energy malnutrition as  294–295 summary for  302b Nutritional imbalance, cell injury and  O Obesity adipose tissue and  304–305 clinical consequences of  305 gut hormones and  305 leptin and  304 nutritional diseases and  302–305 summary for  305b Obligate intracellular bacteria  311 Obstructive lesion, aortic coarctation and  373–374 Obstructive lung disease asthma as  468–470 bronchiectasis as  470–472 chronic bronchitis as  467 discussion of  463–472, 463t, 464f emphysema as  463–466 Obstructive overinflation  466 Occupational asthma  470 Occupational cancer  171t Oligodendroglioma  843 morphology of  843b–844b, 844f Oligohydramnios sequence  246–247, 247f Oncocytoma  547 Oncofetal antigens  206 Oncogene  173, 182 Oncogene, mutated  204–205 Oncogene addiction  180 Oncology  162 Onion-skin lesion  130 Opsonization  114–115, 115f, 117 Oral candidiasis (thrush)  552 Oral cavity disease of salivary glands and  555–557 odontogenic cysts and tumors of  557–558 oral inflammatory lesions of  552 proliferative and neoplastic lesions of  552–554 summary for  554b Oral contraceptive (OC)  283–284 Oral inflammatory lesion aphthous ulcers as  552 herpes simplex virus infections as  552 oral candidiasis as  552 summary for  552b Organic solvent  276 Organochlorine  276 Organ systems, ionizing radiation effects and  292–293, 292f, 292t Osler-Weber-Rendu disease See Hereditary hemorrhagic telangiectasia Osteitis deformans See Paget disease Osteoarthritis clinical course of  783, 783f the joints and  782–790 morphology of  782b–783b, 782f obesity and  305 pathogenesis of  783b summary for  790 Osteoblastoma  776 morphology of  776b Osteochondroma as cartilage-forming tumors  777–778, 777f clinical features of  778 morphology of  778b summary for  781 Osteogenesis imperfecta (OI)  767–768 Osteoid osteoma as bone-forming tumor  776 morphology of  776b, 776f summary for  781 Osteoma  775–776 Osteomalacia acquired bone disease and  771 morphology of  300b–301b vitamin D and  298–300 Osteomyelitis acquired diseases of bone and  773–774 pyogenic osteomyelitis as  773–774 tuberculous osteomyelitis as  774 897 Index 898 Osteopetrosis  767–768 Osteoporosis acquired bone disease and  768–770, 769t, 772 clinical course of  770 exogenous estrogens and  282–283 morphology of  768b–769b, 769f pathogenesis of  766f, 769b–770b, 769f vitamin D and  299–300 Osteosarcoma bone tumors as  776–777 clinical features of  777 morphology of  776b–777b, 776f pathogenesis of  777b summary for  782 Ostium primum ASD  371b Ostium secundum ASD  371b Outdoor air pollution  272–273 morphology of  273b Ovary follicle and luteal cysts and  695 other tumors of  698–700, 699t polycystic ovarian disease and  695–696 tumors of  696–698 Oxidative stress See Free radicals, oxygen-derived Oxygen deprivation  Ozone  272–273, 272t P Paget disease (osteitis deformans) acquired bone disease as  770–771 clinical course of  771 morphology of  770b, 770f pathogenesis of  771b summary for  772 Paget disease, extramammary  683–684, 684f summary of  684 Paget disease of the nipple  710 Panacinar emphysema  464, 464f, 465b Pancarditis  391b Pancreas congenital anomalies of agenesis and  646 annular pancreas as  646 congenital cysts as  646 ectopic pancreas as  646 pancreas divisum as  646 overview of  645 pancreatic neoplasms and  651–654 pancreatitis and  646–651 Pancreas, congenital cysts of  646 Pancreas, ectopic  646 Pancreas, endocrine diabetes mellitus and  739–750 pancreatic neuroendocrine tumors and  751–752 Pancreas divisum  646 Pancreatic abnormality  223–227 Pancreatic carcinoma clinical features of  654 introduction to  652–654 morphology of  653b–654b, 654f pathogenesis of  653b, 653f Pancreatic neoplasm cystic neoplasms as  651–652 intraductal papillary mucinous neoplasms as  652 mucinous cystic neoplasms as  652 serous cystadenomas as  651 pancreatic carcinoma and  652–654 summary for  654b Pancreatic neuroendocrine tumor (PanNET) endocrine pancreas and  751–752 gastrinomas and  752 insulinomas and  751 Pancreatic pseudocyst acute pancreatitis and  649 morphology of  649b, 649f Pancreatitis acute pancreatitis and  646–649 chronic pancreatitis and  649–651 and the pancreas  646–651 summary for  651b Pancreatitis, acute clinical features of  648–649 inflammatory disorders of  646–649, 646t morphology of  647b, 647f pancreatic pseudocysts as  648–649 pathogenesis of  647b–648b, 648f Pancreatitis, chronic clinical features of  651 morphology of  650b, 650f the pancreas and  649–651 pathogenesis of  650b Pancreatitis, hemorrhagic  647b Pancreatitis, lymphoplasmacytic sclerosing  650b Pancytopenia  442–443 Papanicolaou smear See Cytologic (Papanicolaou) smear Papillary carcinoma of the thyroid clinical features of  733 morphology of  732b–733b, 732f summary for  735 the thyroid and  732–733 Papillary fibroelastoma  405 Papillary muscle dysfunction  383–384 Papilloma  162 Paraneoplastic syndromes  208–209, 209t Parasitic disease  585–586 Parathyroid carcinoma  736b–737b Parathyroid gland endocrine system and  735–738 hyperparathyroidism and  735–738 hypoparathyroidism and  738 Parathyroid hyperplasia  736b–737b Parenchymal hemorrhage, primary brain  817, 817f, 819 morphology of  817b Parenchymal infection arboviruses and  827 brain abscesses and  826 cytomegalovirus and  828 fungal encephalitis and  829 herpesviruses and  827–828 human immunodeficiency virus and  828 of nervous system  826–831 other meningoencephalitides as  829–831 poliovirus and  828 polyomavirus and progressive multifocal leukoencephalopathy as  828–829 rabies virus and  828 viral encephalitis and  826–829 Parenchymal injury, traumatic  820–821 morphology of  820b, 820f Parkinson disease (PD) clinical features of  839–840 morphology of  839b, 839f parkinsonism and  839–840 pathogenesis of  839b Index Paroxysmal nocturnal hemoglobinuria (PHN) hemolytic anemias and  417 pathogenesis of  417b Parvovirus B19  255–256, 256f Passive congestion circulatory disorders of liver and  633 morphology of  633b, 633f Passive smoke inhalation See Tobacco smoke, environmental Patent ductus arteriosus clinical features of  372 