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Chapter 12

The Hematopoietic and Lymphoid SystemsJON C. ASTER, MD, PhD

Leukemia/LymphomaSmall Lymphocytic Lymphoma/Chronic Lymphocytic

LeukemiaFollicular LymphomaMantle Cell LymphomaDiffuse Large B-Cell LymphomaBurkitt LymphomaMultiple Myeloma and Related Plasma Cell DisordersHodgkin LymphomaMiscellaneous Lymphoid Neoplasms

Myeloid NeoplasmsAcute Myelogenous LeukemiaMyelodysplastic SyndromesChronic Myeloproliferative Disorders

Histiocytic NeoplasmsLangerhans Cell Histiocytoses

Etiologic and Pathogenetic Factors in White CellNeoplasia: Summary and PerspectivesChromosomal Translocations and OncogenesInherited Genetic FactorsViruses and Environmental AgentsIatrogenic Factors

BLEEDING DISORDERS

Disseminated Intravascular CoagulationThrombocytopeniaImmune Thrombocytopenic PurpuraHeparin-Induced ThrombocytopeniaThrombotic Microangiopathies: Thrombotic

Thrombocytopenic Purpura and Hemolytic-UremicSyndrome

RED CELL DISORDERS

Anemia of Blood Loss: HemorrhageThe Hemolytic AnemiasHereditary SpherocytosisSickle Cell AnemiaThalassemia

β-Thalassemiaα-Thalassemia

Glucose-6-Phosphate DehydrogenaseDeficiency

Paroxysmal Nocturnal HemoglobinuriaImmunohemolytic AnemiasHemolytic Anemias Resulting from Mechanical

Trauma to Red CellsMalariaAnemias of Diminished ErythropoiesisIron Deficiency AnemiaAnemia of Chronic DiseaseMegaloblastic Anemias

Folate (Folic Acid) Deficiency AnemiaVitamin B12 (Cobalamin) Deficiency Anemia:

Pernicious AnemiaAplastic AnemiaMyelophthisic AnemiaLaboratory Diagnosis of AnemiasPolycythemia

WHITE CELL DISORDERS

Non-Neoplastic Disorders of White CellsLeukopenia

Neutropenia/AgranulocytosisReactive Leukocytosis

Infectious MononucleosisReactive Lymphadenitis

Acute Nonspecific LymphadenitisChronic Nonspecific LymphadenitisCat Scratch Disease

Neoplastic Proliferations of White CellsLymphoid Neoplasms

Precursor B- and T-Cell Lymphoblastic

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422 CHAPTER 12 The Hematopoietic and Lymphoid Systems

Disorders of the hematopoietic and lymphoid systemsencompass a wide range of diseases that are tradition-ally sorted into disorders that primarily affect red cells,white cells, or the hemostatic system, which includesplatelets and clotting factors. The most common red celldisorders lead to anemia, a state of red cell deficiency.White cell disorders, in contrast, are most often causedby excess proliferation, which usually has a neoplasticbasis. Hemostatic derangements result in hemorrhagicdiatheses (bleeding disorders). Finally, splenomegaly, afeature of several hematopoietic diseases, is discussed atthe end of the chapter, as are tumors of the thymus.

Although these divisions are useful, in reality the pro-duction, function, and destruction of red cells, white cells,and components of the hemostatic system are closelylinked, and pathogenic derangements primarily affectingone cell type or component of the system often lead toalterations in others. For example, in certain conditionsB lymphocytes make autoantibodies against componentsof the red cell membrane. The opsonized red cells are rec-

numbers of newly formed red cells (reticulocytes) in theperipheral blood. In contrast, disorders of decreased redcell production (aregenerative anemias) are characterizedby reticulocytopenia.

Another classification of anemias is based on the mor-phology of red cells, which often correlates with the causeof their deficiency. Specific red cell features that provideetiologic clues include the cell size (normocytic, micro-cytic, or macrocytic), the degree of hemoglobinization—which is reflected in the color of the cells (normochromicor hypochromic)—and the shape of the cells. These features are judged subjectively by visual inspection ofperipheral smears and are also expressed quantitativelythrough the following indices:

• Mean cell volume (MCV): the average volume perred cell, expressed in femtoliters (cubic microns)• Mean cell hemoglobin (MCH): the average content(mass) of hemoglobin per red cell, expressed inpicograms• Mean cell hemoglobin concentration (MCHC): theaverage concentration of hemoglobin in a given volumeof packed red cells, expressed in grams per deciliter

Coagulation DisordersDeficiencies of Factor VIII/von Willebrand Factor

Complexvon Willebrand DiseaseFactor VIII Deficiency (Hemophilia A, Classic

Hemophilia)Factor IX Deficiency (Hemophilia B, Christmas Disease)

DISORDERS THAT AFFECT THE SPLEEN AND THYMUS

SplenomegalyDisorders of the ThymusThymic HyperplasiaThymoma

ognized and destroyed by phagocytes in the spleen, whichbecomes enlarged. The increased red cell destructioncauses anemia, which in turn drives a compensatoryhyperplasia of red cell progenitors in the bone marrow.

Other levels of interplay and complexity stem from thedispersed nature of the lymphohematopoietic system,which is not confined to a single anatomic site. Whenconsidering hematopoietic disorders, it is important toremember that both normal and malignant lymphoid andhematopoietic cells “traffic” between various compart-ments. Hence, a patient who is diagnosed by lymph node biopsy to have a malignant lymphoma may also be found to have neoplastic lymphocytes in the bonemarrow and blood. The malignant lymphoid cells in themarrow may suppress hematopoiesis, giving rise tocytopenias, and the further seeding of tumor cells to the liver and spleen may cause organomegaly. Thus, inboth benign and malignant hematolymphoid disorders, asingle underlying abnormality can result in diverse, sys-temic manifestations.

RED CELL DISORDERS

Disorders of red cells can result in anemia or, less commonly, polycythemia (i.e., an increase in the numberof red cells). Anemia is a reduction in the oxygen-transporting capacity of blood, which usually stems froma reduction of the total circulating red cell mass to below-normal amounts.

Anemia can result from excessive bleeding, increasedred cell destruction, or decreased red cell production.These mechanisms serve as a basis for classifying anemias(Table 12–1). With the exception of the anemia of chronicrenal failure, in which erythropoietin-producing cells inthe kidney are lost, the decrease in tissue oxygen tensionthat attends anemia usually triggers increased erythro-poietin production. This drives a compensatory hyperpla-sia of erythroid precursors in the bone marrow and, insevere anemias, the appearance of extramedullaryhematopoiesis within the secondary hematopoietic organs(the spleen, liver, and lymph nodes). In well-nourishedindividuals who become anemic because of acute bleedingor increased red cell destruction (hemolysis), the compen-satory response can increase the regeneration of red cellsfivefold to eightfold. The hallmark of increased marrowoutput is reticulocytosis, the appearance of increased

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CHAPTER 12 The Hematopoietic and Lymphoid Systems 423

compromised pulmonary or cardiac function. Pallor,fatigue, and lassitude are common to all anemias, and arethe primary presenting symptoms of the most commontypes, such as that caused by iron deficiency. Anemiascaused by the premature destruction of red cells in theperipheral blood (hemolytic anemias) are associated withhyperbilirubinemia, jaundice, and pigment gallstones.Anemias that stem from ineffective hematopoiesis (thepremature death of erythroid progenitors in the marrow)are associated with inappropriately high levels of ironabsorption from the gut, which can lead to iron overload(secondary hemochromatosis) and eventual damage toendocrine organs and the heart. If left untreated, severecongenital anemias, such as β-thalassemia major,inevitably result in growth retardation, skeletal abnor-malities, and cachexia.

Table 12–1 Classification of Anemia According toUnderlying Mechanism

Blood Loss

Acute: traumaChronic: lesions of gastrointestinal tract, gynecologic disturbances

Increased Destruction (Hemolytic Anemias)

Intrinsic (intracorpuscular) abnormalitiesHereditary

Membrane abnormlitiesMembrane skeleton proteins: spherocytosis, elliptocytosisMembrane lipids: abetalipoproteinemia

Enzyme deficienciesGlycolytic enzymes: pyruvate kinase, hexokinaseEnzymes of hexose monophosphate shunt: glucose-6-

phosphate dehydrogenase, glutathione synthetaseDisorders of hemoglobin synthesis

Deficient globin synthesis: thalassemia syndromesStructurally abnormal globin synthesis

(hemoglobinopathies): sickle cell anemia, unstable hemoglobins

AcquiredMembrane defect: paroxysmal nocturnal hemoglobinuria

Extrinsic (extracorpuscular) abnormalitiesAntibody mediated

Isohemagglutinins: transfusion reactions, erythroblastosis fetalis (Rh disease of the newborn)

Autoantibodies: idiopathic (primary), drug-associated, systemic lupus erythematosus

Mechanical trauma to red cellsMicroangiopathic hemolytic anemias: thrombotic

thrombocytopenic purpura, disseminated intravascular coagulation

Infections: malaria

Impaired Red Cell Production

Disturbance of proliferation and differentiation of stem cells: aplastic anemia, pure red cell aplasia, anemia of renal failure,anemia of endocrine disorders

Disturbance of proliferation and maturation of erythroblastsDefective DNA synthesis: deficiency or impaired utilization of

vitamin B12 and folic acid (megaloblastic anemias)Defective hemoglobin synthesis

Deficient heme synthesis: iron deficiencyDeficient globin synthesis: thalassemiasAnemia of renal failure

Unknown or multiple mechanisms: myelodysplastic syndrome, anemia of chronic inflammation, myelophthisic anemias dueto marrow infiltrations

SUMMARY

Pathology of AnemiasCAUSES

• Blood loss (hemorrhage)• Increased red cell destruction (hemolysis)• Decreased red cell production

MORPHOLOGY

• Microcytic (iron deficiency, thalassemia)• Macrocytic (folate or B12 deficiency)• Normocytic but with abnormal shapes (heredi-tary spherocytosis, sickle cell disease)

CLINICAL MANIFESTATIONS

• Acute: shortness of breath, organ failure, shock• Chronic:

� With hemolysis: skeletal abnormalities becauseof expansion of marrow; growth retardation;jaundice and gallstones

� With defective erythropoiesis: iron overload,heart and endocrine failure

• Red cell distribution width (RDW): the coefficient ofvariation of red cell volume.

In modern clinical laboratories, specialized instru-ments directly measure or automatically calculate the redcell indices. Adult reference ranges are shown in Table12–2.

As we will discuss, the clinical consequences of anemiaare determined by its severity, speed of onset, and under-lying pathogenic mechanism. If the onset is slow, adap-tations take place that partially compensate for the deficitin O2 carrying capacity, such as increases in plasmavolume, cardiac output, respiratory rate, and red cell 2,3-diphosphoglycerate levels. These changes can largely mit-igate the effects of mild to moderate anemia in otherwisehealthy individuals, but are less effective in those with

ANEMIA OF BLOOD LOSS: HEMORRHAGE

With acute blood loss, the immediate threat to the patientis hypovolemia (shock) rather than anemia. If the patientsurvives, hemodilution begins at once and achieves its fulleffect within 2 to 3 days, unmasking the extent of the redcell loss. The anemia is normocytic and normochromic.Recovery from blood loss anemia is enhanced by a risein the erythropoietin level, which stimulates increased redcell production within several days. The onset of themarrow response is marked by reticulocytosis.

With chronic blood loss, iron stores are graduallydepleted. Iron is essential for hemoglobin synthesis andeffective erythropoiesis, and its deficiency thus leads to achronic anemia of underproduction. Iron deficiency

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anemia can occur in other clinical settings as well, and itis described later in this chapter along with other anemiasof diminished erythropoiesis.

THE HEMOLYTIC ANEMIAS

Normal red cells have a life span of about 120 days.Anemias that are associated with accelerated destructionof red cells are termed hemolytic anemias. Destructioncan be caused by either inherent (intracorpuscular) redcell defects, which are usually inherited, or external(extracorpuscular) factors, which are usually acquired.Several examples are listed in Table 12–1.

Before discussing the various disorders individually,we will describe certain general features of hemolyticanemias. All are characterized by (1) an increased rate ofred cell destruction, (2) a compensatory increase in ery-thropoiesis that results in reticulocytosis, and (3) theretention by the body of the products of red cell destruc-tion (including iron). Because the iron is conserved andrecycled readily, red cell regeneration can keep pace withthe hemolysis. Consequently, these anemias are almostinvariably associated with a marked erythroid hyperpla-sia within the marrow and an increased reticulocytecount in peripheral blood. In severe hemolytic anemias,extramedullary hematopoiesis often develops in thespleen, liver, and lymph nodes.

Destruction of red cells can occur within the vascularcompartment (intravascular hemolysis) or within the cells of the mononuclear phagocyte (reticuloendothelial)system (extravascular hemolysis). Intravascular hemoly-sis can result from mechanical trauma (e.g., a defectiveheart valve) or biochemical or physical agents thatdamage the red cell membrane (e.g., fixation of comple-ment, exposure to clostridial toxins, or heat). Regardlessof cause, hemolysis leads to hemoglobinemia, hemoglo-binuria, and hemosiderinuria. The conversion of theheme pigment to bilirubin can result in unconjugatedhyperbilirubinemia and jaundice. Massive intravascular

hemolysis sometimes leads to acute tubular necrosis(Chapter 14). Haptoglobin, a circulating protein thatbinds and clears free hemoglobin, is often absent fromthe plasma.

Extravascular hemolysis, the more common mode ofred cell destruction, takes place largely within the phago-cytic cells of the spleen and liver. The mononuclearphagocyte system removes damaged or immunologicallytargeted red cells from the circulation. Because extremealterations of shape are necessary for red cells to suc-cessfully navigate the splenic sinusoids, any reduction inred cell deformability makes this passage difficult andleads to splenic sequestration, followed by phagocytosis.As will be described, diminished deformability is animportant cause of red cell destruction in a variety ofhemolytic anemias. Extravascular hemolysis is not asso-ciated with hemoglobinemia and hemoglobinuria, but itoften produces jaundice and, if long-standing, can lead tothe formation of bilirubin-rich gallstones (so-calledpigment stones). Haptoglobin amounts are alwaysdecreased, because some hemoglobin invariably escapesinto the plasma. In most forms of hemolytic anemia thereis a reactive hyperplasia of the mononuclear phagocytesystem, which results in splenomegaly.

In chronic hemolytic anemias, changes in iron metab-olism lead to increases in iron absorption from the gut.Because the pathways for the excretion of excess iron arelimited, this often causes iron to accumulate, giving riseto systemic hemosiderosis (Chapter 1) or, in very severecases, secondary hemochromatosis (Chapter 16).

We will now discuss some of the common hemolyticanemias.

Hereditary SpherocytosisThis disorder is characterized by an inherited (intrinsic)defect in the red cell membrane that renders the cellsspheroidal, less deformable, and vulnerable to splenicsequestration and destruction. Hereditary spherocytosis(HS) is transmitted most commonly as an autosomaldominant trait; approximately 25% of patients have amore severe autosomal recessive form of the disease.

Pathogenesis. In HS the primary abnormality resides inone of a group of proteins that form a meshlike sup-portive skeleton on the intracellular face of the red cellmembrane (Fig. 12–1). The major protein in this skele-ton is spectrin, a long, flexible heterodimer that is linkedto the membrane at two points: through ankyrin andband 4.2 to the intrinsic membrane protein band 3; andthrough band 4.1 to the intrinsic membrane protein glycophorin. The horizontal spectrin–spectrin and verti-cal spectrin–intrinsic membrane protein interactionsserve to stabilize the membrane and are responsible for the normal shape, strength, and flexibility of the redcell.

The common pathogenic feature of all HS mutationsis that they weaken the vertical interactions between themembrane skeleton and the intrinsic membrane proteins.The mutations most frequently involve ankyrin, band 3,and spectrin, but mutations in other components of theskeleton have also been described. In all types of HS thered cells have reduced membrane stability and conse-

Table 12–2 Adult Reference Ranges for Red Blood Cells*

Units Men Women

Hemoglobin (Hb) g/dL 13.6–17.2 12.0–15.0

Hematocrit (HCT) % 39–49 33–43

Red cell count × 106/mm3 4.3–5.9 3.5–5.0

Reticulocyte count % 0.5–1.5 0.5–1.5

Mean cell volume (MCV) fL 76–100 76–100

Mean cell Hb (MCH) pg 27–33 27–33

Mean cell Hb g/dL 33–37 33–37concentration (MCHC)

Red cell distribution 11.5–14.5width (RDW)

*Reference ranges vary among laboratories. The reference rangesfor the laboratory providing the result should always be used wheninterpreting a laboratory test.

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quently lose membrane fragments after their release intothe periphery, while retaining most of their volume. As aresult, the ratio of surface area to volume of HS cellsdecreases until the cells become spherical, at which pointno further membrane loss is possible (see Fig. 12–1).

The spleen plays a major role in the destruction ofspherocytes. Red cells must undergo extreme degrees ofdeformation to leave the cords of Billroth and enter thesplenic sinusoids. The discoid shape of normal red cellsallows considerable latitude for changes in cell shape. Incontrast, because of their spheroidal shape and limiteddeformability, spherocytes are sequestered in the spleniccords and eventually destroyed by macrophages, whichare plentiful. The critical role of the spleen is illustratedby the invariably beneficial effect of splenectomy;although the red cell defect and spherocytes persist, theanemia is corrected.

Clinical Course. The characteristic clinical features areanemia, splenomegaly, and jaundice. The severity of the anemia is highly variable, ranging from subclinical to profound; most commonly it is moderate in se-verity. Because of their spheroidal shape, HS red cellsshow increased osmotic fragility when placed in hypo-tonic salt solutions, a characteristic that is helpful fordiagnosis.

The clinical course is often stable but may be punctu-ated by aplastic crises. Such episodes are often triggeredby the infection of bone marrow erythroblasts by par-vovirus B19, which causes a transient cessation of red cellproduction. Because HS red cells have a shortened lifespan, the failure of erythropoiesis for even a few daysresults in a rapid worsening of the anemia. Such episodesare self-limited, but some patients need blood transfu-sions until the infection clears.

Band 3 GP

Lipid bilayer

Actinα

αSpectrinβ

β4.2 Ankyrin 4.1

4.1

Normal

Spherocyte

Splenicmacrophage

Figure 12–1

The red cell membrane cytoskeleton and the effect of alterations in the cytoskeleton proteins on red cell shape. With mutations thataffect the integrity of the membrane cytoskeleton, the normal biconcave erythrocyte loses membrane fragments. To accommodate theloss of surface area, the cell adopts a spherical shape. Such spherocytic cells are less deformable than normal and are therefore trappedin the splenic cords, where they are phagocytosed by macrophages. GP, glycophorin.

Morphology

On smears, the red cells lack the central zone of pallorbecause of their spheroidal shape (Fig. 12–2). Sphero-cytosis, though distinctive, is not diagnostic; it is seenin other conditions, such as immune hemolyticanemias (discussed later), in which there is a loss of cellmembrane relative to cell volume. The excessive redcell destruction and resultant anemia lead to a con-pensatory hyperplasia of marrow red cell progenitorsand an increase in red cell production, which is markedby peripheral blood reticulocytosis. Splenomegaly isgreater and more common in HS than in any other formof hemolytic anemia. The splenic weight is usuallybetween 500 and 1000gm and can be even greater. Theenlargement results from marked congestion of thecords of Billroth and increased numbers of mononu-clear phagocytes. Phagocytosed red cells are frequentlyseen within macrophages lining the sinusoids and, inparticular, within the cords. In long-standing casesthere is prominent systemic hemosiderosis. The othergeneral features of hemolytic anemias described earlierare also present, including cholelithiasis, which occursin 40% to 50% of HS patients.

Figure 12–2

Hereditary spherocytosis (peripheral smear). Note the anisocytosisand several dark-appearing spherocytes with no central pallor.Howell-Jolly bodies (small dark nuclear remnants) are also presentin the red cells. (Courtesy of Dr. Robert W. McKenna, Departmentof Pathology, University of Texas Southwestern Medical School,Dallas, Texas.)

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There is no specific treatment for HS. Splenectomy isbeneficial for those who are symptomatic, because themajor site of red cell destruction is removed. The bene-fits of splenectomy must be weighed against the risk of increased susceptibility to infections, particularly inchildren.

Sickle Cell AnemiaThe hemoglobinopathies are a group of hereditary disor-ders that are defined by the presence of structurally abnor-mal hemoglobins. Of the more than 300 varianthemoglobins that have been discovered, one-third areassociated with significant clinical manifestations. Theprototypical (and most prevalent) hemoglobinopathy iscaused by a mutation in the β-globin chain gene thatcreates sickle hemoglobin (HbS). The disease associatedwith HbS, sickle cell anemia, is discussed here; otherhemoglobinopathies are infrequent and beyond our scope.