left-to-right shunts and  369t, 370f, 371–372 Patent foramen ovale  370–371 Pathology, introduction to  Pediatric disease congenital anomalies and  245–248, 246f fetal hydrops and  254–257 introduction to  245–268, 245t molecular diagnosis of Mendelian/complex disorders and  263–268 necrotizing enterocolitis and  252 perinatal infections and  249 prematurity/fetal growth restrictions and  249–250 respiratory distress syndrome and  250–251 sudden infant death syndrome and  252–254 tumors/tumor-like lesions and  257–262 Pemphigus (vulgaris and foliaceus) blistering disorders and  858–859, 862 clinical features of  859 morphology of  859b, 859f–860f pathogenesis of  858b–859b, 859f Penis inflammatory lesions of  657 malformations of  657 neoplasms of  657–658 Peptic ulceration, acute clinical features of  565 inflammatory disease of the stomach and  565 morphology of  565b pathogenesis of  565b Peptic ulcer disease (PUD) clinical features of  568–569 epidemiology of  568 inflammatory diseases of the stomach and  568–569 morphology of  568b, 568f pathogenesis of  565f, 568b Peptide display system  123–125 Pericardial disease heart diseases and  403–404 pericardial effusions as  404 pericarditis as  403–404 Pericardial effusion  404 Pericarditis clinical features of  403–404 morphology of  403b, 403f pericardial disease as  384, 403–404 Pericarditis, acute bacterial  403b Pericarditis, chronic  403b Pericarditis, constrictive  403b Perinatal infection  249 Peripheral nerve disorder introduction to  797–799, 798f nerve injury disorders and  798–799 patterns of injury and  797–798 summary for  800b Peripheral nerve injury disorders associated with  799t chronic inflammatory demyelinating polyneuropathy as  799 diabetic peripheral neuropathy as  799 Guillain-Barre syndrome as  798–799 summary for  800b toxic, vasculitic, inherited forms of  799–800 patterns of  797–798, 798f Peripheral nerve sheath malignant tumors of  808 neurofibromas as  807 neurofibromatosis type as  808 Schwannomas and neurofibromatosis type as  806–807 traumatic neuroma as  808 tumors of  806–808 Peripheral nerve sheath schwannoma  806–808 morphology of  807b, 807f Peripheral nerve sheath tumor, malignant  808 morphology of  808b Peripheral neuropathy summary for  800b toxic, vasculitic, inherited forms of  799, 800f Peripheral T cell lymphoma  443 Peutz-Jeghers syndrome  592–593, 594f Phagocyte oxidase  143 Phagocytosis  37–39, 39f, 112f, 114–115 Phenylketonuria (PKU)  227–228, 227f summary for  228, 228b Pheochromocytoma adrenal medulla tumors and  760–761 clinical features of  761 morphology of  760b–761b, 760f–761f Phlebothrombosis  356 See also Venous thrombosis Phyllodes tumor  707 Physical agent cell injury and  injury by electrical injury and  289 ionizing radiation and  289–293 mechanical trauma as  287 thermal injury and  288–289 toxicity of  271–272 Pickwickian syndrome  305 Pigeon breast deformity  300 Pigment  24, 25f Pilocytic astrocytoma  842–843 morphology of  843b Pituitary adenoma adrenocorticotropic hormone producing adenomas as  719–720 growth hormone producing adenomas as  719 morphology of  718b, 718f–719f other anterior pituitary neoplasms as  720 pathogenesis of  718b and pituitary gland  717–720, 717t (See also Hyperpituitarism) prolactinomas as  719 summary of  719, 720b Pituitary adenoma, nonfunctioning  720 Pituitary carcinoma  720 Pituitary gland as endocrine system  716–721, 716f–717f hyperpituitarism/pituitary adenomas and  717–720 hypopituitarism and  720–721 posterior pituitary syndromes and  721 prolactinomas and  719 PKU See Phenylketonuria (PKU) Placental-fetal transmission  318 Placental inflammation/infection  701 899 900 Index Plasma protein-derived mediator coagulation and Kinin system as  51–52 complement system as  50–51, 50f summary for  52b Plasminogen activator inhibitor (PAI)  80, 85f Platelet activation of  80, 82 adhesion and  82 aggregation of  82 discussion of  81–82 endothelial interaction with  81f, 82 normal hemostasis and  80f normal hemostasis and  79 summary for  82b Platelet-activating factor (PAF)  47–48 Platelet activation  82, 82b Platelet adherence  79 Platelet adhesion  80f–81f, 82 Platelet aggregation  81f, 82, 82b Platelet contraction  82 Pleiotropy  218–219 Pleomorphic undifferentiated sarcoma  794 Pleomorphic adenoma  163, 556–557, 557f morphology of  556b–557b Pleomorphic fibroblastic sarcoma  794, 794f Pleomorphism  165, 165f Pleural effusion  511 Pleural lesion of the lungs  511–512 malignant mesothelioma as  512 pleural effusion and pleuritis as  511 pneumothorax, hemothorax, chylothorax as  511–512 Pleuritis  511 Plexiform neurofibroma  807, 808b Plummer syndrome  728b Pneumoconiosis asbestosis as  477 coal worker’s pneumoconiosis as  475 as fibrosing disease  474–478, 474t mineral dust and  277 pathogenesis of  474b–475b silicosis as  476 summary for  478b Pneumocystis pneumonia in the immunocompromised host  501–502 morphology of  502b, 502f Pneumonia caused by other pathogens Haemophilus influenzae as  489 Klebsiella pneumoniae as  489–490 Legionella pneumophila as  490 Moraxella catarrhalis as  489 Pseudomonas aeruginosa as  490 Staphylococcus aureus as  489 community-acquired acute morphology of  488b, 489f pneumonias caused by other important pathogens and  488–490 as pulmonary infection  486–490 streptococcus pneumoniae infections as  487–488 community-acquired atypical clinical features of  490–491 influenza infections as  491 influenza virus type A/HINI infection as  491 morphology of  490b, 491f as pulmonary infections  490–491 summary for  491b in the immunocompromised host cytomegalovirus infections and  500–501 pneumocystis pneumonia and  501–502 as pulmonary infection  500–502 Pneumonia (P jiroveci) HIV infections and  151, 151t, 313 Pneumonia, chronic nontuberculous mycobacterial disease as  499 as pulmonary infection  492–499 tuberculosis and  493–498 Pneumonia, cryptogenic organizing  473–474, 474f Pneumonia, hospital-acquired  491–492 Pneumothorax  511 Podocyte injury  522f, 523, 528 Poliovirus  828 Pollution, environmental air pollution as  272–273 industrial/agricultural exposures as  276–277 metals as  273–276 Polyarteritis nodosa (PAN) autoimmune diseases and  135 clinical features of  352 morphology of  352b, 352f vasculitis and  352 Polycystic kidney disease, autosomal recessive clinical course of  544 cystic diseases and  544 morphology of  544b summary for  544 Polycystic ovarian disease  695–696 Polycythemia  425, 425t Polycythemia vera as chronic myeloproliferative disorder  447 clinical course of  447–448 morphology of  447b Polymerase chain reaction (PCR) analysis  264–266, 266f Polymerase chain reaction (PCR) analysis molecular diagnosis and  211 Polymorphism complex multigenic disorders and  234 genetic abnormalities and  216–217 linkage analysis and  245–246 P-450 enzymes and  271–272 Polymyositis  805, 806f Polyneuritis multiplex  798 Polyneuropathy  798 Polyomavirus  828–829 Polyp, endometrial  693 Polyp, hamartomatous colonic polyps and  592–593, 593t, 600 juvenile polyps as  592 Peutz-Jeghers syndrome as  592–593 Polyp, inflammatory colonic polyps as  592, 600 gastric polyps and  569, 572 morphology of  569b Polyp, juvenile  592 morphology of  592b, 594f Polyp, nomenclature for  162, 163f Polypoid cystitis (ureter)  668 Portal hypertension ascites and  609 liver disease and  608–609, 609f Portal vein obstruction/thrombosis  632–634 Portopulmonary hypertension  610 Port wine stain  357 Posterior fossa anomaly  823 Posterior pituitary syndrome  721 Index Postmortem clot  88b–89b Postnatal genetic analysis  268 Potter sequence See Oligohydramnios sequence Prader-Willi syndrome  243–245, 244f Preeclampsia/eclampsia clinical features of  704 diseases of pregnancy and  703–704 morphology of  704b summary for  704b Pregnancy, diseases of ectopic pregnancy as  701 gestational trophoblastic disease as  701–703 placental inflammations and infections as  701 preeclampsia/eclampsia as  703–704 Pregnancy, ectopic diseases of pregnancy and  701 morphology of  701b summary for  701b Prematurity, infant  249–250 Primary amyloidosis immunocyte dyscrasias as  155 lymphoplasmacytic lymphoma and  438 Primary biliary cirrhosis (PBC) cholestatic liver diseases and  627, 627t clinical course of  627 morphology of  627b–628b, 627f–628f pathogenesis of  627b Primary hypercoagulability  81f, 87 Primary immune deficiency common variable immunodeficiency as  141 genetic deficiencies of innate immunity as  142–143 hyper-IgM syndrome as  141 introduction to  139–143, 140f isolated IgA deficiency as  141 lymphocyte activation defects as  142 severe combined immunodeficiency as  142 summary for  142–143, 143b with thrombocytopenia and eczema  142 thymic hypoplasia as  141 X-linked agammaglobulinemia as  140–141 Primary sclerosing cholangitis (PSC) cholestatic liver diseases and  627t, 628–629 clinical course of  629 morphology of  628b, 629f Primary syphilis  672, 673f Primary tuberculosis  495–496, 496f Primitive neuroectodermal tumor (PNET) See Ewing sarcoma Prinzmetal angina  376 Prion  309–314 Prion disease Creutzfeldt-Jakob disease as  831 nervous system infections and  831–832, 831f variant Creutzfeldt-Jakob disease as  831 Progressive massive fibrosis (PMF)  475, 475f See also Coal worker’s pneumoconiosis (CWP) Progressive multifocal leukoencephalopathy (PML)  828–829 morphology of  829b, 829f Progressive pulmonary tuberculosis  497b Prolactinoma  719–720 Prostaglandin anti-inflammatory drugs and  46–47 arachidonic acid metabolites and  46–47 Prostate benign prostatic hyperplasia and  664–665 carcinoma of  665–668 male genital system and  663–668, 663f prostatitis and  663–664 Prostatitis clinical features of  664 prostate disease and  663–664 summary for  664b Prosthetic cardiac valve  395–396 Protein damage to  16 intracellular accumulation of  23 Protein, signal-transducing ABL and  180 introduction to  179–180 RAS protein and  179–180 Protein-coding gene alterations other than mutations epigenetic changes as  217 genetic abnormalities and  216–218 non-coding RNA alterations as  217–218 sequence and copy number variations as  216–217 mutations in  216 Protein-energy malnutrition (PEM) discussion of  294–295 kwashiorkor as  294–295 marasmus as  294 morphology of  295b secondary protein-energy malnutrition and  295 Proteoglycan  64 Protozoa  313 PSA test  211 Pseudogout  789–790 Pseudomonas aeruginosa  490 Psoriasis chronic inflammatory dermatosis and  854–855 clinical features of  854–855 morphology of  854b, 855f pathogenesis of  854b Pulmonary angiitis  485 Pulmonary anthracosis  475b Pulmonary disease as drug- and radiation-induced  478 of vascular origin diffuse alveolar hemorrhage syndromes as  485 pulmonary embolism, hemorrhage, infarction as  482–483 pulmonary hypertension as  484 Pulmonary disease, obstructive vs restrictive  462–463 Pulmonary embolism, hemorrhage, infarction clinical features of  483 diseases of vascular origin and  482–483 morphology of  482b, 483f summary for  483b Pulmonary eosinophilia  481 Pulmonary hypertension clinical features of  484 morphology of  484b, 485f pathogenesis of  484b of vascular origin  484 Pulmonary hypertension, secondary  134 Pulmonary hypertensive heart disease See Cor Pulmonale Pulmonary infection aspiration pneumonias as  492 chronic pneumonias as  492–499 community-acquired acute pneumonias as  486–490 community-acquired atypical pneumonias as  490–491 histoplasmosis, coccidioidomycosis, blastomycosis as  499–500 hospital-acquired pneumonias as  491–492 in human immunodeficiency virus infection  504 lung abscess as  492 the lungs and  486–504, 487f, 488t 901 Index 902 Pulmonary infection (Continued) opportunistic fungal infections as  502–504 pneumonia in the immunocompromised host as  500–502 Pulmonary thromboembolism  90, 90f Purulent inflammation See Inflammation, suppurative Pyelonephritis  746–747 Pyelonephritis, acute clinical course of  534f, 535 morphology of  534b–535b, 534f pathogenesis of  533b–534b, 534f summary for  537 tubulointerstitial nephritis and  533–535 Pyelonephritis, chronic clinical course of  536 morphology of  535b, 536f summary for  537 tubulointerstitial nephritis and  535–536 Pyelonephritis, chronic obstructive  