HbS, like 90% of other abnormal hemoglobins, resultsfrom a single amino acid substitution in the globin chain.Normal hemoglobins, as may be recalled, are tetramerscomposed of two pairs of similar chains. On average, thenormal adult red cell contains 96% HbA (α2β2), 3%HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2). Substitutionof valine for glutamic acid at the sixth position of the β-chain produces HbS. In homozygotes all HbA is replacedby HbS, whereas in heterozygotes only about half isreplaced.

Incidence. Approximately 8% of American blacks areheterozygous for HbS. In parts of Africa where malariais endemic the gene frequency approaches 30%, as aresult of a small but significant protective effect of HbSagainst Plasmodium falciparum malaria. In the UnitedStates sickle cell anemia affects approximately one ofevery 600 blacks, and worldwide, sickle cell anemia is themost common form of familial hemolytic anemia.

Etiology and Pathogenesis. Upon deoxygenation, HbSmolecules undergo polymerization, a process also refer-

red to as gelation or crystallization. These polymersdistort the red cell, which assumes an elongated crescen-tic, or sickle, shape (Fig. 12–3). Sickling of red cells is ini-tially reversible upon reoxygenation; however, membranedamage occurs with each episode of sickling, and even-tually the cells accumulate calcium, lose potassium andwater, and become irreversibly sickled.

Many variables influence sickling of red cells in vivo.The three most important ones are as follows:

• The presence of hemoglobins other than HbS. In heterozygotes approximately 40% of Hb is HbS; theremainder is HbA, which interacts only weakly withdeoxygenated HbS. The presence of HbA slows the rateof polymerization greatly, and as a result the red cellsof heterozygotes have little tendency to sickle in vivo.Such individuals are said to have the sickle cell trait.HbC, another mutant β-globin, is fairly common. Thecarrier rate for HbC in American blacks is about 2.3%;as a result about one in 1250 newborns are double heterozygotes because they have inherited HbS fromone parent and HbC from the other. HbC has a greatertendency to aggregate with HbS than does HbA, andthose with HbS and HbC (called HbSC disease) aresymptomatic. Conversely, HbF interacts more weaklywith HbS, and therefore newborns with sickle cellanemia do not manifest the disease until they are 5 to6 months old, when the HbF falls to adult levels.• The concentration of HbS in the cell. The tendencyfor deoxygenated HbS to form the insoluble polymersthat create sickle cells is strongly dependent on the con-centration of HbS. Thus, red cell dehydration, whichincreases the Hb concentration, greatly facilitates sick-ling and can trigger occlusion of small blood vessels.Conversely, the coexistence of α-thalassemia (describedlater) reduces the Hb concentration and therefore theseverity of sickling. The relatively low concentration ofHbS also contributes to the lack of sickling in het-erozygotes with sickle cell trait.• The length of time that red cells are exposed to lowoxygen tension. Normal transit times for red cells

AB

Figure 12–3

Peripheral blood smear from a patient with sickle cell anemia. A, Low magnification shows sickle cells, anisocytosis, poikilocytosis, andtarget cells. B, Higher magnification shows an irreversibly sickled cell in the center. (Courtesy of Dr. Robert W. McKenna, Department ofPathology, University of Texas Southwestern Medical School, Dallas, Texas.)

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passing through capillaries are not sufficient for significant aggregation of deoxygenated HbS to occur.Hence, sickling is confined to microvascular bedswhere blood flow is sluggish. This is normally the casein the spleen and the bone marrow, which are promi-nently affected by sickle cell disease. In other vascularbeds, it has been suggested that particularly importantpathogenic roles are played by two factors: inflamma-tion and increased red cell adhesion. As you will recall,blood flow in inflamed tissues is slowed, as a result ofthe adhesion of leukocytes and red cells to activatedendothelium and the exudation of fluid through leakyvessels. This prolongs the red cell transit times, makingclinically significant sickling more likely. Sickle red cellsalso have a greater tendency than normal red cells toadhere to endothelial cells, apparently because mem-brane damage makes them sticky. In fact, the adhesionof sickle red cells to cultured endothelial cells correlateswith clinical severity, presumably because this “sticki-ness” reflects a greater risk for delays in transit acrossmicrovascular beds in vivo.

Two major consequences stem from the sickling of redcells (Fig. 12–4). First, repeated episodes of deoxygena-tion cause membrane damage and dehydration of redcells, which become rigid and irreversibly sickled. Thesedysfunctional red cells are recognized and removed bymononuclear phagocyte cells, producing a chronic ex-travascular hemolytic anemia. Overall, the mean life spanof red cells in sickle cell anemia patients averages only 20days (one-sixth of normal). Second, the sickling of red

HbA

Glutamic acid

Pointmutation

HbS

Valine

Oxygenated

Deoxygenated

Reversibly sickled

Irreversiblysickled

HbS polymersHbS solution

Normal red cell

Increased RBC transittimes in inflamed tissues

Membrane changesIncreased adhesiveness

Infarct (e.g., bone marrow) Infarct (e.g., lung)

Sickle cell

Splenic cord

Sinusoid

Macrophage

Endothelium

Vascular occlusion

Microvascular occlusionby sickle cells

Microvascular occlusionby sickle cells

G

C

T

A

G

C

G

C

A

T

G

C

SPLEEN Hemolysis, congestion,infarction

Venoussinus

Inflammation

Cell adhesion

Transudationof fluid

Figure 12–4

Pathophysiology and morphologic consequences of sickle cell anemia.

Morphology

The anatomic alterations in sickle cell anemia stemfrom the following three aspects of the disease: (1) thesevere chronic hemolytic anemia; (2) the increasedbreakdown of heme pigments, which are processedinto bilirubin; and (3) the microvascular obstruction,which provokes tissue ischemia and infarction. Inperipheral smears, bizarre elongated, spindled, or boat-shaped irreversibly sickled red cells are evident (seeFig. 12–3). Both the anemia and the vascular stasis leadto fatty changes in the heart, liver, and renal tubules.There is a compensatory hyperplasia of erythroid prog-enitors in the marrow. The burgeoning marrow oftencauses bone resorption and secondary new bone for-mation, resulting in prominent cheekbones andchanges in the skull resembling a “crew-cut” inroentgenograms. Extramedullary hematopoiesis canalso appear in the spleen and liver.

In children there is moderate splenomegaly (splenicweight as great as 500gm) caused by congestion of thered pulp, which is stuffed with sickled red cells.However, the chronic splenic erythrostasis results in

cells produces widespread microvascular obstructions,which result in ischemic tissue damage and pain crises.Vaso-occlusion does not correlate with the number ofirreversibly sickled cells and therefore appears to resultfrom factors, such as infection, inflammation, dehydra-tion, and acidosis, that trigger the sickling of reversiblysickled cells.

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Clinical Course. Homozygous sickle cell disease usuallybecomes apparent after the sixth month of life, since HbFis gradually replaced by HbS. The anemia is severe; mostpatients have hematocrit values of 18% to 30% (normalrange, 35%–45%). The chronic hemolysis is associatedwith marked reticulocytosis and hyperbilirubinemia.From the time of onset, the process runs an unremittingcourse, punctuated by sudden crises. The most serious ofthese are the vaso-occlusive, or pain, crises. Pain crisescan involve many sites but are most common in the bonemarrow, where they often progress to infarction andnecrosis.

A feared complication is the acute chest syndrome,which can be triggered by pulmonary infections or fatemboli from necrotic marrow that secondarily involve the lung. The blood flow in the inflamed, ischemic lungbecomes sluggish and “spleenlike,” leading to sicklingwithin hypoxemic pulmonary beds. This exacerbates theunderlying pulmonary dysfunction, creating a viciouscycle of worsening pulmonary and systemic hypoxemia,sickling, and vaso-occlusion. Another major complica-tion is central nervous system stroke, which sometimesoccurs in the setting of the acute chest syndrome.Although virtually any organ can be damaged byischemic injury in the course of the disease, the acutechest syndrome and stroke are the two leading causes ofischemia-related death.

A second acute event, the aplastic crisis, represents asudden but usually temporary cessation of erythropoiesis.As in hereditary spherocytosis, these are usually triggeredby parvovirus infection of erythroblasts, and, whilesevere, are self-limited.

In addition to these crises, patients with sickle celldisease are prone to infections. Both children and adultswith sickle cell disease are functionally asplenic, makingthem susceptible to infections caused by encapsulatedbacteria, such as pneumococci. In adults the basis for“hyposplenism” is autoinfarction. In the earlier child-hood phase of splenic enlargement, congestion caused bytrapped sickled red cells apparently interferes with bac-terial sequestration and killing; hence, even children withenlarged spleens are at risk for fatal septicemia. Defectsin the alternative complement pathway that impair theopsonization of encapsulated bacteria are also observed.For reasons that are not entirely clear, patients with sicklecell disease are particularly predisposed to Salmonellaosteomyelitis.

In full-blown sickle cell disease, at least some irre-versibly sickled red cells can be seen on an ordinaryperipheral blood smear. In sickle cell trait, sickling can beinduced in vitro by exposing cells to marked hypoxia.Ultimately, the diagnosis depends on the electrophoreticdemonstration of HbS. Prenatal diagnosis of sickle cellanemia can be performed by analyzing the DNA in fetalcells obtained by amniocentesis or biopsy of chorionicvilli (Chapter 7).

The clinical course of patients with sickle cell anemiais highly variable. As a result of improvements in sup-portive care, an increasing number of patients are surviving into adulthood and producing offspring. Ofparticular importance is prophylactic treatment withpenicillin to prevent pneumococcal infections. Approxi-mately 50% of patients survive beyond the fifth decade.In contrast, sickle cell trait causes symptoms rarely andonly under extreme conditions, such as following vigor-ous exertion at high altitudes.

Hydroxyurea, a “gentle” inhibitor of DNA synthesis,has been shown to reduce pain crises and lessen theanemia. Hydroxyurea increases the red cell levels of HbF,acts as an anti-inflammatory agent by inhibiting the pro-duction of white cells, increases the MCV, and is oxidizedby heme groups to produce NO, a potent vasodilator andinhibitor of platelet aggregation. These complementaryintracorpuscular and extracorpuscular effects are believedto work together to lessen microvascular sickling and itsattendant signs and symptoms.

ThalassemiaThe thalassemias are a heterogeneous group of inheriteddisorders caused by mutations that decrease the rate ofsynthesis of α- or β-globin chains. As a consequence thereis a deficiency of hemoglobin, with additional secondaryred cell abnormalities caused by the relative excess of theother unaffected globin chain.

Molecular Pathogenesis. A diverse collection of molecu-lar defects underlies the thalassemias, which are inheritedas autosomal codominant conditions. Recall that adulthemoglobin, or HbA, is a tetramer composed of two αchains and two β chains. The α chains are encoded bytwo α-globin genes, which lie in tandem on chromo-some 11, while the β chains are encoded by a single β-globin gene located on chromosome 16. The mutationsthat cause thalassemia are particularly common amongMediterranean, African, and Asian populations. The clin-ical features vary widely depending on the specific com-bination of alleles that are inherited by the patient (Table12–3), as will be described below.

β-Thalassemia

The β-globin mutations associated with β-thalassemia fallinto two categories: (1) β0, in which no β-globin chainsare produced; and (2) β+, in which there is reduced (but detectable) β-globin synthesis. Sequencing of β-thalassemia genes has revealed more than 100 differentresponsible mutations, the majority of which consist ofsingle-base changes. Individuals inheriting one abnormalallele have thalassemia minor or thalassemia trait, which

progressive hypoxic tissue damage, which eventuallyreduces the spleen to a functionally useless nubbin offibrous tissue. This process, referred to as autosplenec-tomy, is complete by adulthood.

Vascular congestion, thrombosis, and infarction canaffect any organ, including bones, liver, kidney, retina,brain, lung, and skin. The bone marrow is particularlyprone to ischemia, because of its relatively sluggishblood flow and high rate of metabolism. Priapism,another common problem, can lead to penile fibrosis and eventual erectile dysfunction. As with the otherhemolytic anemias, hemosiderosis and gallstones arecommon.

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is asymptomatic or mildly symptomatic. Most individu-als inheriting any two β0 and β+ alleles have β-thalassemiamajor; occasionally, individuals inheriting two β+ alleleshave a milder disease termed β-thalassemia intermedia.In contrast to α-thalassemias, described later, gene dele-tions rarely underlie b-thalassemias (Table 12–3).

Most of the mutations in β-thalassemia fall into oneof three molecular subtypes (Fig. 12–5):

• The promoter region controls the initiation and rateof transcription. Some mutations lie within promoterregions and typically lead to reduced globin gene tran-scription. Because some β-globin is synthesized, suchalleles are designated β+.• Mutations in the coding sequences are usually asso-ciated with more serious consequences. For example,in some cases a single-nucleotide change in one of the exons leads to the formation of a termination, or“stop” codon, which interrupts translation of β-globinmessenger RNA (mRNA) and completely prevents thesynthesis of β-globin. Such alleles are designated β0.

• Mutations that lead to aberrant mRNA processingare the most common cause of b-thalassemia. Most ofthese affect introns, but some have been located withinexons. If the mutation alters the normal splice junc-tions, splicing does not occur, and all of the mRNAformed is abnormal. Unspliced mRNA is degradedwithin the nucleus, and no β-globin is made. However,some mutations affect the introns at locations awayfrom the normal intron-exon splice junction. Thesemutations create new sites that are substrates for theaction of splicing enzymes at abnormal locations-within an intron, for example. Because normal splicesites remain intact, both normal and abnormal splicingoccur, and normal β-globin mRNA is decreased but notabsent. Thus, depending on their position, splice junc-tion mutations can create either β0 or β+ alleles.

Two conditions contribute to the pathogenesis of theanemia in b-thalassemia. The reduced synthesis of β-globin leads to inadequate HbA formation, so that theMCHC is low, and the cells appear hypochromic and

Table 12–3 Clinical and Genetic Classification of Thalassemias

Clinical Nomenclature Genotype Disease Molecular Genetics

β-Thalassemias

Thalassemia major Homozygous or compound Severe, requires bloodheterozygous transfusions regularly

Defects in transcription, processing, or(β0/β0, β0/β+, or β+/β+)translation of mRNA, resulting in absent

β-thalassemia trait β/β+ or β/β0 Asymptomatic, with mild (β0) or decreased (β+) synthesis of β-globinmicrocytic anemia, ormicrocytosis without anemia

α-Thalassemias

Hydrops fetalis −/− Fatal in utero

HbH disease −/−α Moderately severe anemia

Gene deletions spanning one or bothα-thalassemia trait −/αα (Asian) or −α/−α Similar to β-thalassemia trait α-globin loci

(black African)

Silent carrier −α/αα Asymptomatic, normal red cells

β+Thalβ0Thalβ0Thalβ+Thal

5´ 3´

Exon-1 Exon-2 Exon-3

Transcription defectRNA splicing defectTranslation defect

Promotersequence

*** *

Figure 12–5

The β-globin gene and some sites at which point mutations giving rise to β-thalassemia have been localized. Asterisks within circles indi-cate the most common sites of mutations that cause different types of β-thalassemia. (Modified from Wyngaarden JB, Smith LH, BennettJC [eds]: Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992.)

⎫

⎬

⎪⎪⎪

⎭

⎪⎪⎪

⎫

⎬

⎪⎪⎪

⎭

⎪⎪⎪

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microcytic. Even more important is red cell hemolysis,which results from the unbalanced rates of β-globin and α-globin chain synthesis. Unpaired α chains forminsoluble aggregates that precipitate within the red cellsand cause membrane damage that is severe enough toprovoke extravascular hemolysis (Fig. 12–6). Erythrob-lasts in the bone marrow are also susceptible to damagethrough the same mechanism, which in severe β-thalassemia results in the destruction of the majority oferythroid progenitors before their maturation into redcells. This intramedullary destruction of erythroid pre-cursors (ineffective erythropoiesis) has another untowardeffect: it is associated with an inappropriate increase in

the absorption of dietary iron, which often leads to ironoverload.

α-Thalassemia

The molecular basis of α-thalassemia is quite differentfrom that of β-thalassemia. Most of the α-thalassemiasare caused by deletions that remove one or more of theα-globin gene loci. The severity of the disease that resultsfrom these lesions is directly proportional to the numberof α-globin genes that are missing (see Table 12–3). Forexample, the loss of a single α-globin gene is associatedwith a silent-carrier state, whereas the deletion of all four α-globin genes is associated with fetal death in

HbA(α2β2)

Normal erythroblast Abnormal erythroblast

NORMAL β-THALASSEMIA

Normal red blood cells

Dietary iron

Reduced β-globin synthesis,

with relativeexcess of α-globin

HbA

Most erythroblastsdie in bone marrow

(Ineffective erythropoiesis)

Tissue anoxia

Bloodtransfusions

Reduce

ANEMIA

Systemic iron overload(secondary hemochromatosis)

Skeletal deformities

Few abnormalred cells leave

Hypochromicred cell

Destruction ofaggregate-containing

red cells in spleen

Insoluble α-globin aggregate

α-globinaggregate

Normal HbA

Increasediron

absorption

Erythropoietinincrease

Marrow expansion

Liver

Heart

Figure 12–6

Pathogenesis of β-thalassemia major. Note that aggregates of excess α-globin are not visible on routine blood smears. Blood transfu-sions, on the one hand, correct the anemia and reduce stimulus for erythropoietin secretion and deformities induced by marrow expan-sion; on the other hand, they add to systemic iron overload.

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Clinical Course. β-thalassemia major manifests itselfpostnatally as HbF synthesis diminishes. Affected chil-dren fail to develop normally, and their growth isretarded from shortly after birth. They are sustained onlyby repeated blood transfusions, which improve theanemia and reduce the skeletal deformities associatedwith excessive erythropoiesis. With transfusions alonesurvival into the second or third decade is possible, butgradually systemic iron overload develops. The combi-nation of iron present in transfused red cells and theincreased uptake of dietary iron from the gut leadinevitably to iron overload. The latter stems from inap-propriately low levels of plasma hepcidin, a negative regulator of iron uptake that is “underexpressed” in

conditions (such as β-thalassemia major) that are associ-ated with ineffective erythropoiesis. Unless patients aretreated aggressively with iron chelators, cardiac failurefrom secondary hemochromatosis commonly occurs andoften causes death in the second or third decade of life.When feasible, bone marrow transplantation at an earlyage is the treatment of choice.

In β-thalassemia minor there is usually only a mildmicrocytic hypochromic anemia; generally, these patientshave a normal life expectancy. Iron deficiency anemia isassociated with a similar red cell appearance and must beexcluded by appropriate laboratory tests, described laterin this chapter. The diagnosis of β-thalassemia minor ismade by Hb electrophoresis. In addition to reducedamounts of HbA (α2β2), the level of HbA2 (α2δ2) isincreased. The diagnosis of β-thalassemia major can gen-erally be made on clinical grounds. The peripheral bloodshows a severe microcytic hypochromic anemia, withmarked variation in cell shapes (poikilocytosis). Thereticulocyte count is increased. Hb electrophoresis showsprofound reduction or absence of HbA and increasedlevels of HbF. The HbA2 level may be normal orincreased. Prenatal diagnosis of both forms of tha-lassemia can be made by DNA analysis.

HbH disease (caused by deletion of three α-globingenes) is not as severe as β-thalassemia major, since α-and β-globin chain synthesis is not as imbalanced andhematopoiesis is effective. Anemia is moderately severe,but patients usually do not require transfusions. Thus, theiron overload that is so common in β-thalassemia majoris rarely seen. α-Thalassemia trait (caused by deletion oftwo α-globin genes) is often an asymptomatic conditionassociated with microcytic red cells and mild anemia.

Glucose-6-Phosphate Dehydrogenase DeficiencyThe red cell is vulnerable to injury by endogenous andexogenous oxidants, which are normally inactivated byreduced glutathione (GSH). Abnormalities affecting theenzymes that are required for GSH production reduce the ability of red cells to protect themselves from oxida-tive injury and lead to hemolytic anemias. The prototype(and most prevalent) of these anemias is that associatedwith a deficiency of glucose-6-phosphate dehydrogenase(G6PD). The G6PD gene is on the X chromosome. Morethan 400 G6PD variants have been identified, but only afew are associated with disease. One of the most impor-tant is the G6PD A− variant, which is carried by approx-imately 10% of black males in the United States. G6PDA− has normal enzymatic activity but a decreased half-life. Because red cells lack the capacity for protein syn-thesis, older G6PD A− red cells become progressivelydeficient in enzyme activity and more vulnerable tooxidant stress.

G6PD deficiency produces no symptoms until thepatient is exposed to an environmental factor (most com-monly infectious agents or drugs) that results in increasedoxidant stress. The drugs incriminated include anti-malarials (e.g., primaquine), sulfonamides, nitrofuran-toin, phenacetin, aspirin (in large doses), and vitamin Kderivatives. More commonly, episodes of hemolysis are

Morphology

Only the morphologic changes in β-thalassemia, whichis more common in the United States, will be described.In β-thalassemia minor the abnormalities are confinedto the peripheral blood. In smears the red cells appearsmall (microcytic), pale (hypochromic), and regular inshape. Target cells are often seen, a feature that resultsfrom the relatively large surface area-to-volume ratio,which leads Hb to collect in a central, dark-red“puddle.” In smears from patients with β-thalassemiamajor the microcytosis and hypochromia are muchmore pronounced, and there is marked poikilocytosis,anisocytosis, and reticulocytosis. Nucleated red cells(normoblasts) are also seen, which reflect the underly-ing erythropoietic drive.

The anatomic changes in β-thalassemia major aresimilar to those seen in other hemolytic anemias butextreme in degree. The combination of ineffective ery-thropoiesis and hemolysis results in a striking hyper-plasia of erythroid progenitors, with a shift toward earlyforms. The expanded erythropoietic marrow may com-pletely fill the intramedullary space of the skeleton,invade the bony cortex, impair bone growth, andproduce skeletal deformities. The extramedullaryhematopoiesis and the hyperplasia of the mononuclearphagocytes result in prominent splenomegaly,hepatomegaly, and lymphadenopathy. The ineffectiveerythropoietic precursors consume nutrients andproduce growth retardation and a degree of cachexiareminiscent of that seen in cancer patients. Unlesssteps are taken to prevent iron overload, over the spanof years severe hemosiderosis develops (see Fig. 12–6).

utero, because the blood has virtually no oxygen-delivering capacity. With loss of three α-globin genesthere is a relative excess of β-globin or chains other thanα-globin. Excess β-globin (or γ-globin chains early in life)forms relatively stable β4 and γ4 tetramers known asHbH and Hb Bart, respectively, that cause less membranedamage than do free α-globin chains. Therefore, thehemolytic anemia and ineffective erythropoiesis tend beless severe in α-thalassemia than in β-thalassemia. Unfor-tunately, both HbH and Hb Bart have an abnormallyhigh affinity for oxygen, which renders them ineffectiveat delivering oxygen to the tissues.

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triggered by infections, which induced phagocytes toproduce free radicals as part of the normal host response.These offending agents produce oxidants such as hydro-gen peroxide that are sopped up by GSH, which is con-verted to oxidized glutathione in the process. Becauseregeneration of GSH is impaired in G6PD-deficient cells,hydrogen peroxide is free to “attack” other red cell com-ponents, including globin chains, which have sulfhydrylgroups that are susceptible to oxidation. Oxidized Hbdenatures and precipitates, forming intracellular inclu-sions called Heinz bodies, which can damage the cellmembrane sufficiently to cause intravascular hemolysis.Other cells that are less severely damaged neverthelsssuffer from a loss of deformability, and their cell mem-branes are further damaged when splenic phagocytesattempt to “pluck out” the Heinz bodies, creating so-called bite cells (Fig. 12–7). All of these changes predis-pose the red cells to becoming trapped in the splenicsinusoids and destroyed by the phagocytes (extravascularhemolysis).

Drug-induced hemolysis is acute and of variable clin-ical severity. Typically, patients develop evidence ofhemolysis after a lag period of 2 or 3 days. Because theG6PD gene is on the X chromosome, all the red cells ofaffected males are affected. However, because of randominactivation of one X chromosome in women (Chapter7), heterozygous females have two distinct populations ofred cells, one normal and the other deficient in G6PDactivity. Thus, affected males are more vulnerable tooxidant injury, whereas most carrier females are asymp-tomatic, except those with a very large proportion of defi-cient red cells (a chance situation known as unfavorablelyonization). In G6PD A−, the enzyme deficiency is mostmarked in older red cells, which are thus more suscepti-ble to lysis. Since the marrow compensates by producingnew (young) resistant red cells, hemolysis tends to abate

even if drug exposure continues. In other variants, suchas G6PD Mediterranean, found mainly in the MiddleEast, the enzyme deficiency and the hemolysis that occurupon exposure to oxidants are more severe.

Paroxysmal Nocturnal HemoglobinuriaA rare disorder of unknown etiology, paroxysmal noc-turnal hemoglobinuria (PNH) is mentioned here becauseit is the only form of hemolytic anemia that results froman acquired membrane defect secondary to a mutationthat affects myeloid stem cells. The mutant gene, calledPIGA, is required for the synthesis of a specific type ofintramembranous glycolipid anchor, phosphatidylinositolglycan (PIG), which is a component of diverse membrane-associated proteins. Without the membrane anchor, these“PIG-tailed” proteins cannot be expressed on the surfaceof cells. The affected proteins include several that limitthe spontaneous activation of complement on the surfaceof cells. As a result, PIG-deficient precursors give rise to red cells that are inordinately sensitive to the lyticactivity of complement. It is believed that the hemolysisis nocturnal because the blood becomes acidic duringsleep (because of CO2 retention) and an acid pH maypromote hemolysis. It is not known why red cell destruc-tion is paroxysmal. Several other PIG-tailed proteins aredeficient from the membranes of granulocytes andplatelets, possibly explaining the striking susceptibility ofthese patients to infections and intravascular thromboses.

PIGA is X-linked, and thus normal cells have only asingle active PIGA gene, mutation of which is sufficientto give rise to PIG deficiency. Because all myeloid lineagesare affected in PNH, the responsible mutations mustoccur in a multipotent stem cell. Remarkably, most, if notall, normal individuals harbor small numbers of PIG-deficient bone marrow cells that have mutations identi-cal to those that cause PNH. It is believed that clinicallyevident PNH occurs only in rare instances in which thePIG-deficient clone has a survival advantage. One is thesetting of primary bone marrow failure (aplastic anemia),which appears most often to be caused by immune-mediated destruction or suppression of marrow stemcells. It is hypothesized that in PNH patients, autoreactiveT cells specifically recognize PIG-tailed surface antigenson normal bone marrow progenitors. Because PIG-deficient stem cells do not express these targets, theyescape immune attack and eventually replace the normalmarrow elements. Therapy with an antibody that inhibitsthe C5–9 complement membrane complex (and therebyred cell hemolysis) is currently under evaluation.

Immunohemolytic AnemiasAntibodies that recognize determinants on red cell membranes cause these uncommon forms of hemolyticanemia. The antibodies may arise spontaneously or beinduced by exogenous agents such as drugs or chemicals.Immunohemolytic anemias are classified based on (1) thenature of the antibody and (2) the presence of certain predisposing conditions (summarized in Table 12–4).

Whatever the cause of antibody formation, the diag-nosis of immunohemolytic anemias depends on the detec-

Figure 12–7

Peripheral blood smear from a patient with glucose-6-phosphatedehydrogenase deficiency after exposure to an oxidant drug.Inset, red cells with precipitates of denatured globin (Heinzbodies) revealed by supravital staining. As the splenic macro-phages pluck out these inclusions, “bite cells” like the one in thissmear are produced. (Courtesy of Dr. Robert W. McKenna, Depart-ment of Pathology, University of Texas Southwestern MedicalSchool, Dallas, Texas.)

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tion of antibodies and/or complement on patient red cells. This is done using the direct Coombs antiglobulintest, which measures the capacity of antibodies raised inanimals against human immunoglobulins or complementto agglutinate red cells from the patient. The indirectCoombs test, in which patient serum is tested for theability to agglutinate defined red cells, can then be usedto characterize the target of the autoantibody.

Warm Antibody Immunohemolytic Anemias. These are caused by immunoglobulin G (IgG) or, rarely,immunoglobulin A (IgA) antibodies that are active at37°C. More than 60% of cases are idiopathic (primary),while another 25% are associated with an underlyingdisease affecting the immune system (e.g., systemic lupuserythematosus [SLE]) or are induced by drugs. The hemol-ysis usually results from the opsonization of red cells bythe autoantibodies, which leads to erythrophagocytosis in the spleen and elsewhere. Spheroidal cells resemblingthose seen in hereditary spherocytosis are often found inthe peripheral blood smear. Presumably, cell membrane isremoved during attempted phagocytosis of antibody-coated cells. This reduces the surface area-to-volume ratio and leads to the formation of spherocytes, which arerapidly destroyed in the spleen, as described earlier. Theclinical severity of immunohemolytic anemias is quitevariable. Most patients have chronic mild anemia withmoderate splenomegaly and often require no treatment.

The mechanisms of hemolysis induced by drugs arevaried and in some cases poorly understood. Drugs suchas α-methyldopa induce autoantibodies that are directedagainst intrinsic red cell antigens, in particular Rh bloodgroup antigens, producing an anemia that is indistin-guishable from primary idiopathic immunohemolyticanemia. Presumably, the drug alters native epitopes andthus allows a bypass of T-cell tolerance to the membraneproteins (see Chapter 5). In other cases, drugs such aspenicillin act as haptens and induce an antibody responseby binding to a red cell membrane protein. Sometimesantibodies bind to a drug in the circulation and formimmune complexes, which are then deposited on red cellmembranes. Here they may fix complement or act asopsonins, either of which can damage red cells and leadto hemolysis.

Cold Antibody Immunohemolytic Anemias. Theseanemias are caused by low-affinity immunoglobulin M

(IgM) antibodies, which bind to red cell membranes onlyat temperatures below 30°C, which are commonly expe-rienced in distal parts of the body (e.g., ears, hands, andtoes). Although IgM fixes complement well, the latersteps of complement fixation occur inefficiently at tem-peratures below 37°C. As a result, most cells with boundIgM pick up some C3b but are not lysed in the periph-ery. When these cells travel to warmer areas, the weaklybound IgM antibody is released, but the coating of C3bremains. Because C3b is an opsonin (Chapter 2), the cellsare phagocytosed by the mononuclear phagocyte system,especially Kupffer cells; hence, the hemolysis is extravas-cular. Cold agglutinins sometimes develop transientlyduring recovery from pneumonia caused by Mycoplasmasp. and infectious mononucleosis, producing a mildanemia of little clinical importance. A chronic cold agglutinin hemolytic anemia occurs in association withlymphoid neoplasms or as an idiopathic condition. Inaddition to anemia, Raynaud phenomenon often occursin these patients as a result of the agglutination of redcells in the capillaries of exposed parts of the body.

Hemolytic Anemias Resulting fromMechanical Trauma to Red CellsRed cells are disrupted by physical trauma in a variety ofcircumstances. Clinically important hemolytic anemiasare sometimes caused by cardiac valve prostheses or bythe narrowing and partial obstruction of the vasculature.Traumatic hemolytic anemia can be seen incidentally fol-lowing any activity that produces repeated physical blows(e.g., marathon racing and bongo drumming) but is ofclinical importance mainly in patients with mechanicalheart valves, which can cause sufficiently tubulent bloodflow to shear red cells. Microangiopathic hemolyticanemia is observed in a variety of pathologic states inwhich small vessels become partially obstructed. Themost frequent of these conditions is disseminatedintravascular coagulation (DIC; see later), in which thenarrowing is caused by the intravascular deposition offibrin. Other causes of microangiopathic hemolyticanemia include malignant hypertension, SLE, thromboticthrombocytopenic purpura, hemolytic-uremic syndrome,and disseminated cancer, all of which produce vascularlesions that predispose the circulating red cells tomechanical injury. The morphologic alterations in theinjured red cells (schistocytes) are striking and quite characteristic; “burr cells,” “helmet cells,” and “trianglecells” may be seen (Fig. 12–8). While the recognition ofmicroangiopathic hemolysis often provides an importantdiagnostic clue, in and of itself it is not usually a majorclinical problem.

MalariaIt has been estimated that 200 million persons suffer fromthis infectious disease, which is one of the most wide-spread afflictions of humans. Malaria is endemic in Asiaand Africa, but with widespread jet travel, cases nowoccur all over the world. Malaria is caused by one of fourtypes of protozoa. Of these, the most important is Plas-modium falciparum, which causes tertian malaria (falci-

Table 12–4 Classification of ImmunohemolyticAnemias

Warm Antibody Type

Primary (idiopathic)

Secondary: B-cell lymphoid neoplasms (e.g., chronic lymphocytic leukemia), autoimmune disorders (e.g., systemic lupus erythe-matosus), drugs (e.g., α-methyldopa, penicillin, quinidine)

Cold Antibody Type

Acute: Mycoplasma infection, infectious mononucleosis

Chronic: idiopathic, B-cell lymphoid neoplasms (e.g., lymphoplasmacytic lymphoma)

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parum malaria), a serious disorder with a high fatalityrate. The other three species of Plasmodium that infecthumans (P. malariae, P. vivax, and P. ovale) cause rela-tively benign disease. All forms are transmitted only bythe bite of female Anopheles mosquitoes, and humans arethe only natural reservoir.

Etiology and Pathogenesis. The life cycle of plasmodia iscomplex. As mosquitoes feed on human blood, sporo-zoites are introduced from the saliva and within a fewminutes infect liver cells. Here, the parasites multiplyrapidly to form a schizont containing thousands of mero-zoites. After a period of days to several weeks that varieswith the Plasmodium species, the infected hepatocytesrelease the merozoites, which quickly infect red cells.Intraerythrocytic parasites either continue asexual repro-duction to produce more merozoites or give rise to game-tocytes that are capable of infecting the next hungrymosquito. During their asexual reproduction in red cells,the parasites first develop into trophozoites that aresomewhat distinctive for each of the four forms ofmalaria. Thus, the species of malaria that is responsiblefor an infection can be identified in appropriately stainedthick smears of peripheral blood. The asexual phase iscompleted when the trophozoites give rise to new mero-zoites, which escape by lysing the red cells.

Clinical Features. The distinctive clinical and anatomicfeatures of malaria are related to the following:

• Showers of new merozoites are released from the redcells at intervals of approximately 48 hours for P.vivax, P. ovale, and P. falciparum, and 72 hours for P.malariae. The clinical spikes of shaking, chills, andfever coincide with this release.• The parasites destroy large numbers of red cells andthus cause hemolytic anemia.• A characteristic brown malarial pigment, probably aderivative of Hb that is identical to hematin, is released

from the ruptured red cells along with the merozoites,discoloring principally the spleen, but also the liver,lymph nodes, and bone marrow.• Activation of the phagocytic defense mechanisms of the host leads to marked hyperplasia of the mononu-clear phagocyte system throughout the body, reflectedin massive splenomegaly. Less frequently, the liver mayalso be enlarged.

Fatal falciparum malaria often involves the brain, acomplication known as cerebral malaria. Normally, redcells bear negatively charged surfaces that interact poorlywith endothelial cells. Infection of red cells with P. falciparum induces the appearance of positively chargedsurface knobs containing parasite-encoded proteins,which bind to adhesion molecules expressed on activatedendothelium. Several endothelial cell adhesion moleculeshave been proposed to mediate this interaction, includ-ing intercellular adhesion molecule 1, which leads to thesequestration of red cells in postcapillary venules. In thebrain this process gives rise to engorged cerebral vesselsthat are full of parasitized red cells and often occluded bymicrothrombi. Cerebral malaria is rapidly progres-sive; convulsions, coma, and death usually occur withindays to weeks. Fortunately, falciparum malaria morecommonly pursues a more chronic course that may bepunctuated at any time by a dramatic complicationknown as blackwater fever. The trigger for this uncom-mon complication is obscure, but it is associated withmassive hemolysis, leading to jaundice, hemoglobinemia,and hemoglobinuria.

With appropriate chemotherapy, the prognosis forpatients with most forms of malaria is good; however,treatment of falciparum malaria is becoming more diffi-cult, as a result of the emergence of drug-resistant strains.Because of the potentially serious consequences of thisdisease, early diagnosis and treatment are particularlyimportant but are sometimes delayed in nonendemic set-tings. The ultimate solution is an effective vaccine, whichis long sought but still elusive.

SUMMARY

Hemolytic Anemias

• Hereditary Spherocytosis:� Autosomal dominant disorder caused by inher-

ited mutations that affect the red cell mem-brane skeleton, leading to loss of membraneand eventual conversion of red cells to sphero-cytes, which are phagocytosed and removed inthe spleen.

� Manifested by anemia, splenomegaly.• Sickle Cell Anemia:

� Autosomal recessive disorder that results froma mutation in β-globin that causes deoxy-genated hemoglobin to self-associate into longpolymers that distort (sickle) the red cell.

� Blockage of vessels by aggregates of sickled cellscauses acute pain crises and tissue infarction.

Figure 12–8

Microangiopathic hemolytic anemia. The peripheral blood smearfrom a patient with hemolytic-uremic syndrome shows severalfragmented red cells. (Courtesy of Dr. Robert W. McKenna, Depart-ment of Pathology, University of Texas Southwestern MedicalSchool, Dallas, Texas.)

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ANEMIAS OF DIMINISHEDERYTHROPOIESIS

This category includes anemias that are caused by aninadequate dietary supply of substances that are neededfor hematopoiesis, particularly iron, folic acid, andvitamin B12. Other disorders that suppress erythropoiesisinclude those associated with bone marrow failure (aplas-tic anemia) or the replacement of the bone marrow bytumor or inflammatory cells (myelophthisic anemia). In the following sections some common examples ofanemias resulting from nutritional deficiencies andmarrow suppression are discussed individually.

Iron Deficiency AnemiaIt is estimated that anemia affects about 10% of the pop-ulation in developed countries and 25% to 50% in devel-oping countries. In both settings the most common causeof anemia is iron deficiency, which is without questionthe most common form of nutritional deficiency. Thefactors responsible for iron deficiency differ in variouspopulations and can be best considered in the context ofnormal iron metabolism.

Total body iron content is about 2gm for women and6gm for men. Approximately 80% of functional bodyiron is found in hemoglobin, with the remainder beingfound in myoglobin and iron-containing enzymes (e.g.,catalase and cytochromes). The iron storage pool, repre-sented by hemosiderin and ferritin-bound iron, containson average 15% to 20% of total body iron. Stored ironis found mainly in the liver, spleen, bone marrow, andskeletal muscle. Because serum ferritin is largely derivedfrom the storage pool of iron, its concentration is a good

indicator of the adequacy of body iron stores. Assessmentof bone marrow iron stores is another reliable, but moreinvasive, method for estimating body iron content. Ironis transported in the plasma by an iron-binding proteincalled transferrin. In normal persons, transferrin is about33% saturated with iron, yielding serum iron levels thataverage 120μg/dL in men and 100μg/dL in women.Thus, the total iron-binding capacity of serum is in therange of 300μg/dL to 350μg/dL.

As might be expected given the very high prevalenceof iron deficiency in human populations, evolutionarypressures have yielded metabolic pathways that arestrongly biased toward the retention of iron. There is noregulated pathway for iron excretion, which is limited tothe 1 to 2mg/day that is lost by the shedding of mucosaland skin epithelial cells. Iron balance therefore is main-tained largely by regulating the absorption of dietaryiron. The normal daily western diet contains 10mg to 20mg of iron. Most of this is in the form of heme con-tained in animal products, with the remainder being inor-ganic iron in vegetables. About 20% of heme iron (incontrast to 1% to 2% of nonheme iron) is absorbable,so the average western diet contains sufficient iron tobalance fixed daily losses.

Iron is absorbed in the duodenum, where it must passthrough the apical and basolateral membranes of entero-cytes (Fig. 12–9). Nonheme iron is carried across each of these two membranes by distinct transporters. Afterreduction by ferric reductase, the reduced iron is trans-ported by the divalent metal transporter (DMT1) acrossthe apical membrane into the cytoplasm. At least twoadditional proteins are then required for the basolateraltransfer of iron to transferrin in the plasma: ferroportin,which acts as a transporter; and hephaestin, which oxi-dizes the iron. Both DMT1 and ferroportin are widelydistributed in the body and are involved in iron transportin other tissues as well. As depicted in Figure 12–9, onlya fraction of the iron that enters the cell is delivered toplasma transferrin by the action of ferroportin. Theremainder is bound to ferritin and lost through the exfo-liation of mucosal cells.