535 Pyelonephritis, chronic reflux-associated  535 Pyogenic granuloma  358, 358f Pyogenic liver abscess  635 Pyogenic meningitis, acute  825 morphology of  825b, 825f Pyogenic osteomyelitis acquired bone disease and  773–774 clinical features of  774 morphology of  774b, 774f Pyrin  155–156 R Rabies virus  828 Radiation See Ionizing radiation Radiation carcinogenesis  200–201 summary for  201b Radon  273 Rapidly progressive glomerulonephritis (RPGN)  531–533 See also Crescentic glomerulonephritis anti-glomerular basement membrane antibody–mediated crescentic glomerulonephritis as  532 and glomerular diseases  531–533 immune complex–mediated crescentic glomerulonephritis as  532 pathogenesis of  532b pauci-immune crescentic glomerulonephritis as  532–533 summary for  533b RAS protein  179–180, 179f Rate of growth cancer stem cells/lineages and  166–167 neoplasms and  166–167 Raynaud phenomenon  355 RB gene  182–184 summary for  184b–185b RDS See Respiratory distress syndrome (RDS) Reactive oxygen species (ROS) accumulation of  14–16, 14f–15f cell-derived mediators and  49–50 ischemia-reperfusion injury and  17 production of  38 Reactive proliferation myositis ossificans as  793f nodular fasciitis as  793, 793f Reactive systemic amyloidosis  155 Reactive tuberculosis See Tuberculosis, secondary Recurrent sinonasal polyp  226 Red cell disorder anemia of blood loss  409 anemias of diminished erythropoiesis and  419–424 hematopoietic system and  408–425, 408t–409t hemolytic anemias and  409–419 polycythemia and  425 summary for  409b Red infarct  92b–93b, 93f, 94 Red thrombi  88b–89b Reflux esophagitis clinical features of  560–561 diseases of the esophagus and  560–561 the esophagus and  560–561 morphology of  560b, 561f pathogenesis of  560b Reflux nephropathy  535–536 Regeneration, cell and tissue control of cell proliferation and  59, 59f growth factors of  61–62 introduction to  59–65 proliferative capacities of tissue and  59–60 role of extracellular matrix in  63–65, 63f role of regeneration in tissue repair and  65 stem cells and  60 summary of  61b Rejection, acute  138 Rejection, antibody-mediated  137–138 Rejection, chronic  137f, 138 Rejection, hyperactive  137–138 Rejection, hyperacute  137–138, 137f Renal atherosclerosis  746–747 Renal cell carcinoma chromophobe renal carcinomas as  548 clear cell carcinomas as  547 clinical course of  548–549 morphology of  548b, 548f papillary renal cell carcinomas as  547–548 summary for  549b as tumors of the kidney  547–549 Renal cell carcinoma, papillary  548b Renal disease  517–518 Renal stones clinical course of  545 morphology of  545b pathogenesis of  545b, 545t urinary outflow obstruction and  545 Reperfusion  381–383, 382f Replicative potential, limitless cancer cells and  190–191, 191f summary for  191b Resorption atelectasis  460 Respiratory bronchiolitis  481 Respiratory distress syndrome (RDS) of the newborn  250–251, 250f clinical features of  251 morphology of  251b, 251f pathogenesis of  250b–251b summary  251b–252b premature infants and  249 Respiratory tract microbe transmission/dissemination through  316–319 Restrictive cardiomyopathy  401 morphology of  401b Retinoblastoma (RB) clinical features of  261 discussion of  260–261 morphology of  261b Retinoblastoma (RB) gene  182–184 pathogenesis of  183f Retinopathy, diabetic  744, 747, 747f Retroperitoneal fibrosis (ureter)  668 Rhabdomyomas  404b Index Rhabdomyosarcoma  794–795 morphology of  795b, 795f Rheumatic fever, acute  391b Rheumatic heart disease  110, 391b Rheumatic valvular disease clinical features of  391–392 morphology of  391b, 392f pathogenesis of  391b valvular heart disease as  391–392 Rheumatoid arthritis (RA) autoimmune diseases  131 clinical features of  785–786 of the joints  784–786 morphology of  785b, 785f–786f pathogenesis of  784b, 784f summary for  790 Rheumatoid vasculitis  355 Rickets acquired bone disease and  771 morphology of  300b–301b vitamin D and  298–300, 300f Rickettsia  311–313 Riedel thyroiditis  726 RNA virus, oncogenic  201, 201f summary for  202b Rolling  35–37, 36t ROS See Reactive oxygen species (ROS) Rotavirus  585–586 Roundworms (nematode)  314, 314f S Sacrococcygeal teratoma  258, 258f Saddle embolus  90, 90f Salivary gland, disease of neoplasms as  555–557 sialadenitis as  555 summary for  557b xerostomia as  555 Salmonellosis infectious enterocolitis and  583–584 pathogenesis of  584b Sanger sequencing  265, 266f Sarcoidosis clinical features of  480 epidemiology of  478–479 etiology and pathogenesis of  479b as granulomatous disease  478–480 morphology of  479b–480b, 479f summary for  480b Sarcoma  162 Sarcoma botryoides  685 Scar formation angiogenesis and  66–67 connective tissue remodeling and  68 fibroblasts and connective tissue in  68 growth factors involved in  42f, 68 introduction to  65–68 remodeling of connective tissue and  68 steps in  65–66, 66f summary for  69b Scarring chronic inflammation and  309–314 morphology of  325b, 325f Scleroderma See Systemic sclerosis (SS) Scleroderma, limited  132 Sclerosing adenosis  706 morphology of  706b, 706f Scrotum  658–663 Scurvy  301 Seborrheic keratosis as epithelial lesions of the skin  862–863 morphology of  862b, 862f Secondary immune deficiency  143 Secondary syphilis  672–673 Secondary tuberculosis clinical features of  498 morphology of  497b, 497f–498f as type of tuberculosis  496 Seminoma  163 Sensorimotor polyneuropathy, distal symmetric  799 Septic shock  94, 95f Sequence  216–217 Sequencing, whole genome  212–213, 212f–213f Serous carcinoma  692b, 693f Serous cystadenoma  651, 651f Serous tumor, ovarian epithelial  697 morphology of  697b, 697f Severe combined immunodeficiency (SCID)  142–143 Sexually transmitted disease (STD) chancroid as  677 genital herpes simplex as  678 gonorrhea and  674–675 granuloma inguinale as  677 human papillomavirus infection as  678 lymphogranuloma venereum as  676 male genital system and  671–678, 671t microbe dissemination and  318 nongonococcal urethritis and cervicitis as  676 trichomoniasis as  677–678 Sézary syndrome  443 Sheehan postpartum pituitary necrosis  