When the body is replete with iron, most of the ironthat enters duodenal cells is bound to ferritin and nevertransferred to transferrin; in iron deficiency, or whenthere is ineffective erythropoiesis, transfer to plasmatransferrin is enhanced. This balance is regulated by hep-cidin, a small hepatic peptide that is synthesized andsecreted in an iron-dependent fashion. Plasma hepcidinbinds to ferroportin and induces its internalization anddegradation; thus, when hepcidin concentrations arehigh, ferroportin levels fall, and less iron is transferredout of the enterocytes to transferrin. Conversely, whenhepcidin levels are low, as occurs in hemochromatosis(Chapter 16), transport of iron from the enterocytes toplasma is increased, resulting eventually in systemic ironoverload.

Negative iron balance and consequent anemia can re-sult from a variety of causes:

• Low dietary intake alone is rarely the cause of irondeficiency in the United States, because the averagedaily dietary intake of 10mg to 20mg is more than

� Red cell membrane damage that attendsrepeated bouts of sickling results in a moderateto severe hemolytic anemia.

• Thalassemias:� Group of autosomal co-dominant disorders in

which mutations in the α- or β-globin genesresult in reduced hemoglobin synthesis, causinga microcytic, hypochromic anemia. In β-thalassemia unpaired α-globin chains formaggregates that damage red cell precursors andfurther impair erythropoiesis.

• Glucose-6-Phosphate Dehydrogenase (G6PD)Deficiency:

� X-linked disorder in which red cells are unusu-ally susceptible to damage caused by oxidants.

• Immunohemolytic Anemias:� Caused by antibody binding to red cell surface

antigens, which may be normal red cell con-stituents or antigens that are modified byhaptens (such as drugs).

� Antibody binding can result in red cell opsoniza-tion and phagocytosis in the spleen or comple-ment fixation and intravascular hemolysis.

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enough for males and adequate for females. In otherparts of the world, however, low intake and poorbioavailability from predominantly vegetarian diets arean important cause of iron deficiency.• Malabsorption can occur with sprue and celiacdisease or after gastrectomy (Chapter 15).• Increased demands not met by normal dietary intakeoccur around the world during pregnancy and infancy.• Chronic blood loss is the most important cause ofiron deficiency anemia in the western world; this lossmay occur from the gastrointestinal tract (e.g., pepticulcers, colonic cancer, hemorrhoids, hookwormdisease) or the female genital tract (e.g., menorrhagia,metrorrhagia, cancers).

Regardless of the cause, iron deficiency develops insid-iously. At first iron stores are depleted, leading to adecline in serum ferritin and the absence of stainable ironin the bone marrow. This is followed by a decrease inserum iron and a rise in the serum iron-binding capacity.Ultimately the capacity to synthesize hemoglobin, myo-globin, and other iron-containing proteins is diminished,leading to anemia, impaired work and cognitive perfor-mance, and even reduced immunocompetence.

Clinical Course. In most instances, iron deficiency anemiais asymptomatic. Nonspecific manifestations, such asweakness, listlessness, and pallor, may be present insevere cases. With long-standing severe anemia, thinning,flattening, and eventually “spooning” of the fingernailssometimes appears. A curious but characteristic neu-robehavioral complication is pica, the compunction toconsume non-foodstuffs such as dirt or clay.

Diagnostic criteria include anemia, hypochromic andmicrocytic red cell indices, low serum ferritin and serumiron levels, low transferrin saturation, increased totaliron-binding capacity, and, ultimately, response to irontherapy. Persons frequently die with this form of anemiabut rarely of it. It is important to remember that in rea-sonably well-nourished persons, microcytic hypochromic

Morphology

Except in unusual circumstances, iron deficiencyanemia is relatively mild. The red cells are microcyticand hypochromic, reflecting the reductions in MCV andMCHC (Fig. 12–10). For unclear reasons, iron deficiencyis often accompanied by an increase in the plateletcount. Although erythropoietin levels are increased, themarrow response is blunted by the iron deficiency, and thus the marrow cellularity is usually only slightly in-creased. Extramedullary hematopoiesis is uncommon.

Figure 12–10

Hypochromic microcytic anemia of iron deficiency. Note the smallred cells containing a narrow rim of hemoglobin at the periphery.Compare to the scattered, fully hemoglobinized cells derived froma recent blood transfusion given to the patient. (Courtesy of Dr.Robert W. McKenna, Department of Pathology, University of TexasSouthwestern Medical School, Dallas, Texas.)

FOODIRON

Heme iron

Nonhemeiron

Fe3+

Fe2+

DMT1

Duodenalcytochrome B

Heme transporter

Mucosalferritin

Lost by sheddingof epithelial cells

Fe2+

Fe3+

Ferroportin 1

Hephaestin

Portal blood

Liver

Hepcidin

Erythroidmarrow

Plasmatransferrin

Figure 12–9

Iron absorption. Mucosal uptake of heme and nonheme iron is depicted. When the storage sites of the body are replete with iron anderythropoietic activity is normal, most of the absorbed iron is lost into the gut by shedding of the epithelial cells. Conversely, when bodyiron requirements increase or when erythropoiesis is stimulated, a greater fraction of the absorbed iron is transferred into plasma trans-ferrin, with a concomitant decrease in iron loss through mucosal ferritin. DMT1, divalent metal transporter 1.

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anemia is not a disease but rather a symptom of someunderlying disorder.

Anemia of Chronic DiseaseThis is the most common form of anemia in hospitalizedpatients. It superficially resembles the anemia of iron defi-ciency, but it stems from inflammation-induced seques-tration of iron within the cells of the mononuclearphagocyte (reticuloendothelial) system. It occurs in avariety of chronic inflammatory disorders, including thefollowing:

• Chronic microbial infections, such as osteomyelitis,bacterial endocarditis, and lung abscess• Chronic immune disorders, such as rheumatoidarthritis and regional enteritis• Neoplasms, such as Hodgkin lymphoma and carci-nomas of the lung and breast

The serum iron levels are usually low, and the red cellscan be normocytic and normochromic, or, as in anemiaof iron deficiency, hypochromic and microcytic. However,the anemia of chronic disease is associated with increasedstorage iron in the bone marrow, a high serum ferritinconcentration, and a reduced total iron-binding capacity,all of which readily rule out iron deficiency. This combi-nation of findings is attributable to high concentrationsof circulating hepcidin, which inhibits ferroportin andthereby block the transfer of iron from the mononuclearphagocyte storage pool to the erythroid precursors. Theelevated hepcidin concentrations are caused by pro-inflammatory cytokines, which enhance the synthesis ofhepcidin by the liver. In addition, chronic inflammationalso blunts the compensatory increase in erythropoietinlevels, which is not adequate for the degree of anemia.The teleologic explanation for iron sequestration in thepresence of a wide variety of chronic inflammatory dis-orders is unclear; it may serve to inhibit the growth ofiron-dependent microorganisms or to augment certainaspects of host immunity. Administration of erythropoi-etin and iron can improve the anemia, but only effectivetreatment of the underlying condition is curative.

Megaloblastic AnemiasThere are two principal causes of megaloblastic anemia:folate deficiency and vitamin B12 deficiency. Both vitaminsare required for DNA synthesis, and, hence, the effects oftheir deficiency on hematopoiesis are quite similar.However, as will be described, the causes and conse-quences of folate and vitamin B12 deficiency differ inimportant ways.

Pathogenesis. The morphologic hallmark of megaloblas-tic anemias is an enlargement of erythroid precursors(megaloblasts), which gives rise to abnormally large redcells (macrocytes). The other myeloid lineages are alsoaffected. Most notably, granulocyte precursors areenlarged (giant metamyelocytes) and yield highly charac-teristic hypersegmented neutrophils. Underlying the cel-lular gigantism is an impairment of DNA synthesis, whichresults in a delay in nuclear maturation and cell division.Because the synthesis of RNA and cytoplasmic elementsproceeds at a normal rate and thus outpaces that of the

nucleus, the hematopoietic precursors show nuclear-cytoplasmic asynchrony. This maturational derangementcontributes to anemia in several ways. Some megaloblastsare so defective in DNA synthesis that they undergo apop-tosis in the marrow (ineffective hematopoiesis). Otherssucceed in maturing into red cells but do so after fewercell divisions; as a result, the total output from these pre-cursors is diminished. Granulocyte and platelet precursorsare similarly affected. As a result, most patients withmegaloblastic anemia develop pancytopenia (anemia,thrombocytopenia, and granulocytopenia).

Figure 12–11

Comparison of normoblasts (left) and megaloblasts (right). Themegaloblasts are larger, have relatively immature nuclei with finelyreticulated chromatin, and have an abundant basophilic cyto-plasm. (Courtesy of Dr. José Hernandez, Department of Pathology,University of Texas Southwestern Medical School, Dallas, Texas.)

Morphology

Certain morphologic features are common to all formsof megaloblastic anemias. The bone marrow ismarkedly hypercellular, as a result of increasednumbers of megaloblasts. These cells are larger thannormoblasts and have a delicate, finely reticulatednuclear chromatin (suggestive of nuclear immaturity)and an abundant, strikingly basophilic cytoplasm (Fig.12–11). As the megaloblasts differentiate and begin toacquire hemoglobin, the nucleus retains its finely dis-tributed chromatin and fails to undergo the chromatinclumping typical of an orthochromatic normoblast.Similarly, the granulocytic precursors also demonstratenuclear-cytoplasmic asynchrony, yielding giantmetamyelocytes. Megakaryocytes, too, may be abnor-mally large and have bizarre multilobed nuclei.

In the peripheral blood the earliest change is usuallythe appearance of hypersegmented neutrophils, whichappear even before the onset of anemia. Normally, neu-trophils have three or four nuclear lobes, but in mega-loblastic anemias neutrophils often have five or more.The red cells typically include large, egg-shaped macro-ovalocytes; the MCV is often greater than 110fL(normal, 82–92fL). Although macrocytes appear hyper-chromic, in reality the MCHC is normal. Large, mis-shapen platelets may also be seen. Morphologicchanges in other systems, especially the gastrointesti-nal tract, also occur, giving rise to some of the clinicalfeatures.

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Folate (Folic Acid) Deficiency Anemia

Megaloblastic anemia secondary to folate deficiency isnot common, but marginal folate stores occur with sur-prising frequency even in apparently healthy individuals.The risk of clinically significant folate deficiency is highin those with a poor diet (the economically deprived, theindigent, and the elderly) or increased metabolic needs(pregnant women and patients with chronic hemolyticanemias).

Ironically, folate is widely prevalent in nearly all foodsbut is readily destroyed by 10 to 15 minutes of cooking.Thus, the best sources of folate are fresh uncooked veg-etables and fruits. Food folates are predominantly inpolyglutamate form and must be split into monogluta-mates for absorption, a conversion that is hampered byacidic foods and substances found in beans and otherlegumes. Phenytoin (Dilantin) and a few other drugs also inhibit folate absorption, while others, such asmethotrexate, inhibit folate metabolism. The principalsite of intestinal absorption is the upper third of the smallintestine; thus, malabsorptive disorders that affect thislevel of the gut, such as celiac disease and tropical sprue,can impair folate uptake.

The metabolism and physiologic functions of folate are complex. Here, it is sufficient to note that, afterabsorption, folate is transported in the blood mainly asa monoglutamate. Within cells it is further metabolizedto several derivatives, but its conversion from dihydrofo-late to tetrahydrofolate by the enzyme dihydrofolatereductase is particularly important. Tetrahydrofolate actsas an acceptor and donor of one-carbon units in a varietyof steps involved in the synthesis of purines and thymidy-late, the building blocks of DNA, and its deficiencyaccounts for the inadequate DNA synthesis that is char-acteristic of megaloblastic anemia.

The onset of the anemia is insidious and is associatedwith nonspecific symptoms such as weakness and easyfatigability. The clinical picture may be complicated bythe coexistent deficiency of other vitamins, especially inalcoholics. Because the gastrointestinal tract, like thehematopoietic system, is a site of rapid cell turnover,symptoms referable to the alimentary tract are commonand often severe. These include sore tongue and cheilo-sis. It should be stressed that, unlike in vitamin B12 defi-ciency, neurologic abnormalities do not occur.

The diagnosis of a megaloblastic anemia is readilymade from examination of a smear of peripheral bloodand bone marrow. The anemia of folate deficiency is bestdistinguished from that of vitamin B12 deficiency by mea-suring serum and red cell folate and vitamin B12 levels.

Vitamin B12 (Cobalamin) Deficiency Anemia:Pernicious Anemia

Inadequate levels of vitamin B12, or cobalamin, result ina megaloblastic macrocytic anemia similar to that causedby folate deficiency. However, vitamin B12 deficiency canalso cause a demyelinating disorder involving the periph-eral nerves and, ultimately and most importantly, thespinal cord. There are many causes of vitamin B12 defi-

ciency. The term pernicious anemia, a relic of the dayswhen the cause and therapy of this condition wereunknown, is used to describe vitamin B12 deficiencyresulting from inadequate gastric production or defectivefunction of intrinsic factor. Intrinsic factor plays a criti-cal role in the absorption of vitamin B12, a complex mul-tistep process that proceeds as follows:

1. Peptic digestion releases dietary vitamin B12, whichthen binds to salivary B12-binding proteins calledcobalophilins, or R binders.

2. R-B12 complexes are transported to the duodenumand processed by pancreatic proteases; this releasesB12, which attaches to intrinsic factor secreted fromthe parietal cells of the gastric fundic mucosa.

3. The intrinsic factor–B12 complex passes to the distalileum and attaches to the epithelial intrinsic factorreceptors, which leads to absorption of vitamin B12.

4. The absorbed B12 is bound to transport proteinscalled transcobalamins, which then deliver it to theliver and other cells of the body.

Etiology. Among the many potential causes of cobalamindeficiency, long-standing malabsorption is the mostcommon and important. Vitamin B12 is abundant in allanimal foods, including eggs and dairy products, and isresistant to cooking and boiling. Even bacterial contam-ination of water and nonanimal foods can provide ade-quate amounts. As a result, deficiencies due to diet arerare and are virtually confined to strict vegans. Oncevitamin B12 is absorbed, the body handles it very effi-ciently. It is stored in the liver, which normally containsreserves that are sufficient to support bodily needs for 5to 20 years.

Until proved otherwise, a deficiency of vitamin B12 (inthe western world) is caused by pernicious anemia. Thisdisease seems to stem from an autoimmune reactionagainst parietal cells and intrinsic factor itself, which pro-duces gastric mucosal atrophy (Chapter 15). Several associations favor an autoimmune basis:

• Autoantibodies are present in the serum and gastricjuice of most patients with pernicious anemia. Threetypes of antibodies have been found: parietal canalic-ular antibodies, which bind to the mucosal parietalcells; blocking antibodies, which block the binding ofvitamin B12 to intrinsic factor; and binding antibodiesthat react with intrinsic factor–B12 complex andprevent it from binding to the ileal receptor.• An occurrence of pernicious anemia with otherautoimmune diseases such as Hashimoto thyroiditis,Addison disease, and type I diabetes mellitus is welldocumented.• The frequency of serum antibodies to intrinsic factoris increased in patients with other autoimmune diseases.

Chronic vitamin B12 malabsorption is also seen fol-lowing gastrectomy (which leads to loss of cells produc-ing intrinsic factor) or resection of ileum (which preventsabsorption of intrinsic factor–B12 complex), and in dis-orders that involve the distal ileum (such as Crohndisease, tropical sprue, and Whipple disease). In individ-

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uals older than 70 years of age, gastric atrophy andachlorhydria can interfere with the production of acidand pepsin, which are needed to release the vitamin fromits bound form in the diet.

The metabolic defects that are responsible for theanemia are intertwined with folate metabolism. VitaminB12 is required for recycling of tetrahydrofolate, and henceits deficiency reduces the availability of the form of folatethat is required for DNA synthesis. As expected, given thisrelationship, the anemia of vitamin B12 deficiencyimproves with administration of folates. In contrast, thebiochemical basis of the neuropathy in vitamin B12 defi-ciency is unclear, and administration of folate may actuallyexacerbate the neurologic disease. The principal neuro-logic lesions associated with vitamin B12 deficiency aredemyelination of the posterior and lateral columns of thespinal cord, sometimes beginning in the peripheral nerves.In time, axonal degeneration may supervene. The severityof neurologic manifestations is not related to the degree ofanemia. Indeed, uncommonly, the neurologic diseaseoccurs in the absence of overt megaloblastic anemia.

Clinical Features. Manifestations of vitamin B12 defi-ciency are nonspecific. As with any other anemia, thereis pallor, easy fatigability, and, in severe cases, dyspneaand even congestive heart failure. The increased destruc-tion of erythroid progenitors may give rise to mild jaun-dice. Gastrointestinal symptoms similar to those seen infolate deficiency are seen. The spinal cord disease beginswith symmetric numbness, tingling, and burning in feetor hands, followed by unsteadiness of gait and loss ofposition sense, particularly in the toes. Although theanemia responds dramatically to parenteral vitamin B12,the neurologic manifestations often fail to resolve. As dis-cussed in Chapter 15, patients with pernicious anemiahave an increased risk of gastric carcinoma.

The diagnostic features of pernicious anemia include(1) low serum vitamin B12 levels, (2) normal or elevatedserum folate levels, (3) serum antibodies to intrinsicfactor, (4) moderate to severe megaloblastic anemia, (5)leukopenia with hypersegmented granulocytes, and (6) adramatic reticulocytic response (within 2–3 days) to par-enteral administration of vitamin B12.

Aplastic AnemiaAplastic anemia is a disorder in which multipotentmyeloid stem cells are suppressed, leading to marrowfailure and pancytopenia. Notwithstanding its name,aplastic anemia should not be confused with selectivesuppression of erythroid stem cells (pure red cell aplasia),in which anemia is the only manifestation.

Etiology and Pathogenesis. In more than half of cases,aplastic anemia is idiopathic. In the remainder, an expo-sure to known myelotoxic agents, such as drugs or chemicals, can be identified. With some agents, themarrow damage is predictable, dose related, and usuallyreversible. Included in this category are antineoplasticdrugs (e.g., alkylating agents, antimetabolites), benzene,and chloramphenicol. In other instances marrow toxicityoccurs as an apparent “idiosyncratic” or hypersensitivity

reaction to small doses of known myelotoxic drugs (e.g.,chloramphenicol) or to drugs such as sulfonamides,which are not myelotoxic in other persons.

Aplastic anemia sometimes arises after certain viralinfections, most often community-acquired viral hepati-tis. The specific virus responsible is not known; hepatitisviruses A, B, and C are apparently not the culprits.Marrow aplasia develops insidiously several months afterrecovery from the hepatitis and follows a relentlesscourse.

The pathogenetic events leading to marrow failureremain vague, but it seems that autoreactive T cells mayplay an important role. This is supported by a variety ofexperimental data and clinical experience, which hasshown that in 70% to 80% of cases aplastic anemiaresponds to immunosuppressive therapy aimed at T cells.Much less clear are the events that trigger the T-cell attackon marrow stem cells; perhaps viral antigens, drug-derived haptens, and/or genetic damage create neoanti-gens within stem cells that serve as targets for the immunesystem.

Rare but interesting genetic conditions are also asso-ciated with marrow failure. Of note, a small fraction ofpatients with “acquired” aplastic anemia have inheriteddefects in telomerase, which you will recall is needed forthe maintenance and stability of chromosomes. In thesesettings intrinsic defects lead directly to damage andsenescence of hematopoietic stem cells.

Morphology

The bone marrow in aplastic anemia typically ismarkedly hypocellular, with greater than 90% of theintertrabecular space being occupied by fat. The limitedcellularity often consists of only lymphocytes andplasma cells. These changes are better appreciated inbone marrow biopsy specimens than in marrow aspi-rates, which often yield a “dry tap.” A number of sec-ondary changes often accompany marrow failure.Anemia may cause fatty change in the liver, and throm-bocytopenia and granulocytopenia may result in hem-orrhages and bacterial infections, respectively. Therequirement for transfusions may eventually causehemosiderosis.