452b Shigellosis clinical features of  584b infectious enterocolitis and  583 morphology of  583b pathogenesis of  583b Shock clinical course for  97 introduction to  94–97, 94t morphology of  97b pathogenesis of  94–96 stages of  96–97 summary for  97b Shock lung  97b Shunt, left-to-right atrial septal defect/patent foramen ovale and  370–371 congenital heart disease and  370–372, 370f patent ductus arteriosus and  371–372 ventricular septal defects and  371 Shunt, portosystemic hepatorenal syndrome and  610 liver disease and  609–610 portopulmonary hypertension/hepatopulmonary syndrome and  610 splenomegaly and  609 Shunt, right-to-left congenital heart disease and  372–373, 372f tetralogy of Fallot and  372–373 transposition of the great arteries and  373 Sialadenitis  555, 556f, 557 Sicca syndrome  131 Sickle cell anemia clinical course of  413 hemolytic anemias and  411–413 incidence of  411–413 morphology of  411f, 412b–413b 903 904 Index Sickle cell anemia (Continued) pathogenesis of  411b–412b, 412f summary for  419 SIDS See Sudden infant death syndrome (SIDS) Sigmoid diverticulitis clinical features of  586–587 inflammatory intestinal disease and  586–587 morphology of  586b, 586f, 591f pathogenesis of  586b summary for  587b Silicosis clinical features of  476 morphology of  476b, 476f as pneumoconiosis  476 summary for  478 Single-gene disorder with atypical patterns of inheritance  241–244 alterations of imprinted region disease as  243–244 mutations in mitochondrial genes disease as  243 triplet repeat mutations as  241 Single-gene disorder, transmission patterns of autosomal dominant inheritance as  219–220 autosomal recessive inheritance as  220 summary for  220b X-linked disorders as  220 Single-nucleotide polymorphism (SNP)  222–223 array-based genomic hybridization and  264 linkage analysis and  266 sequence and copy number variations and  216–217 Sinusoidal obstruction syndrome  634, 634f Sinus venosus ASD  371b Sjögren syndrome discussion of  131–132 morphology of  132b, 132f pathogenesis of  127t, 131b summary for  132b Skeletal muscle acquired disorders of  805–806 inflammatory myopathies as  805 toxic myopathies as  805–806 inherited disorders of  802–805 channelopathies, metabolic and mitochondrial myopathies as  805 dystrophinopathies as  802–804 X-linked and autosomal muscular dystrophies as  804–805 patterns of injury for  801–802, 803f summary for  806b Skeletal muscle tumor, rhabdomyosarcoma as  794–795 Skin benign and premalignant tumors of  862–869 blistering disorders of  857–861 chronic inflammatory dermatoses and  854–856 infectious dermatoses and  856–857 introduction and terminology for  851 microbe transmission/dissemination and  316, 318–319 SLE morphology and  130, 130f systemic sclerosis morphology and  133, 134f Skin wound healing by first intention and  70–71, 70f healing by second intention and  70f–71f, 71–72 summary for  72b wound strength and  72 Small airway disease See Chronic bronchiolitis Small cell carcinoma (SCLC)  506b–509b, 509f Small-for-gestational-age (SGA) infant  249–250 Small lymphocytic lymphoma (SLL)  433–434 summary for  443 Smog  272–273 Smokeless tobacco  277, 279 Smoking-related interstitial disease  481, 482f and chronic interstitial lung disease  481 Sodium retention  77–78 Soft tissue fibrohistiocytic tumors and  794 fibrous tumors and tumor-like lesions of  792 introduction to  791–796, 792t skeletal muscle tumors and  794–795 smooth muscle tumors and  795 synovial sarcoma and  795 tumors of adipose tissue and  792 Spermatocytic seminoma  660b–662b Spider telangiectasias  357–358 Spinal cord abnormality  823 Spinocerebellar ataxia (SCA)  840–841 Spirochetal infection neuroborreliosis as  826 neurosyphilis as  826 Spleen  456–457 amyloidosis and  157 SLE morphology and  130 splenomegaly as  456 Splenomegaly CML and  447 hairy cell leukemia and  442–443 portosystemic shunt and  609 spleen disorders and  456 Spondyloarthropathy, seronegative  786 Spontaneous maturation  258–259 Spontaneous regression  258–259 Squamous cell carcinoma clinical features of  863–864 of the esophagus  563–564 clinical features of  563–564 morphology of  563b, 563f pathogenesis of  563b lung tumors and  506b–509b malignant epidermal tumors and  863–864 morphology of  863b, 864f nomenclature for  162–163, 165f of the oral cavity  554 morphology of  554b, 555f pathogenesis of  554b pathogenesis of  863b of the vagina  684 Staging, cancer tumor and  208–210 Staphylococcus aureus  489 Stasis thrombi See Red thrombi Steatohepatitis, nonalcoholic  305 Steatosis See Fatty change Steatosis, drug/toxin-mediated injury with  625 morphology of  626b Steatosis, hepatocellular  621b–622b, 621f Stem cell  60, 61b, 61f cancer of  166–167 Stem cell, adult  60 Stem cell, cardiac  385 Stem cell, embryonic (ES cell)  60 Stenting, endovascular  362, 363f Stomach carcinoid tumor as  571–572 gastric adenocarcinoma as  570–571 gastric polyps as  569 gastrointestinal stromal tumor as  572 inflammatory diseases of  564–569 acute gastritis as  564 acute peptic ulceration as  565 Index chronic gastritis as  565 peptic ulcer disease as  568–569 lymphoma as  571 neoplastic disease of  569–572 carcinoid tumor as  571–572 gastric adenocarcinoma as  570–571 gastric polyps as  569 gastrointestinal stromal tumor as  572 lymphoma as  571 summary for  572b–573b Streptococcus pneumoniae infection  487–488 Stress cellular adaptations to  3–5 cellular response to  1–3, 2f Structural abnormality, cytogenetic disorders and  235–236, 235f–236f Sturge-Weber syndrome  257–258 See also Port wine stain Subdural hematoma  821–822 morphology of  821f, 822b Subdural infection of nervous system  824–825 Sudden cardiac death (SCD)  386, 386f Sudden infant death syndrome (SIDS) discussion of  252–254, 253t morphology of  253b pathogenesis of  253b summary for  254b Sulfur dioxide  273 Superior vena cava syndrome  356 Surface epithelial tumor (ovarian)  696–697 Syndrome of inappropriate ADH (SIADH)  721 Synovial cyst  790 Synovial sarcoma morphology of  795b–796b, 795f soft tissue disease and  795–796 Syphilis congenital syphilis and  