Clinical Course. Aplastic anemia affects persons of allages and both sexes. The slowly progressive anemiacauses the insidious development of weakness, pallor, and dyspnea. Thrombocytopenia often presents withpetechiae and ecchymoses. Granulocytopenia may bemanifested only by frequent and persistent minor infec-tions or by the sudden onset of chills, fever, and prostra-tion. It is important to distinguish aplastic anemia fromanemias caused by marrow infiltration (myelophthisicanemia), “aleukemic leukemia,” and granulomatous diseases. Because pancytopenia is common to these conditions, their clinical manifestations may be indistinguishable, but they are easily distinguished byexamination of the bone marrow. Splenomegaly is char-acteristically absent in aplastic anemia; if it is present, the

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Laboratory Diagnosis of AnemiasThe diagnosis of anemia is established by a decrease inthe hemoglobin and the hematocrit to levels that arebelow normal. Based on the red cell hemoglobin content and size, anemias can be placed into three major subgroups: normocytic normochromic, microcytichypochromic, and macrocytic. The presence of red cellswith a particular morphology, such as spherocytes,sickled cells, and fragmented cells, provide additional eti-ologic clues. The specialized tests cited below are partic-ularly important in establishing the diagnosis of certainclasses of anemia:

• Gel electrophoresis: used to detect abnormal hemo-globins, such as HbS• Coombs test: used to diagnose immunohemolyticanemias• Reticulocyte counts: used to distinguish betweenanemias caused by red cell destruction (hemolysis) anddepressed production (marrow failure)• Iron indices (serum iron, serum iron-binding capac-ity, transferrin saturation, and serum ferritin concen-trations): used to distinguish between hypochromicmicrocytic anemias caused by iron deficiency, anemiaof chronic disease, and thalassemia minor• Serum and red cell folate and vitamin B12 concen-trations: used to identify the cause of megaloblasticanemia• Plasma unconjugated bilirubin and haptogloblinconcentrations: used to support the diagnosis ofhemolytic anemia

In isolated anemia, tests performed on the peripheralblood usually suffice to establish a cause. In contrast,when anemia occurs in combination with thrombocy-topenia and/or granulocytopenia, it is much more likelyto be associated with marrow aplasia or infiltration; inthese instances, a marrow examination is often critical fordiagnosis.

POLYCYTHEMIA

Polycythemia, or erythrocytosis, as it is sometimesreferred to, denotes an increase in the blood concentra-tion of red cells, which usually correlates with an increasein the hemoglobin concentration. Polycythemia may berelative, when there is hemoconcentration caused by adecrease in plasma volume, or absolute, when there is an

diagnosis of aplastic anemia should be seriously ques-tioned. Typically, the red cells are normocytic and nor-mochromic, although slight macrocytosis is occasionallypresent; reticulocytes are reduced in number.

The prognosis of marrow aplasia is quite unpre-dictable. As mentioned earlier, withdrawal of toxic drugsmay lead to recovery in some cases. The idiopathic formhas a poor prognosis if left untreated. Bone marrowtransplantation is an extremely effective form of therapy,especially if performed in nontransfused patients youngerthan 40 years of age. It is proposed that transfusions sen-sitize patients to alloantigens, producing a high engraft-ment failure rate following bone marrow transplantation.As mentioned earlier, patients who are poor transplantcandidates may benefit from immunosuppressive therapy.

Myelophthisic AnemiaThis form of anemia is caused by the extensive replace-ment of the marrow by tumors or other lesions. It is mostcommonly associated with metastatic breast, lung, orprostate cancer, but other cancers, advanced tuberculosis,lipid storage disorders, and osteosclerosis can produce asimilar clinical picture. The principal manifestations ofmarrow infiltration include anemia and thrombocytope-nia; in general, the white cell series is less affected. Characteristically, misshapen red cells, some resemblingteardrops, are seen in the peripheral blood. Immaturegranulocytic and erythrocytic precursors may also be seen(leukoerythroblastosis), along with a slightly elevatedwhite cell count. Treatment is focused on the manage-ment of the underlying condition.

SUMMARY

Anemias of Diminished Erythropoiesis

• Iron Deficiency Anemia:� Inadequate intake of iron results in insufficient

hemoglobin synthesis and hypochromic andmicrocytic red cells.

• Anemia of Chronic Disease:� Caused by production of inflammatory

cytokines, which cause iron to be sequesteredin macrophages, resulting in an anemia that isusually normochromic and normocytic.

• Megaloblastic Anemia:� Caused by deficiencies of folate or vitamin B12,

which lead to inadequate synthesis of thymi-dine and defective DNA replication.

� Results in enlarged abnormal hematopoieticprecursors (megaloblasts) in the bone marrow,ineffective hematopoiesis, and (in most cases)pancytopenia.

• Aplastic Anemia:� Caused by bone marrow failure (hypocellular-

ity) due to diverse causes, including exposuresto toxins and radiation, idiosyncratic reactionsto drugs and viruses, and inherited defects inDNA repair and the enzyme telomerase.

• Myelophthisic Anemia:� Caused by replacement of the bone marrow by

infiltrative processes such as metastatic carci-noma and granulomatous disease.

� Leads to the release of early erythroid and gran-ulocytic precursors (leukoerythroblastosis) andthe appearance of tear-drop red cells in theperipheral blood.

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increase in the total red cell mass. Relative polycythemiaresults from any cause of dehydration, such as waterdeprivation, prolonged vomiting, diarrhea, or the exces-sive use of diuretics. Absolute polycythemia is said to beprimary when the increase in red cell mass results froman autonomous proliferation of the myeloid stem cells,and secondary when the red cell progenitors are prolif-erating in response to an increase in erythropoietin.Primary polycythemia (polycythemia vera [PCV]) is aclonal, neoplastic proliferation of myeloid progenitors,which is considered later in this chapter with the othermyeloproliferative disorders. The increases in erythro-poietin that are seen in secondary polycythemias have avariety of causes (Table 12–5).

Etiology and Pathogenesis. The mechanisms that causeneutropenia can be broadly divided into two categories:

• Inadequate or ineffective granulopoiesis. Reducedgranulopoiesis is a manifestation of generalizedmarrow failure, which occurs in aplastic anemia and avariety of leukemias. Cancer chemotherapy agents alsoproduce neutropenia by inducing transient marrowaplasia. Alternatively, some neutropenias are isolated,with only the differentiation of committed granulocyticprecursors being affected. These forms of neutropeniaare most often caused by certain drugs or, more uncom-monly, by neoplastic proliferations of cytotoxic T cellsand natural killer (NK) cells.• Accelerated removal or destruction of neutrophils.This can be encountered with immune-mediated injuryto neutrophils (triggered in some cases by drugs), or itmay be idiopathic. Increased peripheral utilization canoccur in overwhelming bacterial, fungal, or rickettsialinfections. An enlarged spleen can also lead to seques-tration and accelerated removal of neutrophils.

Table 12–5 Pathophysiologic Classification of Polycythemia

Relative

Reduced plasma volume (hemoconcentration)

Absolute

Primary: Abnormal proliferation of myeloid stem cells, normal or low erythropoietin levels (polycythemia vera); inherited activat-ing mutations in the erythropoietin receptor (rare)

Secondary: Increased erythropoietin levelsAppropriate: lung disease, high-altitude living, cyanotic heartdiseaseInappropriate: erythropoietin-secreting tumors (e.g., renal cellcarcinoma, hepatoma, cerebellar hemangioblastoma); surrepti-tious erythropoietin use (e.g., in endurance athletes)

Morphology

The anatomic alterations in the bone marrow dependon the underlying basis of the neutropenia. Marrowhypercellularity is seen when the neutropenia resultsfrom excessive destruction of the mature neutrophils orfrom ineffective granulopoiesis, such as occurs inmegaloblastic anemia. In contrast, agents such asdrugs that suppress granulocytopoiesis are associatedwith a marked decrease in maturing granulocytic pre-cursors in the marrow. Erythropoiesis and megakary-opoiesis can be normal if the responsible agentspecifically affects the granulocytes, but with mostmyelotoxic drugs all marrow elements are affected.

Disorders of white cells include deficiencies (leukopenias)and proliferations, which may be reactive or neoplastic.Reactive proliferation in response to an underlyingprimary, often microbial, disease is fairly common. Neoplastic disorders, though less common, are moreominous; they cause approximately 9% of all cancerdeaths in adults and a staggering 40% in childrenyounger than 15 years. In the following discussion wefirst describe some non-neoplastic conditions and thenconsider in some detail the malignant proliferations ofwhite cells.

NON-NEOPLASTIC DISORDERS OF WHITE CELLS

Leukopenia

Leukopenia results most commonly from a decrease ingranulocytes, which are the most prevalent circulatingwhite cells. Lymphopenias are much less common; theyare associated with congenital immunodeficiency diseasesor are acquired in association with specific clinical states,such as advanced human immunodeficiency virus (HIV)infection or treatment with corticosteroids. Only themore common leukopenias that affect granulocytes arediscussed here.

Neutropenia/Agranulocytosis

A reduction in the number of granulocytes in blood isknown as neutropenia or sometimes, when severe, asagranulocytosis. Characteristically, the total white cellcount is reduced to 1000 cells/μL and in some instancesto as few as 200 to 300 cells/μL. Affected persons areextremely susceptible to bacterial and fungal infections,which can be severe enough to cause death.

WHITE CELL DISORDERS

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Clinical Course. The initial symptoms are often malaise,chills, and fever, with subsequent marked weakness and fatigability. Infections constitute the major problem.They commonly take the form of ulcerating, necrotizinglesions of the gingiva, floor of the mouth, buccal mucosa,pharynx, or other sites within the oral cavity (agranulo-cytic angina). These lesions often show a massive growth of microorganisms, due to the inability to mounta leukocyte response. In addition to removal of theoffending drug and control of infections, treatmentefforts may also include the administration of granulo-cyte colony-stimulating factor, which stimulates neu-trophil production by the bone marrow.

Reactive LeukocytosisAn increase in the number of white cells is common in avariety of reactive inflammatory states caused by micro-bial and nonmicrobial stimuli. Leukocytoses are rela-tively nonspecific and can be classified on the basis of theparticular white cell series affected (Table 12–6). As willbe discussed later, in some cases reactive leukocytosis maymimic leukemia. Such leukemoid reactions must be distinguished from true malignancies of the white cells. Infectious mononucleosis, a form of lymphocytosiscaused by Epstein-Barr virus (EBV) infection, merits sep-arate consideration because it gives rise to a distinctivesyndrome.

Infectious Mononucleosis

In the Western world, infectious mononucleosis is anacute, self-limited disease of adolescents and young adultsthat is caused by B lymphocytotropic EBV, a member ofthe herpesvirus family. The infection is characterized by(1) fever, sore throat, and generalized lymphadenitis; (2)an increase of lymphocytes in blood, many of which havean atypical morphology; and (3) an antibody and T cellresponse to EBV. It should be noted that cytomegalovirusinfection induces a similar syndrome, which can be dif-ferentiated only by serologic methods.

Epidemiology and Immunology. EBV is ubiquitous in allhuman populations. Where economic deprivation resultsin inadequate living standards, EBV infection early in lifeis nearly universal. At this age, symptomatic disease isuncommon, and, even though infected hosts develop animmune response (described later), more than half con-tinue to shed virus. In contrast, in developed countriesthat enjoy better standards of hygiene, infection is usuallydelayed until adolescence or young adulthood. Forreasons that are not clear, only about 20% of healthyseropositive persons in developed countries shed thevirus, and only about 50% of those who are exposed to the virus acquire the infection. Transmission to aseronegative “kissing cousin” usually involves direct oralcontact. It is hypothesized (but not proven) that the virusinitially infects oropharyngeal epithelial cells and thenspreads to underlying lymphoid tissue (tonsils and ade-noids), where B lymphocytes, which have receptors forEBV, are infected. The infection of B cells takes one oftwo forms. In a minority of cells, the infection leads toviral replication and eventual cell lysis accompanied bythe release of virions. In most cells, however, the infec-tion is nonproductive, and the virus persists in latent formas an extrachromosomal episome. B cells that are latentlyinfected with EBV undergo polyclonal activation andproliferation, as a result of the action of several EBV pro-teins (Chapter 6). These cells disseminate in the circula-tion and secrete antibodies with several specificities,including the well-known heterophil anti-sheep red cellantibodies that are recognized in diagnostic tests formononucleosis. During this early acute infection, EBV isshed in the saliva; it is not known if the source of thesevirions is oropharyngeal epithelial cells or B cells.

A normal immune response is extremely important incontrolling the proliferation of EBV-infected B cells andspread of virus. Early in the course of the infection, IgM,and, later, IgG, antibodies are formed against viral capsidantigens. The latter persist for life. More important in thecontrol of polyclonal B-cell proliferation are cytotoxicCD8+ T cells and NK cells. Virus-specific cytotoxic Tcells appear as atypical lymphocytes in the circulation, afinding that is characteristic of acute mononucleosis. Inotherwise healthy persons, the fully developed humoraland cellular responses to EBV act as brakes on viral shed-ding, limiting the number of infected B cells rather thaneliminating them. Latent EBV remains in a few B cellsand possibly oropharyngeal epithelial cells as well. Aswill be seen, impaired immunity in the host can have disastrous consequences.

Table 12–6 Causes of Leukocytosis

Neutrophilic Leukocytosis

Acute bacterial infections, especially those caused by pyogenic organisms; sterile inflammation caused by, for example, tissuenecrosis (myocardial infarction, burns)

Eosinophilic Leukocytosis (Eosinophilia)

Allergic disorders such as asthma, hay fever, allergic skin diseases (e.g., pemphigus, dermatitis herpetiformis); parasiticinfestations; drug reactions; certain malignancies (e.g., Hodgkindisease and some non-Hodgkin lymphomas); collagen vasculardisorders and some vasculitides; atheroembolic disease(transient)

Basophilic Leukocytosis (Basophilia)

Rare, often indicative of a myeloproliferative disease (e.g., chronic myelogenous leukemia)

Monocytosis

Chronic infections (e.g., tuberculosis), bacterial endocarditis, rickettsiosis, and malaria; collagen vascular diseases (e.g.,systemic lupus erythematosus); and inflammatory bowel diseases(e.g., ulcerative colitis)

Lymphocytosis

Accompanies monocytosis in many disorders associated with chronic immunologic stimulation (e.g., tuberculosis, brucellosis);viral infections (e.g., hepatitis A, cytomegalovirus, Epstein-Barrvirus); Bordetella pertussis infection

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not unusual. It can appear with little or no fever and only malaise, fatigue, and lymphadenopathy, raising thespecter of lymphoma; as a fever of unknown origin, unas-sociated with significant lymphadenopathy or other local-ized findings; as hepatitis that is difficult to differentiatefrom one of the hepatotropic viral syndromes (Chapter16); or as a febrile rash resembling rubella. Ultimately,the diagnosis depends on the following findings, inincreasing order of specificity: (1) lymphocytosis with thecharacteristic atypical lymphocytes in the peripheralblood, (2) a positive heterophil reaction (monospot test),and (3) a rising titer of antibodies specific for EBV anti-gens (viral capsid antigens, early antigens, or Epstein-Barr nuclear antigen). In most patients, mononucleosisresolves within 4 to 6 weeks, but sometimes the fatiguelasts longer. Occasionally, one or more complicationssupervene. Perhaps the most common of these is hepaticdysfunction, associated with jaundice, elevated hepaticenzyme levels, disturbed appetite, and, rarely, even liverfailure. Other complications involve the nervous system,kidneys, bone marrow, lungs, eyes, heart, and spleen(including fatal splenic rupture).

EBV is a potent transforming virus that plays a role ina number of human malignancies, including several typesof B-cell lymphoma (Chapter 6). A serious complicationin those lacking T-cell immunity (particularly organ andbone marrow transplant recipients) is that the EBV-drivenB-cell proliferation can run amok, leading to death. Thisprocess can be initiated by an acute infection or the reac-tivation of a latent B-cell infection and generally beginsas a polyclonal proliferation that progresses to overtmonoclonal B-cell lymphoma over time. Reconstitutionof immunity (e.g., by cessation of immunosuppressivetherapy) is sometimes sufficient to cause complete regres-sion of the B-cell proliferation, which is uniformly fatalif left untreated.

The importance of T cells and NK cells in the controlof EBV infection is driven home by X-linked lympho-proliferative syndrome, a rare inherited immunodefi-ciency characterized by inability to mount an immuneresponse against EBV. Most affected boys have a muta-tion in the SH2D1A gene, which encodes a signalingprotein that is important in the activation of T cells andNK cells. On exposure to EBV, more than 50% of theseboys develop an overwhelming infection that is usuallyfatal. Of the remainder, some develop lymphoma orhypogammaglobulinemia, the basis of which is notunderstood.

Reactive LymphadenitisInfections and nonmicrobial inflammatory stimuli notonly cause leukocytosis but also involve the lymph nodes,which act as defensive barriers. Any immune responseagainst foreign antigens is often associated with lymphnode enlargement (lymphadenopathy). The infectionsthat cause lymphadenitis are numerous and varied andmay be acute or chronic. In most instances, the histologicappearance of the nodes is entirely nonspecific. A some-what distinctive form of lymphadenitis that occurs withcat scratch disease will be described separately.

Figure 12–12

Atypical lymphocytes in infectious mononucleosis. The cell on theleft is a normal small lymphocyte with a compact nucleus fillingthe entire cytoplasm. In contrast, an atypical lymphocyte on theright has abundant cytoplasm and a large nucleus with fine chromatin.

Morphology

The major alterations involve the blood, lymph nodes,spleen, liver, central nervous system, and, occasionally,other organs. There is peripheral blood leukocytosis,with a white cell count that is usually between 12,000and 18,000 cells/μL. Typically more than half of thesecells are large, atypical lymphocytes, 12 to 16μm indiameter, with an abundant cytoplasm that often con-tains azurophilic granules and an oval, indented, orfolded nucleus (Fig. 12–12). These atypical lympho-cytes, which are sufficiently distinctive to suggest thediagnosis, are mainly cytotoxic CD8+ T cells.

The lymph nodes are enlarged throughout the body,including the posterior cervical, axillary, and groinregions. Histologically, the enlarged nodes are floodedby atypical lymphocytes, which occupy the paracortical(T-cell) areas. Occasionally, cells resembling Reed-Sternberg cells, the hallmark of Hodgkin lymphoma,are present. Because of these atypical features, specialtests are sometimes needed to distinguish the reactivechanges of mononucleosis from malignant lymphoma.

The spleen is enlarged in most cases, weighingbetween 300 and 500gm. The histologic changes areanalogous to those of the lymph nodes, showing aheavy infiltration of atypical lymphocytes. As a resultof the increase in splenic size and the infiltration of thetrabeculae and capsule by the lymphocytes, suchspleens are fragile and prone to rupture after evenminor trauma.

Liver function is almost always transiently impairedto some degree. Histologically, atypical lymphocytesare seen in the portal areas and sinusoids, and scat-tered, isolated cells or foci of parenchymal necrosisfilled with lymphocytes may be present. This histologicpicture can be difficult to distinguish from other formsof viral hepatitis.

Clinical Course. Although mononucleosis classically pre-sents as fever, sore throat, lymphadenitis, and the otherfeatures mentioned earlier, atypical presentations are

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Acute Nonspecific Lymphadenitis

This form of lymphadenitis may be confined to a localgroup of nodes draining a focal infection, or be general-ized in systemic bacterial or viral infections.

Cat Scratch Disease

Cat scratch disease is a self-limited lymphadenitis causedby the bacterium Bartonella henselae. It is primarily adisease of childhood; 90% of the patients are youngerthan 18 years of age. It presents as regional lym-phadenopathy, most frequently in the axilla and neck.The nodal enlargement appears approximately 2 weeksafter a feline scratch or, uncommonly, after a splinter orthorn injury. A raised, inflammatory nodule, vesicle, oreschar is sometimes visible at the site of skin injury. Inmost patients the lymph node enlargement regresses over the next 2 to 4 months. Rarely, patients developencephalitis, osteomyelitis, or thrombocytopenia.

Morphology

Macroscopically, inflamed nodes in acute nonspecificlymphadenitis are swollen, gray-red, and engorged.Histologically, there are large germinal centers con-taining numerous mitotic figures. When the cause is apyogenic organism, a neutrophilic infiltrate is seenabout the follicles and within the lymphoid sinuses.With severe infections, the centers of follicles canundergo necrosis, resulting in the formation of anabscess.

Affected nodes are tender and, when abscess for-mation is extensive, become fluctuant. The overlyingskin is frequently red, and penetration of the infectionto the skin can produce draining sinuses. With controlof the infection, the lymph nodes can revert to theirnormal appearance or, if damaged by the immuneresponse, undergo scarring.

Morphology

The anatomic changes in the lymph node in cat scratchdisease are quite characteristic. Initially, sarcoid-likegranulomas are formed, but these then undergo centralnecrosis associated with the accumulation of neu-trophils. These irregular stellate necrotizing granulo-mas are similar in appearance to those seen in certainother infections, such as lymphogranuloma venereum.The microbe is extracellular and can be visualized onlywith silver stains or electron microscopy. The diagno-sis is based on a history of exposure to cats, the clini-cal findings, a positive skin test to the microbialantigen, and the distinctive morphologic changes in thelymph nodes.