673–674 male genital system and  671–674 morphology of  672b primary syphilis and  672, 673f secondary syphilis and  672–673 serologic tests for  674 summary for  674b tertiary syphilis and  673 Systemic disease diet and  306 Systemic immune complex disease  116–117, 116f Systemic inflammatory response syndrome (SIRS)  94–95 Systemic lupus erythematosus (SLE) autoantibodies in  127 as autoimmune disease  125–131, 125t clinical manifestations of  127t, 131 mechanisms of tissue injury in  127–131 morphology of  125t, 128b–130b, 129f pathogenesis of  125b–127b, 126f summary for  131b Systemic miliary tuberculosis  497b Systemic sclerosis (SS) as autoimmune disease  132–134 clinical course for  134 morphology of  133b–134b pathogenesis of  133b, 133f summary for  134b–135b T Tapeworm (cestode)  314 Tay-Sachs disease  229–230, 230f T cell HIV and  146 systemic sclerosis and  133 T cell leukemia, adult  443 T cell lymphoma, adult  443 T cell-mediated hypersensitivity (Type IV) CD4+ T cell inflammatory reactions and  118–119 delayed-type hypersensitivity and  119 introduction to  111, 117–120, 118t, 119f summary for  120b T cell-mediated cytotoxicity and  119–120 T cell mediated rejection  137 T cell receptor (TCR)  101, 101f Tenosynovial giant cell tumor (TGCT) clinical features of  791 joint tumors and  790 morphology of  790b, 791f Teratoma, benign cystic  163, 698–700, 700f Teratoma, immature malignant  700 Teratoma, specialized  700 Tertiary syphilis  673 Testicular atrophy  658–659 Testicular neoplasm  659–663, 660t clinical features of  662–663 morphology of  660b–662b, 660f–662f summary for  663b Testicular torsion  659 Testis cryptorchidism/testicular atrophy and  658–659 inflammatory lesions of  659 male genital system and  658–663 neoplasms of  659–663 vascular disturbances and  659 Tetany, hypocalcemic  298 Tetralogy of Fallot clinical features of  372–373 morphology of  372b right-to-left shunts and  369t, 372–373, 372f Thalassemia clinical course of  416 hemolytic anemias and  413–416 morphology of  415b–416b pathogenesis of  413b–415b, 414f–415f, 414t summary for  419 Thanatophoric dwarfism  767 Thermal burn morphology of  288b–289b thermal injury and  288 Thermal injury hyperthermia as  289 hypothermia as  289 thermal burns as  288 Thiamine deficiency  835 Thoracic aortic aneurysm  346 Thrombocytopenia, heparin-induced  453 Thrombin coagulation cascade and  81f, 83, 85f platelet aggregation and  82 Thromboangiitis obliterans (Buerger disease)  354–355 clinical features of  354–355 morphology of  354b, 354f Thrombocytopenia  78, 87, 424 disseminated intravascular coagulation and  452–454, 453t heparin-induced thrombocytopenia and  453 immune thrombocytopenic purpura and  452–453 thrombotic microangiopathies as  453–454 Thrombocytopenic syndrome, heparin-induced  87 905 906 Index Thromboembolism embolism and  75, 90 HRT and  283 oral contraceptives and  284 Thromboembolism, systemic air embolism as  91–92 amniotic fluid embolism as  91 embolism and  91–92 fat embolism as  91 Thrombophlebitis  356 Thromboplastin See Endothelial injury Thrombosis abnormal blood flow and  86 clotting and  75 endothelial injury and  86 fate of thrombus and  89 hypercoagulability and  87–88 introduction to  86–89, 86f morphology of  88b–89b, 88f summary for  90b Thrombotic microangiopathy pathogenesis of  453b–454b summary for  541 as blood vessel disease of the kidney  540–541 clinical course of  541 morphology of  541b pathogenesis of  540b–541b summary of  541 thrombocytopenia and  453–454 Thrombotic thrombocytopenic purpura (TTP)  541 summary for  456 thrombotic microangiopathies and  453–454 Thromboxane  46 Thrombus clinical correlations for  89 venous thrombosis and  89 fate of  89, 89f Thrush See Oral candidiasis Thymic carcinoma  457b Thymic hyperplasia  457 Thymic hypoplasia  141 Thymoma clinical features of  457 morphology of  457b thymus disorders and  457 Thymoma type I, malignant  457b Thymus disorder introduction to  456–457 thymic hyperplasia as  457 thymoma as  457 Thyroid diffuse/multinodular goiter and  728 and endocrine system  721–735, 722f Graves disease as  726–727 hyperthyroidism and  722–723 hypothyroidism and  723–724 neoplasms of  728–735 adenomas as  729–730 carcinomas of  730–735 introduction to  728–735 summary of  735b thyroiditis as  724–726 Thyroiditis chronic lymphocytic and clinical features of  725 hypothyroidism and  724–725 morphology of  724b–725b, 725f pathogenesis of  724b, 725f chronic lymphocytic (Hashimoto) and summary for  726 chronic lymphocytic thyroiditis and  724–725 other forms of thyroiditis and  726 subacute granulomatous thyroiditis and  725–726 subacute granulomatous thyroiditis (de Quervain) and clinical features of  726 morphology of  726b summary for  726 the thyroid and  725–726 subacute lymphocytic thyroiditis and  726 summary of  726b and the thyroid  724–726 Thyrotoxic myopathy  806 Thyrotroph adenoma  720 Tinea  313 Tissue injury morphology of  8–11 SLE mechanisms of  127–131 summary of  11b Tissue injury, leukocyte-induced  39–40, 41t Tissue necrosis See also Necrosis inflammatory response to infection by  324 morphology of  324b morphology of  9b patterns of  9–11 summary of  11 Tissue repair clinical examples of  70–72 fibrosis in parenchymal organs and  72 healing skin wounds and  70–72 influencing factors of  69–70, 69f overview of  29–30, 58–59, 58f role of extracellular matrix in  63–65 summary for  64b role of regeneration in  65, 65f T lymphocyte cell-mediated immunity and  105–108 effector functions of  107–108, 107f immune system and  101–102, 101f summary for  104 Tobacco smoke carcinogens in  279, 279t combined with alcohol  279, 279f components of  278–279, 279t discussion of  277–279, 278t effects of  277–278, 278f–279f, 278t, 280 indirect-acting chemicals and SLE and  126 summary for  280b Tobacco smoke, environmental  279 Toll-like receptor (TLR)  32, 32f, 52 Total-body irradiation  293, 293t Toxic agents, agricultural exposure to  276–277 Toxic disorder, nervous system and  835–836 Toxic metabolite  271, 271f–272f Toxic myopathy  805–806 TP53 gene evasion of