Morphology

Follicular Hyperplasia. This pattern is associated withinfections or inflammatory processes that activate Bcells, which enter into B-cell follicles and create the fol-licular (or germinal center) reaction. The cells in thereactive follicles include the activated B cells, scatteredphagocytic macrophages containing nuclear debris(tingible body macrophages), and an inconspicuousmeshwork of follicular dendritic cells that function inantigen display to the B cells. Causes of follicular hyper-plasia include rheumatoid arthritis, toxoplasmosis, andthe early stages of HIV infection. This form of lym-phadenitis can be confused morphologically with fol-licular lymphomas (discussed later). Findings that favora diagnosis of follicular hyperplasia are (1) the preser-vation of the lymph node architecture, with normal lym-phoid tissue between germinal centers; (2) variation inthe shape and size of the lymphoid nodules; (3) a mixedpopulation of lymphocytes at various stages of differ-entiation; and (4) prominent phagocytic and mitoticactivity in germinal centers.

Paracortical Hyperplasia. This pattern is characterizedby reactive changes within the T-cell regions of thelymph node. On immune activation parafollicular Tcells transform into large proliferating immunoblaststhat can efface the B-cell follicles. Paracortical hyper-plasia is encountered in viral infections (such as EBV),following certain vaccinations (e.g., smallpox), and inimmune reactions induced by certain drugs (especiallyphenytoin).

Chronic Nonspecific Lymphadenitis

This condition can assume one of three patterns, depend-ing on the causative agent: follicular hyperplasia, para-cortical hyperplasia, or sinus histiocytosis.

Sinus Histiocytosis. This reactive pattern is character-ized by distention and prominence of the lymphaticsinusoids, owing to a marked hypertrophy of liningendothelial cells and an infiltrate of macrophages (his-tiocytes). Sinus histiocytosis is often encountered inlymph nodes draining cancers and may represent animmune response to the tumor or its products.

NEOPLASTIC PROLIFERATIONS OF WHITE CELLS

Tumors represent the most important of the white celldisorders. They can be divided into three broad categoriesbased on the origin of the tumor cells:

• Lymphoid neoplasms, which include non-Hodgkinlymphomas (NHLs), Hodgkin lymphomas, lympho-cytic leukemias, and plasma cell dyscrasias and relateddisorders. In many instances these tumors are com-posed of cells that resemble normal stages of lympho-cyte differentiation, a feature that serves as one of thebases for their classification.• Myeloid neoplasms arise from stem cells that nor-mally give rise to the formed elements of the blood:granulocytes, red cells, and platelets. The myeloid neo-plasms fall into three fairly distinct subcategories: acutemyelogenous leukemias, in which immature progeni-

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tor cells accumulate in the bone marrow; chronicmyeloproliferative disorders, in which inappropriatelyincreased production of formed blood elements leadsto elevated blood cell counts; and myelodysplastic syn-dromes, which are characteristically associated withineffective hematopoiesis and cytopenias.• Histiocytic neoplasms represent proliferative lesionsof histiocytes. Of special interest is a spectrum of pro-liferations comprising Langerhans cells (the Langer-hans cell histiocytoses).

Lymphoid NeoplasmsThe lymphoid neoplasms encompass a group of entitiesthat vary widely in their clinical presentation and behav-ior, thus presenting challenges to students and cliniciansalike. Some of these neoplasms characteristically appearas leukemias, tumors that primarily involve the bonemarrow with spillage of neoplastic cells into the periph-eral blood. Others tend to present as lymphomas, tumorsthat produce masses in involved lymph nodes or othertissues. Plasma cell tumors, the plasma cell dyscrasias,usually present within the bones as discrete masses andcause systemic symptoms related to the production of acomplete or partial monoclonal immunoglobulin. Despitethese tendencies, all lymphoid neoplasms have the poten-tial to spread to lymph nodes and various tissues through-out the body, especially the liver, spleen, and bonemarrow. In some cases lymphomas or plasma cell tumorsspill over into the peripheral blood, creating a leukemia-like picture. Conversely, leukemias of lymphoid cells,originating in the bone marrow, can infiltrate lymphnodes and other tissues, creating the histologic picture oflymphoma. Because of the overlap in clinical presenta-tions, the various lymphoid neoplasms can only be dis-tinguished based on the appearance and molecularcharacteristics of the tumor cells. Stated another way, forpurposes of diagnosis and prognostication, it is mosthelpful to focus on what the tumor cell is, not where itresides in the patient.

Two groups of lymphomas are recognized: Hodgkinlymphoma and non-Hodgkin lymphomas. Although botharise most commonly in lymphoid tissues, Hodgkin lymphoma is set apart by the presence of distinctive neo-plastic Reed-Sternberg giant cells (see below), which ininvolved nodes are usually greatly outnumbered by non-neoplastic inflammatory cells. The biologic behavior andclinical treatment of Hodgkin lymphoma are also differ-ent from those of most NHLs, making the distinction ofpractical importance.

Historically, few areas of pathology have evoked asmuch controversy and confusion as the classification oflymphoid neoplasms, which is perhaps inevitable giventhe intrinsic complexity of the immune system fromwhich they arise. Great progress has been made over thelast decade in this area, however, and an internationalworking group of pathologists, molecular biologists, and clinicians working on behalf of the World HealthOrganization (WHO) has formulated a widely accepted classification scheme that relies on a combination of morphologic, phenotypic, genotypic, and clinical fea-tures. Before we delve into the classification of lymphoid

neoplasms, certain important relevant principles shouldbe emphasized:

• B- and T-cell tumors are often composed of cells that are arrested or derived from specific stages of their normal differentiation pathways (Fig. 12–13).The diagnosis and classification of these tumors reliesheavily on tests (either immunohistochemistry or flowcytometry) that detect lineage-specific antigens (e.g., B-cell, T-cell, and NK-cell markers) and markers of matu-rity. As will become evident, many such markers areidentified according to their cluster of differentiation(CD) number.• The most common lymphomas of adults are derivedfrom follicular center or post-follicular center B cells.This conclusion is drawn from molecular analyses,which have shown that most B-cell lymphomas haveundergone somatic hypermutation, an activity that isconfined to follicular center B cells. Follicular center Bcells also undergo immunoglobulin class switching,and together with somatic hypermutation, these formsof regulated genomic instability seem to place B cellsat a relatively high risk for mutations that can lead totransformation. In fact, many recurrent chromosomaltranslocations that are commonly seen in mature B-cellmalignancies involve the immunoglobulin (Ig) loci andseem to stem from mistakes that are made duringattempted recombination events involving Ig genes. Inthis regard, it is interesting that mature T cells (whichare genomically stable) give rise to lymphomas muchless frequently and very rarely have chromosomaltranslocations involving the T-cell receptor loci.• All lymphoid neoplasms are derived from a singletransformed cell and are therefore monoclonal. As willbe recalled from Chapter 5, during the differentiationof precursor B and T cells there is a somatic rearrange-ment of their antigen receptor genes. This processensures that each lymphocyte makes a single, uniqueantigen receptor. Because antigen receptor generearrangement precedes transformation, the daughtercells derived from a given malignant progenitor sharethe same antigen receptor gene configuration and syn-thesize identical antigen receptor proteins (eitherimmunoglobulins or T-cell receptors). For this reason,analysis of antigen receptor genes and their proteinproducts is frequently used to differentiate monoclonalneoplasms from polyclonal, reactive processes.• As tumors of the immune system, lymphoid neo-plasms often disrupt normal immune regulatory mechanisms. Both immunodeficiency (as evidenced bysusceptibility to infection) and autoimmunity can beseen, sometimes in the same patient. Ironically, patientswith inherited or acquired immunodeficiency are them-selves at high risk of developing certain lymphoid neoplasms, particularly those associated with EBVinfection.• Although NHLs often present at a particular tissuesite, sensitive molecular assays usually show that thetumor is widely disseminated at the time of diagnosis.As a result, with few exceptions, only systemic thera-pies are curative. In contrast, Hodgkin lymphomaoften presents at a single site and spreads in a pre-

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dictable fashion to contiguous lymph node groups. Forthis reason, early in its course, local therapy may beindicated.

The WHO classification of lymphoid neoplasms considers the morphology, cell of origin (determined inpractice by immunophenotyping), clinical features, andgenotype (e.g., karyotype, presence of viral genomes) ofeach entity. It includes all lymphoid neoplasms, includingleukemias and multiple myeloma, and segregates them onthe basis of origin into three major categories: (1) tumorsof B cells, (2) tumors of T cells and NK cells, and (3)Hodgkin lymphoma.

An updated version of the WHO classification of lym-phoid neoplasms is presented in Table 12–7. As can beseen, the diagnostic entities are numerous. Our focus willbe on the subset of neoplasms listed below, whichtogether constitute more than 90% of the lymphoid neo-plasms seen in the United States:

• Precursor B- and T-cell lymphoblastic leukemia/lymphoma (commonly called acute lymphoblasticleukemia, or ALL)• Small lymphocytic lymphoma/chronic lymphocyticleukemia• Follicular lymphoma

• Mantle cell lymphoma• Diffuse large B-cell lymphomas• Burkitt lymphoma• Multiple myeloma and related plasma cell dyscrasias• Hodgkin lymphoma

The salient features of the more common lymphoidneoplasms are summarized in Table 12–8. We will alsotouch on a few of the uncommon entities that have dis-tinctive clinicopathologic features.

Precursor B- and T-Cell LymphoblasticLeukemia/Lymphoma

These are aggressive tumors, composed of immature lym-phocytes (lymphoblasts), which occur predominantly inchildren and young adults. The various lymphoblastictumors are morphologically indistinguishable and oftencause similar signs and symptoms. Because precursor B-and T-cell neoplasms have overlapping features, we willconsider them together.

Just as B-cell precursors normally develop within thebone marrow, pre–B-lymphoblastic tumors characteristi-cally appear in bone marrow and peripheral blood asleukemias. Similarly, pre–T-lymphoblastic tumors com-monly present as masses involving the thymus, which is the

TdT+

DR

CD34

TdT+

DR

CD34

TdT+

DR CD19 CD19 CD19 CD19

Slg

CD34

TdT+

DR

CD10

TdT+

Cμ

DR

CD10 CD20 CD20

DR

CD21CD22

TdT+

CD34

TdT+

CD2

CD7

CD5 CD2 CD5

CD34 CD1

CD2 CD5

CD4

CD2

CD8

TdT+

CD7 CD1CD7

TdT+

CD3

CD8Cytotoxic

EARLY B PRECURSOR

Ig heavy chainrearrangement

Ig heavy ± light chainrearrangements

TCR γ and β chainrearrangements

TCR β and α chainrearrangements

Ig heavy- and light-chainrearrangements

EARLY THYMOCYTES MATURE T CELLSCOMMON

THYMOCYTES

B-CELLPATHWAY

Lymphoidstemcell

T-CELLPATHWAY

PRE-B B CELL PLASMA CELL

Helper-inducer

CD2

CD3

CD4

Figure 12–13

Origin of lymphoid neoplasms. Stages of B- and T-cell differentiation from which specific lymphoid and tumors emerge are shown. CD,cluster of differentiation; DR, human lymphocyte antigen–class II antigens; Ig, immunoglobulin; TCR, T-cell receptor; TdT, terminal deoxyri-bonucleotidyl transferase.

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Table 12–7 The WHO Classification of Lymphoid Neoplasms*

Precursor B-Cell Neoplasms

Precursor B-cell leukemia/lymphoma (B-cell ALL)

Peripheral B-Cell Neoplasms

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL)B-cell prolymphocytic leukemiaLymphoplasmacytic lymphomaMantle cell lymphomaFollicular lymphomaExtranodal marginal zone lymphoma (MALT lymphoma)Splenic marginal zone lymphomaNodal marginal zone lymphomaHairy cell leukemiaPlasmacytoma/plasma cell myelomaDiffuse large B-cell lymphomaBurkitt lymphoma

Precursor T-Cell Neoplasms

Precursor T-cell leukemia/lymphoma (T-cell ALL)

Peripheral T-/NK-Cell Neoplasms

T-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaMycosis fungoides/Sézary syndromePeripheral T-cell lymphoma, not otherwise specified (NOS)Angioimmunoblastic T-cell lymphomaAnaplastic large-cell lymphoma, primary systemic typeEnteropathy-type T-cell lymphomaPanniculitis-like T-cell lymphomaHepatosplenic γδ T-cell lymphomaAdult T-cell lymphoma/leukemia (HTLV1)NK/T-cell lymphoma, nasal typeNK-cell leukemia

Hodgkin Lymphoma

Lymphocyte predominance, nodularNodular sclerosisMixed cellularityLymphocyte-richLymphocyte depletion

*Entries in italics are among the most common lymphoid tumors.

marrow progenitors grow at an even more rapid rate. Theprincipal pathogenetic problem in acute leukemia is ablock in differentiation. This leads to the accumulationof immature leukemic blasts in the bone marrow, whichsuppress the function of normal hematopoietic stem cellsby physical displacement and other poorly understoodmechanisms. Eventually bone marrow failure results,which accounts for the major clinical manifestations of acute leukemia. Thus, the therapeutic goal is to reduce the leukemic clone sufficiently to allow normalhematopoiesis to resume.

Clinical Features of Acute Leukemias. The acuteleukemias have the following characteristics:

• Abrupt stormy onset. Most patients present within3 months of the onset of symptoms.• Symptoms related to depression of normal marrowfunction. These include fatigue (due mainly to anemia),fever (reflecting infections resulting from the absenceof mature leukocytes), and bleeding (petechiae, ecchymoses, epistaxis, gum bleeding) secondary tothrombocytopenia.• Bone pain and tenderness. These result from marrowexpansion and infiltration of the subperiosteum.• Generalized lymphadenopathy, splenomegaly, andhepatomegaly. These reflect dissemination of theleukemic cells, and are more pronounced in ALL thanin AML.• Central nervous system manifestations. Theseinclude headache, vomiting, and nerve palsies resultingfrom meningeal spread; these features are morecommon in children than in adults and are morecommon in ALL than AML.

Laboratory Findings of Acute Leukemias. The diagnosisof acute leukemia rests on the identification of blast formsin the peripheral blood and the bone marrow. The whitecell count is variable; it is somtimes elevated to more than 100,000 cells/μL, but in about 50% of patients it isless than 10,000 cells/μL. Anemia is almost alwayspresent, and the platelet count is usually below 100,000platelets/μL. Neutropenia is also a common finding in the peripheral blood. Uncommonly the peripheral blood examination shows pancytopenia but no blasts(aleukemic leukemia); here, the diagnosis can only beestablished by examining the bone marrow.

site of early stages of normal T-cell differentiation.However, pre–T-cell “lymphomas” often progress rapidlyto a leukemic phase, and other pre–T-cell tumors seem toinvolve only the marrow at presentation. Hence, bothpre–B- and pre–T-lymphoblastic tumors usually take onthe clinical appearance of an acute lymphoblastic leukemia(ALL) at some time during their course. As a group, ALLsconstitute 80% of childhood leukemia, peaking in inci-dence at age 4, with most of the cases being of pre–B-cellorigin. The pre–T-cell tumors are most common in adoles-cent males of between 15 and 20 years of age.

The pathophysiology, laboratory findings, and clinicalfeatures of ALL closely resemble those of acute myeloge-nous leukemia (AML), the other major type of acuteleukemia. Because of these similarities, we will first stepback to review the features common to the acuteleukemias before discussing those that are specific to ALL.

Pathophysiology of Acute Leukemias. Although acuteleukemias are rapidly growing tumors, normal bone

Morphology

Because of different responses to therapy, it is of greatpractical importance to distinguish ALL from AML. Bydefinition, in ALL, blasts compose more than 25% of themarrow cellularity. The nuclei of lymphoblasts inWright-Giemsa–stained preparations have somewhatcoarse and clumped chromatin and one or two nucle-oli (Fig. 12–14A); myeloblasts tend to have finer chro-matin and more cytoplasm, which may containgranules (Fig. 12–14B). The cytoplasm of lymphoblastsoften contains large aggregates of periodic acid–Schiff–positive material, whereas myeloblasts are oftenperoxidase positive.

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Table 12–8 Summary of the More Common Lymphoid Neoplasms

Entity Frequency Salient Morphology

Precursor B-cell lymphoblastic 85% of childhood acute leukemia Lymphoblasts with irregular nuclear contours, condensed leukemia/lymphoma chromatin, small nucleoli, and scant agranular cytoplasm

Precursor T-cell leukemia/ 15% of childhood acute leukemia; Identical to precursor B-cell lymphoblastic leukemia/lymphomalymphoma 40% of childhood lymphomas

Small lymphocytic lymphoma/ 3% to 4% of adult lymphomas; Small resting lymphocytes mixed with variable numbers of largechronic lymphocytic leukemia 30% of all leukemias activated cells; lymph nodes diffusely effaced

Follicular lymphoma 40% of adult lymphomas Frequent small “cleaved” cells mixed with large cells; growth pattern is usually nodular (follicular)

Mantle cell lymphoma 3% to 4% of adult Small to intermediate-sized irregular lymphomas lymphocytes growing in a diffuse

pattern

Extranodal marginal zone ∼5% of adult lymphomas Variable cell size and differentiation; 40% show plasmacytic lymphoma differentiation; B cells home to epithelium, creating

“lymphoepithelial lesions”

Diffuse large B-cell lymphoma 40% to 50% of adult lymphomas Variable; most resemble large germinal center B cells; diffuse growth pattern

Burkitt lymphoma <1% of lymphomas in the United Intermediate-sized round lymphoid cells with several nucleoli; States diffuse tissue involvement associated with apoptosis produces

a “starry-sky” appearance

Plasmacytoma/plasma cell Most common lymphoid neoplasm Plasma cells in sheets, sometimes with prominent nucleoli or myeloma in older adults inclusions containing Ig

Mycosis fungoides Most common cutaneous In most cases, small lymphoid cells with markedly convoluted lymphoid malignancy nuclei; cells often infiltrate the epidermis (Pautrier

microabscesses)

Peripheral T-cell lymphoma, Most common adult T-cell Variable; usually a spectrum of small to large lymphoid cells not otherwise specified lymphoma with irregular nuclear contours(NOS)

Hodgkin lymphoma, nodular Most common type of Hodgkin Lacunar Reed-Sternberg cell variants in a mixed inflammatory sclerosis type lymphoma background; broad sclerotic bands of collagen usually also

present

Hodgkin lymphoma, mixed Second most common form of Frequent classic Reed-Sternberg cells in a mixed inflammatory cellularity type Hodgkin lymphoma background

GI, gastrointestinal; Ig, immunoglobulin.

A B

Figure 12–14

Morphologic comparison of lymphoblasts and myeloblasts. A, Lymphoblastic leukemia/lymphoma. Lymphoblasts have fewer nucleoli thando myeloblasts, and the nuclear chromatin is more condensed. Cytoplasmic granules are absent. B, Acute myeloblastic leukemia (M1subtype). Myeloblasts have delicate nuclear chromatin, prominent nucleoli, and fine azurophilic granules in the cytoplasm. (Courtesy ofDr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)

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Immunophenotype Comments

TdT+ immature B cells (CD19+, variable expression Usually presents as acute leukemia; less common in adults; prognosis is predictedof other B-cell markers) by karyotype

TdT+ immature T cells (CD2+, CD7+, variable Most common in adolescent males; often presents as a mediastinal mass due to expression of other T-cell markers) thymic involvement; highly associated with mutations in NOTCH1

CD5+ B-cell expressing surface Ig Occurs in older adults; usually involves nodes, marrow, and spleen; most patients have peripheral blood involvement; indolent

CD10+ BCL2+ mature B cells that express Occurs in older adults; usually involves nodes, marrow, and spleen; associated with surface Ig t(14;18); indolent

CD5+ mature B cells that express cyclin D1 and Occurs mainly in older males; usually involves nodes, marrow, and spleen; GI tracthave surface Ig also commonly affected; t(11;14) is characteristic; moderately aggressive

CD5- CD10- mature B cells with surface Ig Frequently occurs at extranodal sites involved by chronic inflammation; very indolent; may be cured by local excision

Mature B cells with variable expression of CD10 Occurs in all ages, but most common in older adults; often arise at extranodal sites;and surface Ig aggressive

Mature CD10+ B cells expressing surface Ig Endemic in Africa, sporadic elsewhere; increased frequency in immunosuppressed patients; predominantly affects children; often presents with visceral involvement;highly aggressive

Terminally differentiated plasma cells containing Myeloma presents as disseminated bone disease, often with destructive lytic lesionscytoplasmic Ig Hypercalcemia, renal insufficiency, and bacterial infections are common

CD4+ mature T cells Presents with localized or more generalized skin involvement; generally indolent. Sézary syndrome, a more aggressive variant, is characterized by diffuse skinerythema and peripheral blood involvement

Mature T-cell phenotype (CD3+) Probably spans a diverse collection of rare tumors. Often disseminated, generally aggressive

CD15+, CD30+ Reed-Sternberg cells Most common in young adults, often arises in the mediastinum or cervical lymph nodes

CD15+, CD30+ Reed-Sternberg cells Most common in men, more likely to present at advanced stages than the nodular sclerosis type EBV+ in 70% of cases

Having completed our “short course” in acuteleukemia, we will return to lymphoblastic leukemia/lym-phoma; the AMLs are discussed later.