cell death and  190 as guardian of genome  185–187, 186f summary for  187b tumor suppressor gene as  173 Transforming growth factor-β pathway (TGF-β pathway) discussion of  187 summary of  188b–189b Transmigration  36 Transmural infarct  379 Index Transplant effector mechanisms of graft rejection and  137–138 hematopoietic stem cell transplant and  139 immune recognition of allografts and  135–136 summary for  138b improving graft survival and  138–139 morphology of  137b–138b, 137f rejection of  135–139 Transposition of the great arteries clinical features of  373 right-to-left shunts and  372f, 373 Trauma central nervous system and  820–822 summary of  822b parenchymal injuries and  820–821 vascular injury and  820–821 Traumatic hemolysis  418 Traumatic neuroma  798f, 808 Trichomoniasis  677–678 Trisomy 21 (Down syndrome)  237, 238f, 239 Trophoblastic tumor, placental site  703 summary for  703 Trophozoite  313 Tuberculosis as chronic pneumonia  493–498 etiology of  493 morphology of  495b, 495f–496f pathogenesis of  493b–495b, 494f primary tuberculosis and  495–496 secondary tuberculosis and  496 summary for  499b Tuberculous meningitis  826 morphology of  826b Tuberculous osteomyelitis  774 Tuberous sclerosis (TSC)  847 morphology of  847b Tubules and interstitium, disease affecting acute tubular injury and  537–538 the kidney and  533–538 tubulointerstitial nephritis as  533–537 Tubulointerstitial nephritis (TIN) acute pyelonephritis as  533–535 chronic pyelonephritis and reflux nephropathy as  535–536 diseases affecting tubules/interstitium and  533–537 drug-induced interstitial nephritis as  536–537 summary for  537b Tumor of adipose tissue lipoma and  792 liposarcoma and  792 of the adrenal medulla neuroblastoma and  761 pheochromocytoma as  760–761 of the appendix  601 of the bone bone-forming tumors and  775–777 cartilage-forming tumors and  777–779 diseases of the bone and  774–781, 775t fibrous/fibroosseous tumors and  779–780 miscellaneous bone tumors and  780–781 summary for  781b–782b of the breast  707–713 carcinoma as  708–713 fibroadenoma as  707 intraductal papilloma as  708 phyllodes tumor as  707 of the central nervous system embryonal neoplasms as  844–845 familial tumor syndromes as  847 introduction to  842–847 meningiomas as  846 metastatic tumors as  846–847 neuronal tumors as  844 other parenchymal tumors as  845 summary for  847b–848b effects on host  207–208 of infancy/childhood benign tumors and  257–258, 257f clinical course and prognosis for  259–260 of the joint ganglion and synovial cysts as  790 joint disease and  790–791 tenosynovial giant cell tumor as  790–791 of the kidney  547–549 oncocytoma as  547 renal cell carcinoma as  547–549 Wilms tumor as  549 of the liver benign tumors as  635–639 hepatocellular carcinomas as  637–639 liver diseases and  635–639 precursor lesion of hepatocellular carcinoma as  636–637 summary for  639b of the lung carcinoid tumors as  510–511 carcinomas and  505–510 introduction to  505–511 neoplasia and  162 of the ovary Brenner tumor and  698 clinical correlations of  700 endometrioid tumors and  698 introduction of  696–698, 696f mucinous tumors and  697–698 serous tumors and  697 summary for  700b surface epithelial tumors and  696–697 of the skin benign and premalignant epithelial lesions as  862–863 malignant epidermal tumors as  863–864 melanocytic proliferations as  865–869 of the ureter  668 of the vulva  683–684 carcinoma and  683 condylomas and  683 extramammary Paget disease and  683–684 Tumor, benign focal nodular hyperplasia as  635–636 hepatic adenoma as  636 of infancy and childhood  259–260 of the liver  635–636 Tumor, dysembryoplastic neuroepithelial  844 Tumor, endometrioid  698 Tumor, fibrohistiocytic benign fibrous histiocytoma as  794 pleomorphic fibroblastic sarcoma/pleomorphic undifferentiated sarcoma  794 and soft tissue  794 Tumor, fibroosseous  779–780 Tumor, fibrous of the bone fibrous cortical defect and nonossifying fibroma as  779 fibrous dysplasia as  779–780 907 908 Index Tumor, fibrous (Continued) fibromatoses and  793 fibrosarcoma as  793–794 reactive proliferations and  793 of the soft tissue  792–794 Tumor, germ cell  845 Tumor, Krukenberg  698b Tumor, malignant in infancy and childhood  258–262, 258t neuroblastoma as  258–260 retinoblastoma as  260–261 Wilms tumor as  261–262 Tumor, malignant epidermal basal cell carcinoma as  864 squamous cell carcinoma as  863–864 summary for  864b Tumor, neuronal  844 Tumor, odontogenic  558 Tumor, parenchymal germ cell tumors as  845 primary central nervous system lymphoma as  845 Tumor, smooth muscle leiomyoma as  795 leiomyosarcoma as  795 Tumor, vascular benign and tumor-like conditions of  357–359 intermediate-grade of  360–361 introduction to  357–362, 357t malignant tumors as  361–362 summary for  362b Tumor antigen differentiation antigens and  206 glycolipids/glycoproteins and  206 introduction to  204–206, 205f mutated oncogenes/tumor suppressor genes and  204–205 oncofetal antigens and  206 oncogenic viruses and  206 other mutated genes and  205 overexpressed cellular proteins and  205 Tumor cell, homing of  194–195 Tumor immunity antigens and  204–206 introduction to  204–207 surveillance and evasion by  207 Tumor marker  211 Tumor necrosis factor (TNF)  48, 48f Tumor suppressor gene carcinogenesis and  173, 177, 184 inherited mutations and  171–172 Turner syndrome  240–241, 240f nonimmune hydrops and  255–256 22q11.2 deletion syndrome  237–239 Type diabetes (T1D) clinical features of  748, 750t diabetes mellitus and  739 pathogenesis of  741, 741f summary for  750 Type diabetes (T2D) clinical features of  748, 750t diabetes mellitus and  739 pathogenesis of  741, 742f summary for  750 Type hypersensitivity See Hypersensitivity, immediate Type II hypersensitivity See Antibody-mediated disease Type III hypersensitivity See Immune complex disease Type I interferon, SLE and  126 Typhoid fever  584 Tyrosine kinases, non-receptor  178–179 U Ultraviolet (UV) radiation  126 Upper respiratory tract acute infection  512–513 Upper respiratory tract lesion acute infections and  512–513 