Immunophenotyping. Immunophenotyping is very usefulin subtyping lymphoblastic tumors and distinguishingthem from AML. Terminal deoxytransferase, an enzymethat is specifically expressed in pre-B and pre-T cells, ispresent in more than 95% of cases. Further subtyping ofALL into pre–B- and pre–T-cell types relies on stains forlineage-specific markers, such as CD19 (B cell) and CD3(T cell). Although immunophenotyping has historicallyproven somewhat useful in predicting clinical outcome,the tumor karyotype provides more robust and specificprognostic information.

Karyotypic Changes. Approximately 90% of patientswith lymphoblastic leukemia/lymphoma have nonran-dom karyotypic abnormalities. Most common in pre–B-cell tumors is hyperdiploidy (>50 chromosomes/cell),which is associated with the presence of a cryptic (12;21)chromosomal translocation involving the TEL1 and

AML1 genes. The presence of these aberrations correlateswith a good outcome. Poor outcomes are observed withpre–B-cell tumors that have translocations involving theMLL gene on chromosome 11q23 or the Philadelphia(Ph) chromosome. Pre–T-cell tumors are associated witha group of chromosomal rearrangements that are com-pletely different than those found in pre–B-cell tumors,but none is predictive of outcome.

Activating Mutations in NOTCH1. NOTCH1 is a trans-membrane receptor whose activity is essential for normalT-cell development. NOTCH1 signals promote the pro-liferation and survival of pre-T cells and are capable ofcausing stem cells to differentiate into pre-T cells outsideof the thymus. Interestingly, 55% to 60% of pre–T-celltumors have activating point mutations in NOTCH1,indicating that the NOTCH1 signaling pathway plays acentral role in the development of many pre-T ALLs. Theability of NOTCH1 to promote T-cell developmentoutside the thymus may explain why some patients withpre–T-cell tumors have bone marrow disease and nothymic involvement.

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Prognosis. Treatment of lymphoblastic tumors of child-hood represents one of the great success stories in oncol-ogy. Children 2 to 10 years of age have the best prognosis;most can be cured. Other groups of patients do less well.Variables correlated with worse outcomes include malegender, age younger than 2 or older than 10 years, and ahigh leukocyte count at diagnosis. Age-dependent differ-ences in the frequencies of various karyotypic abnor-malities are likely to explain the relationship of age tooutcome. Tumors with rearrangements of MLL or the Phchromosome (both associated with a poor outcome) aremost common in children younger than age 2 and adults,respectively, whereas tumors with “good prognosis” chro-mosomal aberrations (such as the t[12;21] and hyper-diploidy) are common in the 2- to 10-year age group.

Small Lymphocytic Lymphoma/ChronicLymphocytic Leukemia

These two disorders are morphologically, phenotypically,and genotypically identical, differing only in the extent ofperipheral blood involvement. Arbitrarily, if the periph-eral blood lymphocytosis exceeds 4000 cells/mm3, thepatient is diagnosed with chronic lymphocytic leukemia(CLL); if not, a diagnosis of small lymphocytic lymphoma(SLL) is made. Most patients fit the criteria for CLL,which is the most common leukemia of adults in thewestern world. In contrast, SLL constitutes only 4% ofNHLs. For unclear reasons, both CLL and SLL are muchless common in Asia.

Pathophysiology. The neoplastic B cells, through mecha-nisms that are not understood, suppress normal B-cellfunction, often resulting in hypogammaglobulinemia.Paradoxically, approximately 15% of patients haveautoantibodies against autologous red cells; other auto-antibodies can also be detected. When present, theseautoantibodies are made by nontumor B cells, indicatingthat there is a general breakdown in immune regulation.As time passes the tumor cells tend to displace the normalmarrow elements, leading to anemia, neutropenia, andeventual thromobocytopenia. Immunophenotype, Karyotype, and Molecular Features.

CLL/SLL is a neoplasm of mature B cells expressing thepan–B-cell markers CD19, CD20, and CD23 and surfaceimmunoglobulin heavy and light chains. The tumor cellsalso express CD5, a tendency that is shared (among theB-cell neoplasms) only by mantle cell lymphoma.Approximately 50% of patients have karyotypic abnor-malities, the most common of which are trisomy 12 anddeletions of chromosomes 11 and 12. Unlike other lym-phoid neoplasms, chromosomal translocations are rare.Of interest, most CLL/SLLs have undergone somatichypermutation of their immunoglobulin segments, afinding that is consistent with an origin from a post–follicular center B cell (possibly a memory cell). Less com-monly these tumors are derived from naive B cells thathave not undergone a follicular center reaction; suchtumors appear to have a substantially worse prognosis.

Clinical Features. CLL/SLL is often asymptomatic at presentation. The most common symptoms are nonspe-cific and include easy fatigability, weight loss, andanorexia. Generalized lymphadenopathy and hepato-

Morphology

In SLL/CLL, sheets of small round lymphocytes andscattered ill-defined foci of larger, actively dividing cellsdiffusely efface involved lymph nodes (Fig. 12–15A).The predominant cells are compact, small, resting lym-phocytes with dark-staining round nuclei, scanty cyto-plasm, and little variation in size (Fig. 12–15B). The fociof mitotically active cells are called proliferationcenters; their presence is pathognomonic for CLL/SLL.Mitotic figures are rare except in the proliferationcenters, and there is little or no cytologic atypia. In addi-tion to the lymph nodes, the bone marrow, spleen, andliver are involved in almost all cases. In most patientsthere is an absolute lymphocytosis of small, mature-looking lymphocytes. The neoplastic lymphocytes arefragile and are frequently disrupted during the prepa-ration of smears, which produces characteristicsmudge cells. Variable numbers of larger activated lym-phocytes are also usually present in the blood smear.

A

B

Figure 12–15

Nodal involvement by small lymphocytic lymphoma/chronic lym-phocytic leukemia. A, Low-power view shows diffuse effacementof nodal architecture. B, At high power, the majority of the tumorcells have the appearance of small, round lymphocytes. A single“prolymphocyte,” a larger cell with a centrally placed nucleolus,is also present in this field. (A, Courtesy of Dr. José Hernandez,Department of Pathology, University of Texas SouthwesternMedical School, Dallas, Texas.)

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Morphology

Lymph nodes are effaced by proliferations that usuallyhave a distinctly nodular appearance (Fig 12–16A). Thetumor cells resemble normal follicular center B cells.Most commonly, the predominant neoplastic cells are“centrocyte-like” cells slightly larger than resting lym-phocytes that have angular “cleaved” nuclear contourswith prominent indentations and linear infoldings (seeFig. 12–16B). The nuclear chromatin is coarse and con-densed, and nucleoli are indistinct. These small,cleaved cells are mixed with variable numbers of larger“centroblast-like” cells that have vesicular chromatin,several nucleoli, and modest amounts of cytoplasm. Inmost tumors, centroblast-like cells are a minor compo-nent of the overall cellularity, mitoses are infrequent,and single necrotic cells (cells undergoing apoptosis)

Immunophenotype and Molecular Features. Thesetumors express the pan–B-cell markers CD19 and CD20,CD10, and BCL6, a transcription factor that is requiredfor follicular center formation. In addition, the neoplas-tic cells characteristically express BCL2, a protein that isabsent from normal follicular B cells. As would beexpected of a B cell–derived tumor, the immunoglobulingenes show evidence of somatic hypermutation.

Karyotype. The majority of tumors have a characteristict(14;18) translocation. This translocation fuses the BCL2gene on chromosome 18q21 to the IgH locus on chro-mosome 14 and leads to the inappropriate expression ofBCL2 protein, which functions to prevent apoptosis(Chapter 6).

Clinical Features. Follicular lymphoma occurs predomi-nantly in older persons (rarely before age 20 years) andaffects males and females equally. It usually presents aspainless lymphadenopathy, which is frequently general-ized. Involvement of visceral sites is uncommon, but thebone marrow almost always contains lymphoma at thetime of diagnosis. The natural history is prolonged(median survival, 7–9 years), but follicular lymphoma isnot easily curable, a feature that is common to most ofthe indolent lymphoid malignancies. Their incurabilitymay be related in part to the elevated levels of BCL2,which may protect tumor cells from the effects ofchemotherapeutic agents. In about 40% of patients, fol-licular lymphoma progresses to a diffuse large B-cell lym-phoma, with or without treatment. This is an ominoustransition, because tumors arising from such conversionsare much less curable than de novo diffuse large B-celllymphomas, described later.

splenomegaly are present in 50% to 60% of cases. Thetotal leukocyte count may be increased only slightly (inSLL) or may exceed 200,000 cells/μL. Hypogammaglob-ulinemia develops in more than 50% of the patients,usually late in the course of the disease, and is responsi-ble for increased susceptibility to bacterial infections.Less commonly, autoimmune hemolytic anemia andthrombocytopenia are seen. The course and prognosis areextremely variable. Many patients live more than 10years after diagnosis and die of unrelated causes; themedian survival is 4 to 6 years. However, as time passesCLL/SLL tends to transform to more aggressive tumorsthat resemble either pro-lymphocytic leukemia or diffuselarge B-cell lymphoma. Once transformation occurs, themedian survival is less than 1 year.

Follicular Lymphoma

These are relatively common tumors that constitute 40%of the adult NHLs in the United States. Like CLL/SLL,they occur much less frequently in Asian populations.

A B

Figure 12–16

Follicular lymphoma, involving a lymph node. A, Nodular aggregates of lymphoma cells are present throughout. B, At high magnifica-tion, small lymphoid cells with condensed chromatin and irregular or cleaved nuclear outlines (centrocytes) are mixed with a populationof larger cells with nucleoli (centroblasts). (A, Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas South-western Medical School, Dallas, Texas.)

are not seen. These findings help to distinguish neo-plastic follicles from reactive follicles, in which mitosesand apoptosis are prominent. Uncommonly, centrob-last-like cells predominate, a histology that correlateswith a more aggressive clinical behavior.

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Mantle Cell Lymphoma

Mantle cell lymphomas are composed of B cells thatresemble cells in the mantle zone of normal lymphoid fol-licles. They constitute approximately 4% of all NHLsand occur mainly in older males.

Immunophenotype. The tumor cells usually coexpresssurface IgM and IgD, the pan–B-cell antigens CD19 andCD20, and (like CLL/SLL) CD5. Mantle cell lymphomais distinguished from CLL/SLL by the absence of prolif-eration centers and the presence of cyclin D1 protein.

Karyotype and Molecular Features. Most (and possiblyall) tumors have a t(11;14) translocation that fuses thecyclin D1 gene on chromosome 11 to the IgH locus onchromosome 14. This translocation dysregulates theexpression of cyclin D1, a cell cycle regulator (Chapter6), and explains the characteristically increased cyclin D1protein levels. The immunoglobulin loci have not under-gone somatic hypermutation, consistent with an originfrom a naive B cell.

Clinical Features. Most patients present with fatigue andlymphadenopathy and are found to have generalizeddisease involving the bone marrow, spleen, liver, and(often) the gastrointestinal tract. These tumors areaggressive and incurable, and are associated with amedian survival of 3 to 5 years.

Diffuse Large B-Cell Lymphoma

This diagnostic category includes several forms of NHLthat share certain features, including a B-cell phenotype,a diffuse growth pattern, and an aggressive clinicalhistory. As a group, this is the most important type oflymphoma in adults, as it accounts for approximately50% of adult NHL.

Figure 12–17

Diffuse large B-cell lymphoma. The tumor cells have large nucleiwith open chromatin and prominent nucleoli. (Courtesy of Dr.Robert W. McKenna, Department of Pathology, University of TexasSouthwestern Medical School, Dallas, Texas.)

Morphology

The nuclei of the neoplastic B cells are large (at leastthree to four times the size of resting lymphocytes) andcan take a variety of forms. In many tumors, cells withround, irregular, or cleaved nuclear contours, dispersed

Immunophenotype and Molecular Features. These aremature B-cell tumors that express pan–B-cell antigens,such as CD19 and CD20. Many also express surface IgMand/or IgG. Other antigens (e.g., CD10) are variablyexpressed. These tumors uniformly demonstrate somatichypermutation of immunoglobulin genes, consistent withan origin from a follicular or post-follicular center B cell.

Karyotype. Approximately 30% of tumors have at(14;18) translocation involving the BCL2 gene. Suchtumors may represent “transformed” follicular lym-phomas. About one-third have rearrangements of theBCL6 gene, located on 3q27, and mutations in BCL6 areseen in an even higher fraction of tumors. Both thetranslocations and the mutations seem to cause inappro-priate increases in BCL6 protein levels.

Distinct Subtypes. Several distinctive clinicopathologicsubtypes are included in the general category of diffuselarge B-cell lymphoma. EBV is implicated in the patho-genesis of diffuse large B-cell lymphomas that arise in the setting of the acquired immunodeficiency syndrome(AIDS) and iatrogenic immunosuppression (e.g., in trans-plant patients). In the post-transplant setting, thesetumors often begin as EBV-driven polyclonal B-cell proliferations that may regress if immune function isrestored. Otherwise, with time, progression to mono-

Morphology

Mantle cell lymphomas involve lymph nodes in adiffuse or vaguely nodular pattern. The tumor cells areusually slightly larger than normal lymphocytes andhave an irregular nucleus and inconspicuous nucleoli.Less commonly, the cells are larger and morphologi-cally resemble lymphoblasts. The bone marrow isinvolved in the majority of cases, and about 20% ofpatients have peripheral blood involvement. One unex-plained but characteristic tendency is the frequentinvolvement of the gastrointestinal tract, sometimes inthe form of multifocal submucosal nodules that grosslyresemble polyps (lymphomatoid polyposis).

chromatin, several distinct nucleoli, and modestamounts of pale cytoplasm predominate (Fig. 12–17).Such cells resemble “centroblasts,” the large cells thatare seen in reactive lymphoid follicles. In other tumors,the cells have a large round or multilobulated vesicularnucleus, one or two centrally placed prominent nucle-oli, and abundant cytoplasm that can be either pale or intensely staining. These cells resemble an“immunoblast,” a type of antigen-activated lympho-cyte that is normally found in the paracortex of lymphnodes.

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clonal large B-cell lymphoma is observed. Kaposisarcoma herpesivirus (KSHV), also called human her-pesvirus type 8 (HHV-8) is associated with a rare groupof tumors that present as primary effusion lymphomaswithin the pleura, pericardium, or peritoneum. Thetumor cells are latently infected with KSHV, whichencodes proteins homologous to several known onco-proteins, including cyclin D1. Patients with these primaryeffusion lymphomas are usually immunosuppressed.Note that this virus is also associated with Kaposisarcoma in AIDS patients (Chapter 5). Mediastinal largeB-cell lymphoma usually presents in young females andshows a predilection for spread to abdominal viscera andthe central nervous system.

Clinical Features. Although the median age at presenta-tion is about 60 years, diffuse large B-cell lymphomas canarise at any age; they constitute about 15% of childhoodlymphomas. Patients typically present with a rapidlyenlarging, often symptomatic mass at one or several sites.Extranodal presentations are common. Although the gas-trointestinal tract and the brain are among the more fre-quent extranodal sites, these tumors can arise in virtuallyany organ or tissue. Unlike the more indolent lymphomas(e.g., follicular lymphoma), involvement of the liver,spleen, and bone marrow is not common at the time ofdiagnosis.

Diffuse large cell B-cell lymphomas are aggressivetumors that are rapidly fatal if untreated. With intensivecombination chemotherapy, however, complete remissioncan be achieved in 60% to 80% of the patients; of these,approximately 50% remain free of disease for severalyears and are often cured. For those not cured with con-ventional therapy, other more aggressive treatments (e.g.,high-dose therapy and bone marrow transplantation)offer some hope. Microarray-based molecular profiling ofthese tumors may improve the ability to predict theresponse to current therapies and perhaps even identifytargets for new therapeutic approaches (Chapter 6).

Burkitt Lymphoma

Burkitt lymphoma is endemic in some parts of Africa andsporadic in other areas, including the United States. His-tologically, the African and nonendemic diseases are iden-tical, although there are clinical and virologic differences.The relationship of these disorders to EBV is discussed inChapter 6.

Immunophenotype and Molecular Features. These B-celltumors express surface IgM, κ or λ light chain, the pan–B-cell markers CD19 and CD20, and CD10. Theimmunoglobulin genes are somatically hypermutated,consistent with an origin from a follicular center B cell.

Karyotype. Burkitt lymphoma is always associated withtranslocations involving the MYC gene on chromosome8. Most translocations fuse MYC with the IgH gene onchromosome 14, but variant translocations involving the κ or λ light chain loci on chromosomes 2 and 22,respectively, are also observed. The net result of each isthe dysregulation and overexpression of the MYCprotein. The role of Myc in transformation was discussedin Chapter 6.

Clinical Features. Both the endemic and nonendemicforms affect mainly children and young adults. Burkittlymphoma accounts for approximately 30% of child-hood NHLs in the United States. In both forms, thedisease usually arises at extranodal sites. In Africanpatients, involvement of the maxilla or mandible is thecommon mode of presentation, whereas abdominaltumors involving the bowel, retroperitoneum, andovaries are more common in North America. Leukemicpresentations are uncommon, especially in the endemicform, but do occur and must be distinguished from acutelymphoblastic leukemias, which respond to different drugregimens. Burkitt lymphoma is a high-grade tumor thatis among the fastest growing human neoplasms; however,with very aggressive chemotherapy regimens, the major-ity of patients can be cured.

Multiple Myeloma and Related Plasma Cell Disorders

The common feature that is shared among multiplemyeloma and the plasma cell dyscrasias is that all originate from a clone of B cells that differentiates into

Morphology

The tumor cells are uniform and intermediate in size andhave round or oval nuclei containing two to five promi-nent nucleoli (Fig. 12–18). The nuclear size approximatesthat of benign macrophages within the tumor. There is amoderate amount of basophilic or amphophilic cyto-plasm, which on smears is often seen to contain small,lipid-filled vacuoles. A high mitotic rate is very charac-teristic of this tumor, as is cell death, accounting for thepresence of numerous tissue macrophages containingingested nuclear debris. Because these benignmacrophages are often surrounded by a clear space,they create a “starry sky” pattern.

Figure 12–18

Burkitt lymphoma. The tumor cells and their nuclei are fairlyuniform, giving a monotonous appearance. Note the high mitoticactivity (arrowheads) and prominent nucleoli. The “starry sky”pattern produced by interspersed, lightly staining, normal macro-phages is better appreciated at a lower magnification. (Courtesyof Dr. Robert W. McKenna, Department of Pathology, Universityof Texas Southwestern Medical School, Dallas, Texas.)

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plasma cells and secretes a single complete or partialimmunoglobulin. Because the serum usually containsexcessive amounts of immunoglobulins, these disordershave also been called monoclonal gammopathies, and theassociated immunoglobulin is often referred to as an Mcomponent. Although the presence of an M componentmay be indicative of an overt B-cell malignancy, M com-ponents are fairly common in otherwise normal elderlypersons, a condition called monoclonal gammopathy ofundetermined significance. Collectively these disordersaccount for about 15% of deaths from tumors of whiteblood cells; they are most common in middle-aged andelderly persons.

The plasma cell dyscrasias can be divided into sixmajor variants: (1) multiple myeloma, (2) localized plas-macytoma (solitary myeloma), (3) lymphoplasmacyticlymphoma, (4) heavy-chain disease, (5) primary orimmunocyte-associated amyloidosis, and (6) monoclonalgammopathy of undetermined significance. In all forms,the immunoglobulin genes are somatically hypermutated,consistent with an origin from a post-follicular center Bcell. Each of these disorders will be briefly described, and then the morphologic features of the more commonforms will be presented.