laryngeal tumors and  513–514 nasopharyngeal carcinoma and  513 Ureaplasma  313 Ureter  668–671 Ureteropelvic junction (UPJ) obstruction  668 Urinary bladder neoplasms of  669–671 non-neoplastic conditions of  668–669 Urinary outflow obstruction hydronephrosis and  545–547 renal stones and  545 Urinary tract infection  518 Urogenital tract  317, 319 Urolithiasis  545 Urticaria acute inflammatory dermatoses and  852 clinical features of  852 morphology of  852b pathogenesis of  852b Uterus, body of abnormal uterine bleeding and  690–691, 690t adenomyosis and  689 endometriosis and  689–690 endometritis and  689 proliferative lesions of endometrium/myometrium and  691–694 summary for  691b V Vagina female genital system and  684–685 malignant neoplasms of  684–685 clear cell adenocarcinoma as  685 sarcoma botryoides as  685 squamous cell carcinoma as  684 vaginitis and  684 Vaginitis  684 Variant Creutzfeldt-Jakob disease (vCJD)  831, 832f Varicose vein of the extremities  356 clinical features of  356 of other sites  356 Vascular change acute inflammation and  31, 31f, 33–34 changes in vascular caliber and flow and  31f, 33–34 increased vascular permeability and  33–34, 33f lymphatic vessel responses and  34 summary of  34b Vascular dissemination invasion-metastasis cascade and  194–195 Vascular ectasias  357–358 Vascular injury, traumatic central nervous system and  821–822, 821f epidural hematoma as  821 subdural hematoma as  821–822 Vascular intervention, pathology of endovascular stenting and  362 vascular replacement and  363 Index Vascular malformation  818 morphology of  818b–819b, 819f Vascular organization  328–329, 328f Vascular replacement  363 Vascular smooth muscle cell  330 Vascular tumor, benign bacillary angiomatosis as  359 glomus tumors as  359 hemangiomas as  358–359 lymphangiomas as  359 vascular ectasias as  357–358 Vascular tumor, intermediate-grade hemangioendotheliomas as  361 Kaposi sarcoma as  360–361 Vascular tumor, malignant angiosarcomas as  361–362 hemangiopericytomas as  362 Vascular wall, response to injury by intimal thickening and  334–335, 335f Vasculitis  819 discussion of  348–355, 349f infectious type of  355 noninfectious type of  348–355 summary for  355b Vasoactive amines  112 Vein, disease of superior and inferior vena cava syndromes as  356 thrombophlebitis and phlebothrombosis as  356 varicose veins of the extremities as  356 Velocardiofacial syndrome  237–239 Venoocclusive disease See Sinusoidal obstruction syndrome Venous thrombosis (phlebothrombosis)  87t, 89 paroxysmal nocturnal hemoglobinuria and  417b Ventricular aneurysm  383f, 384 Ventricular septal defect clinical features of  371 left-to-right shunts and  369t, 371, 371f morphology of  371b Verrucae (warts) infectious dermatoses and  857 morphology of  857b, 858f pathogenesis of  857b Verrucous endocarditis  88b–89b Verrucous endocarditis, nonbacterial  130 Viral encephalitis  826–829, 827f Viral hepatitis, acute  619 Viral injury, mechanism of  319–320, 319f Viral meningitis See Aseptic meningitis Virchow’s triad  86, 86f Virus autoimmunity and  124 infectious agents as  309–310, 310t, 311f Virus, oncogenic  206 Vitamin A deficiency states of  297–298 discussion of  296–298, 297f–298f function of  296–298 toxicity of  298 Vitamin B12 deficiency  835 Vitamin B12 deficiency anemia clinical features of  423 as megaloblastic anemia  423 pathogenesis of  423b Vitamin C (ascorbic acid) deficiency of  301 discussion of  301–302 function of  301–302 toxicity of  301–302 Vitamin D deficiency states of  299–301, 301f discussion of  298–301 functions of  299, 299f metabolism of  298–299, 299f toxicity of  301 Vitamin deficiency nutritional disease and  296–302, 302t–303t Vitamin A and  296–298 Vitamin C and  301–302 Vitamin D and  298–301 Von Gierke disease  232–233, 233t von Hippel-Lindau disease  847 morphology of  847b Von Willebrand disease  455 summary for  456 von Willebrand factor (vWF)  80, 81f Vulva non-neoplastic epithelial disorders of  682 tumors of  683–684 summary for  684b vulvitis and  681–682 Vulvitis  681–682 W WAGR syndrome  261–262 Waldenström macroglobulinemia  439–440 Warts See Verrucae Waterhouse-Friderichsen syndrome disseminated intravascular coagulation and  452b metabolic abnormalities and  96 Water retention  77–78 Wegner granulomatosis (WG)  353–354 clinical features of  354 diffuse alveolar hemorrhage syndromes and  485 morphology of  353b–354b, 353f Wernicke-Korsakoff syndrome  281, 302t, 835 morphology of  835b White cell disorder hematopoietic system and  425–449 neoplastic proliferations of histiocytic neoplasms and  449 neoplastic proliferations of  428–449 lymphoid neoplasms and  429–443 myeloid neoplasms as  444–448 as white cell disorders  428–449 non-neoplastic disorders of  425–428 leukopenia as  425–426 reactive leukocytosis as  426–427 reactive lymphadenitis as  427–428 White infarcts  92b–93b, 93f, 94 Wilms tumor discussion of  261–262 morphology of  262b, 262f–263f summary for  262b–263b tumors of the kidney and  549 Wilson disease clinical features of  631 as inherited metabolic disease  630–632 morphology of  631b pathogenesis of  631b Wood smoke  273 Wrist, carpal ligaments of  157–158 909 910 Index X Y Xenobiotics  271, 271f–272f summary for  273 Xeroderma pigmentosum  197 Xerophthalmia (dry eye)  297–298 Xerostomia  131, 132b, 555 X-linked agammaglobulinemia (XLA)  140, 143 X-linked disorder  220 Yellow fever  620 Yolk sac tumor  660b–662b, 661f Z Zollinger-Ellison syndrome  568b ... similar chains On average, the normal adult red cell contains 96% HbA ( 2 2) , 3% HbA2 ( 2 2) , and 1% fetal Hb (HbF, 2 2) HbS is produced by the substitution of PAT H O G E N E S I S On deoxygenation,... made by Hb electrophoresis, which typically reveals a reduced level of HbA ( 2 2) and an increased level of HbA2 ( 2 2) HbH disease can be diagnosed by detection of β4 tetramers by electrophoresis... chromosomes/cell) and the presence of a cryptic ( 12; 21) translocation involving the TEL1 and AML1 genes, while about 25 % of adult pre-B cell tumors harbor the (9 ;22 ) translocation involving the ABL and