Multiple Myeloma. Multiple myeloma, by far the mostcommon of the malignant plasma cell dyscrasias, is aclonal proliferation of neoplastic plasma cells in the bonemarrow that is usually associated with multifocal lyticlesions throughout the skeletal system. The proliferationof neoplastic plasma cells, also called myeloma cells, issupported by the cytokine interleukin 6 (IL-6), which isproduced by fibroblasts and macrophages in the bonemarrow stroma. As is true of other B-cell malignancies,it has been appreciated recently that many myelomashave chromosomal translocations involving the IgH locuson chromosome 14. The identified fusion partnersinclude the cyclin D1, fibroblast growth factor receptor3, and cyclin D3 genes; late in the course, translocationsinvolving MYC are sometimes observed. As might be sur-mised by the list of genes involved by chromosomaltranslocations, dysregulation of D cyclins seems to be ofgeneral importance in multiple myeloma.

The most common M component is IgG (60%), fol-lowed by IgA (20% to 25%); only rarely is it IgM, IgD,or IgE. In the remaining 15% to 20% of cases, the plasmacells produce only κ or λ light chains. Because of theirlow molecular weight, the free light chains are rapidlyexcreted in the urine, where they are termed Bence-Jonesproteins. Even more commonly, malignant plasma cellssecrete complete immunoglobulin molecules and freelight chains and thus produce both serum M componentsand Bence-Jones proteins. As will be seen, the excess lightchains have untoward effects on renal function and arean important aspect of the pathophysiology of multiplemyeloma.

Localized Plasmacytoma. These are solitary lesionsinvolving the skeleton or the soft tissues. Skeletal plas-macytomas tend to occur in the same locations as multi-ple myeloma, whereas extraosseous lesions occur mainlyin the upper respiratory tract (sinuses, nasopharynx,larynx). Modestly elevated M proteins are demonstrable

in some of these patients. Those with solitary skeletalplasmacytomas usually have occult disease elsewhere,and most develop full-blown multiple myeloma over aperiod of 5 to 10 years. Extraosseous (soft tissue) plas-macytomas spread less commonly and are often cured bylocal resection.

Lymphoplasmacytic Lymphoma. This tumor is composedof a mixed proliferation of B cells that range from smallround lymphocytes to plasmacytic lymphocytes toplasma cells. It behaves like an indolent B-cell lymphomaand commonly involves multiple lymph nodes, the bonemarrow, and the spleen at the time of presentation. It is included in the plasma cell dyscrasias because thetumor produces an M component, but, unlike multiplemyeloma, it consists in most cases of IgM. Often, thelarge amount of IgM causes the blood to become viscous,producing a syndrome called Waldenström macroglobu-linemia, described below. Other symptoms are related tothe infiltation of various tissues, particularly the bonemarrow, by tumor cells. The synthesis of immunoglob-ulin heavy and light chains is balanced, so free lightchains and Bence-Jones proteinuria are not seen. Unlikemyeloma, this disease does not produce lytic bone lesions.

Heavy-Chain Disease. This is not a specific entity but agroup of proliferations in which only heavy chains areproduced, most commonly IgA. IgA heavy-chain diseaseshows a predilection for the lymphoid tissues where IgAis normally produced, such as the small intestine and respiratory tract, and may represent a variant of MALTlymphoma (discussed later). The less common IgG heavy-chain disease often presents as diffuse lymphadenopathyand hepatosplenomegaly and histologically resembleslymphoplasmacytic lymphoma.

Primary or Immunocyte-Associated Amyloidosis. It maybe recalled that a monoclonal proliferation of plasmacells that secrete free light chains underlies this form ofamyloidosis (Chapter 5). The amyloid deposits (of ALtype) consist of partially degraded light chains.

Monoclonal Gammopathy of Undetermined Significance.Monoclonal gammopathy of undetermined significance(MGUS) is the term applied to monoclonal gam-mopathies that are detected in asymptomatic individuals.M proteins are found in the serum of 1% to 3% ofasymptomatic healthy persons older than age 50 years,making this the most common plasma cell dyscrasia.Despite the name, it is increasingly apparent that MGUSis a precursor lesion that should be considered a form ofneoplasia. Patients with MGUS develop a well-definedplasma cell dyscrasia (myeloma, lymphoplasmacytic lym-phoma, or amyloidosis) at a rate of 1% per year. More-over, MGUS cells often contain the same chromosomaltranslocations that are found in full-blown multiplemyeloma. Thus, the diagnosis of MGUS should be madewith caution and only after careful exclusion of all otherforms of monoclonal gammopathies, particularly multi-ple myeloma. In general, patients with MGUS have lessthan 3gm/dL of monoclonal protein in the serum and noBence-Jones proteinuria.

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Morphology

Multiple myeloma presents most often as multifocaldestructive bone lesions throughout the skeletalsystem. Although any bone can be affected, the fol-lowing distribution was found in a large series of cases:vertebral column, 66%; ribs, 44%; skull, 41%; pelvis,28%; femur, 24%; clavicle, 10%; and scapula, 10%.These focal lesions generally begin in the medullarycavity, erode the cancellous bone, and progressivelydestroy the cortical bone. The bone resorption resultsfrom the secretion of certain cytokines (e.g., IL-1β,tumor necrosis factor, IL-6) by myeloma cells. Thesecytokines stimulate production of another cytokinecalled RANK-ligand, which promotes the differentiationand activation of osteoclasts (Chapter 21). Plasma celllesions often lead to pathologic fractures, which occurmost frequently in the vertebral column. The bonelesions usually appear radiographically as punched-outdefects of 1 to 4cm in diameter (Fig. 12–19A), but insome cases diffuse skeletal demineralization is evident.Microscopic examination of the marrow reveals anincreased number of plasma cells, which constitute10% to 90% of the cellularity. The neoplastic cells canresemble normal mature plasma cells, but they moreoften show abnormal features, such as prominentnucleoli or abnormal cytoplasmic inclusions containingimmunoglobulin (Fig. 12–19B). With progressivedisease, plasma cell infiltrations of soft tissues can beencountered in the spleen, liver, kidneys, lungs, andlymph nodes, or they may be more widely distributed.Terminally, a leukemic picture may emerge.

Renal involvement, generally called myelomanephrosis, is a distinctive feature of multiple myeloma.Proteinaceous casts are prominent in the distal convo-luted tubules and collecting ducts. Most of these castsare made up of Bence-Jones proteins, but they mayalso contain complete immunoglobulins, Tamm-Hors-fall protein, and albumin. Some casts have tinctorialproperties of amyloid. This is not surprising, in that ALamyloid is derived from Bence-Jones proteins (Chapter5). Multinucleate giant cells created by the fusion ofinfiltrating macrophages usually surround the casts.Very often the epithelial cells lining the cast-filledtubules become necrotic or atrophic because of thetoxic actions of the Bence-Jones proteins. Metastaticcalcification stemming from bone resorption andhypercalcemia may be encountered. When complicatedby systemic amyloidosis, nodular glomerular lesionsare present. Pyelonephritis can also occur as a result ofthe increased susceptibility to bacterial infections. Lesscommonly, interstitial infiltrates of abnormal plasmacells are seen.

In contrast to multiple myeloma, lymphoplasma-cytic lymphoma is not associated with lytic skeletallesions. Instead, the neoplastic cells diffusely infiltratethe bone marrow, lymph nodes, spleen, and sometimesthe liver. Infiltrations of other organs also occur, partic-ularly with disease progression. The cellular infiltrateconsists of lymphocytes, plasma cells, and plasmacy-toid lymphocytes of intermediate differentiation. Theremaining forms of plasma cell dyscrasias have eitheralready been described (e.g., primary amyloidosis;Chapter 5) or are too rare for further description.

tive or otherwise damaging effect of the infiltrating neoplastic cells in various tissues and the abnormalimmunoglobulins secreted by the tumors. In multiplemyeloma the pathologic effects of plasma cell tumors predominate, whereas in lymphoplasmacytic lymphomamost of the signs and symptoms result from the IgMmacroglobulins in the serum.

The peak age of incidence of multiple myeloma is between 50 and 60 years. The major clinicopatho-logic features of this disease can be summarized asfollows:

• Bone pain, resulting from infiltration by neoplasticplasma cells, is extremely common. Pathologic frac-tures and hypercalcemia occur, with focal bone destruc-

A

B

Figure 12–19

Multiple myeloma. A, Radiograph of the skull (lateral view). Thesharply punched-out bone defects are most obvious in the calvar-ium. B, Bone marrow aspirate. Normal marrow cells are largelyreplaced by plasma cells, including atypical forms with multiplenuclei, prominent nucleoli, and cytoplasmic droplets containingimmunoglobulin.

Clinical Course. The clinical manifestations of the plasmacell dyscrasias are varied. They result from the destruc-

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tion and diffuse resorption. Hypercalcemia can causeneurologic manifestations such as confusion andlethargy; it also contributes to renal disease. Anemiaresults from marrow replacement as well as from inhi-bition of hematopoiesis by tumor cells.• Recurrent infections with bacteria such as Staphylo-coccus aureus, Streptococcus pneumoniae, andEscherichia coli are serious clinical problems. Theyresult from severe suppression of normal immunoglob-ulin secretion.• Hyperviscosity syndrome may occur due to excessiveproduction and aggregation of myeloma proteins, butthis is much more characteristic of lymphoplasmacyticlymphoma.• Renal insufficiency occurs in as many as 50% ofpatients. It results from multiple conditions, such asrecurrent bacterial infections and hypercalcemia, butmost importantly from the toxic effects of Bence-Jonesproteins on cells lining the tubules.• Amyloidosis develops in 5% to 10% of patients.

The diagnosis of multiple myeloma can be strongly sus-pected when the characteristic focal, punched-out radio-logic defects in the bone are present—especially whenlocated in the vertebrae or calvarium. Electrophoresis of the serum and urine is an important diagnostic tool. In 99% of cases a monoclonal spike of completeimmunoglobulin or immunoglobulin light chain can bedetected in the serum, in the urine, or in both. In theremaining 1% of cases, monoclonal immunoglobulins canbe found within the plasma cells but not in the serum orurine. Such cases are sometimes called nonsecretorymyelomas. Examination of the bone marrow is used toconfirm the presence of a plasma cell proliferation.

Lymphoplasmacytic lymphoma affects older persons,with the peak incidence being between the sixth andseventh decades. Most clinical symptoms of this diseasecan be traced to the presence of large amounts of IgM(macroglobulin). Because of their size, the macroglo-bulins greatly increase blood viscosity. This gives rise tothe hyperviscosity syndrome known as Waldenströmmacroglobulinemia, which is characterized by the fol-lowing features:

• Visual impairment, related to the striking tortuosityand distention of retinal veins; retinal hemorrhages andexudates can also contribute to the visual problems• Neurologic problems such as headaches, dizziness,tinnitus, deafness, and stupor, stemming from sluggishblood flow and sludging• Bleeding, related to the formation of complexesbetween macroglobulins and clotting factors as well asinterference with platelet functions• Cryoglobulinemia, related to precipitation ofmacroglobulins at low temperatures and producingsymptoms such as Raynaud phenomenon and coldurticaria.

Multiple myeloma is a progressive disease, withmedian survival ranging from 4 to 5 years. The mediansurvival in lymphoplasmacytic lymphoma is somewhatlonger, in the range of 4 to 5 years. Although aggressive

therapies are being tried in both, neither disease ispresently curable.

Hodgkin Lymphoma

Hodgkin lymphoma encompasses a distinctive group ofneoplasms that arise almost invariably in a single lymphnode or chain of lymph nodes and spread characteri-stically in a stepwise fashion to the anatomically con-tiguous nodes. It is separated from the non-Hodgkinlymphomas for several reasons. First, it is characterizedmorphologically by the presence of distinctive neoplasticgiant cells called Reed-Sternberg (RS) cells, which areadmixed with reactive, nonmalignant inflammatory cells.Second, it is often associated with somewhat distinctiveclinical features, including systemic manifestations suchas fever. Third, its stereotypical pattern of spread allowsit to be treated differently than most other lymphoid neo-plasms. Despite these distinguishing features, molecularstudies have shown that it is a tumor of B-cell origin.

Classification. Five subtypes of Hodgkin lymphoma arerecognized: (1) nodular sclerosis, (2) mixed cellularity, (3) lymphocyte predominance, (4) lymphocyte rich, and(5) lymphocyte depletion. The latter two subtypes areuncommon and will not be mentioned further. Beforedelineating the remaining three, however, we shoulddescribe the common denominator among all—RS cellsand variants thereof—and the staging system used tocharacterize the extent of the disease in an individual.

Morphology

The sine qua non for Hodgkin lymphoma is the Reed-Sternberg (RS) cell (Fig. 12–20). This is a large cell(15–45μm in diameter) with an enlarged multilobatednucleus, exceptionally prominent nucleoli, and abun-dant, usually slightly eosinophilic, cytoplasm. Particu-larly characteristic are cells with two mirror-imagenuclei or nuclear lobes, each containing a large (inclu-sion-like) acidophilic nucleolus surrounded by a dis-tinctive clear zone; together they impart an owl-eyeappearance. The nuclear membrane is distinct. As wewill see, such “classic” RS cells are common in themixed-cellularity subtype, uncommon in the nodularsclerosis subtype, and rare in the lymphocyte-predom-inance subtype; in these latter two subtypes, othercharacteristic RS cell variants predominate.

The staging of Hodgkin lymphoma (Table 12–9) is ofclinical importance, because the course, choice oftherapy, and prognosis are all intimately related to thedistribution of the disease.

With this background we can turn to the morpho-logic classification of Hodgkin lymphoma into its sub-groups and point out some of the salient clinicalfeatures of each. Later the manifestations common toall will be presented. The essential features that serveto differentiate the major subgroups (lymphocyte pre-dominance, nodular sclerosis, and mixed cellularity)are the morphology, immunophenotype, and frequencyof the neoplastic elements (RS cells) and the nature ofthe tissue response.

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Figure 12–20

Hodgkin lymphoma. A binucleate Reed-Sternberg cell with large,inclusion-like nucleoli and abundant cytoplasm is surrounded bylymphocytes, and an eosinophil can be seen below. (Courtesy ofDr. Robert W. McKenna, Department of Pathology, University ofTexas Southwestern Medical School, Dallas, Texas.)

Table 12–9 Clinical Staging of Hodgkin and Non-Hodgkin Lymphomas (Ann Arbor Classification)*

Stage Distribution of Disease

I Involvement of a single lymph node region (I) orinvolvement of a single extralymphatic organ or tissue(IE)

II Involvement of two or more lymph node regions onthe same side of the diaphragm alone (II) or withinvolvement of limited contiguous extralymphaticorgans or tissue (IIE)

III Involvement of lymph node regions on both sides ofthe diaphragm (III), which may include the spleen (IIIS),limited contiguous extralymphatic organ or site (IIIE),or both (IIIES)

IV Multiple or disseminated foci of involvement of one ormore extralymphatic organs or tissues with or withoutlymphatic involvement

*All stages are further divided on the basis of the absence (A) orpresence (B) of the following systemic symptoms: significant fever,night sweats, unexplained loss of more than 10% of normal bodyweight.

From Carbone PT, et al.: Symposium (Ann Arbor): staging inHodgkin disease. Cancer Res 31:1707, 1971.

Nodular Sclerosis Hodgkin Lymphoma. This is the mostcommon form. It is equally frequent in men and womenand has a striking propensity to involve the lower cer-vical, supraclavicular, and mediastinal lymph nodes.Most of the patients are adolescents or young adults,and the overall prognosis is excellent. It is character-ized morphologically by:

• The presence of a particular variant of the RS cell,the lacunar cell (Fig. 12–21). This cell is large andhas a single multilobate nucleus with multiplesmall nucleoli and an abundant, pale-stainingcytoplasm. In formalin-fixed tissue, the cytoplasm

often retracts, giving rise to the appearance of cellslying in empty spaces, or lacunae.

• The presence of collagen bands that divide thelymphoid tissue into circumscribed nodules (Fig.12–22). The fibrosis may be scant or abundant, andthe cellular infiltrate may show varying propor-tions of lymphocytes, eosinophils, histiocytes, andlacunar cells. Classic RS cells are infrequent.

The immunophenotype of the lacunar variants isidentical to that of classic RS cells. These cells expressCD15 and CD30 and usually do not express B- and T-cell–specific antigens.

Mixed-Cellularity Hodgkin Lymphoma. This is the mostcommon form of Hodgkin lymphoma in patients olderthan the age of 50 and overall comprises about 25% of

Figure 12–21

Hodgkin lymphoma, nodular sclerosis type. A distinctive “lacunarcell” with multilobed nucleus containing many small nucleoli isseen lying within a clear space created by retraction of its cyto-plasm. It is surrounded by lymphocytes. (Courtesy of Dr. Robert W.McKenna, Department of Pathology, University of Texas South-western Medical School, Dallas, Texas.)

Figure 12–22

Hodgkin lymphoma, nodular sclerosis type. A low-power viewshows well-defined bands of pink, acellular collagen that havesubdivided the tumor cells into nodules. (Courtesy of Dr. RobertW. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)

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Etiology and Pathogenesis. Determining the origin of theneoplastic RS cells of Hodgkin lymphoma has proveddaunting, in part because these cells are rare comparedwith the surrounding reactive inflammatory infiltrate. Ithas been recognized for some time that the L&H variants of RS cells found in nodular lymphocyte-predominance Hodgkin lymphoma express B-cellmarkers, supporting a B-cell origin. By contrast, the RScells in other forms of Hodgkin lymphoma have beenenigmatic, in that they generally do not express lineage-specific lymphoid markers. This uncertainty was finallyresolved by elegant studies performed on single microdis-sected RS cells obtained from cases of mixed-cellularityand nodular-sclerosis Hodgkin lymphoma. Sequenceanalysis of DNA amplified from such cells has shown thateach RS cell from any given case possesses the sameimmunoglobulin gene rearrangements as its neighbor andthat the rearranged immunoglobulin genes have under-gone somatic hypermutation. As a result, it is now agreedthat Hodgkin lymphoma is a neoplasm arising from ger-minal center B cells.

This said, many puzzles remain to be answered. RScells are aneuploid but lack the chromosomal transloca-tions that are common in other germinal center B-celllymphomas and have patterns of gene expression thatbear little resemblance to normal B cells. The events thattransform these cells and alter their appearance and geneexpression programs are still unknown. One clue stemsfrom the involvement of EBV. The EBV genome is present

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cases. There is a male predominance. Classic RS cellsare plentiful within a distinctive heterogeneous cellu-lar infiltrate, which includes small lymphocytes,eosinophils, plasma cells, and benign histiocytes (Fig.12–23). Compared with the other common subtypes,more patients with mixed cellularity have disseminateddisease and systemic manifestations.

Lymphocyte-Predominance Hodgkin Lymphoma. Thissubgroup, comprising about 5% of Hodgkin lymphoma,is characterized by a large number of small resting lym-phocytes admixed with a variable number of benignhistiocytes (Fig. 12–24), often within large, poorlydefined nodules. Other types of reactive cells, such aseosinophils, neutrophils, and plasma cells, are scantyor absent, and classic RS cells are extremely difficult to

Figure 12–23

Hodgkin disease, mixed-cellularity type. A diagnostic, binucleateReed-Sternberg cell is surrounded by multiple cell types, includingeosinophils (bright-red cytoplasm), lymphocytes, and histiocytes.(Courtesy of Dr. Robert W. McKenna, Department of Pathology,University of Texas Southwestern Medical School, Dallas, Texas.)

Figure 12–24

Hodgkin disease, lymphocyte-predominance type. Numerousmature-looking lymphocytes surround scattered, large, pale-staining lymphocytic and histiocytic variants (“popcorn” cells).(Courtesy of Dr. Robert W. McKenna, Department of Pathology,University of Texas Southwestern Medical School, Dallas, Texas.)

find. Scattered among the reactive cells are lympho-histiocytic (L&H) variant RS cells that have a delicatemultilobed, puffy nucleus that has been likened inappearance to popcorn (“popcorn cell”). The typicalnodular growth pattern of lymphocyte-predominanceHodgkin lymphoma has long suggested that this mightbe a neoplasm of follicular B cells; indeed, phenotypicstudies have revealed that the L&H variants express B-cell markers (e.g., CD20). Furthermore, L&H variantshave rearranged and somatically hypermutated IgHgenes, which strongly supports a follicular B-cell origin.Most individuals with this form of the disease presentwith isolated cervical or axillary lymphadenopathy andhave an excellent prognosis.

It is apparent that Hodgkin lymphoma spans a widerange of histologic patterns and that certain forms, withtheir characteristic fibrosis, eosinophils, neutrophils,and plasma cells, come deceptively close to simulatingan inflammatory reactive process. The histologic diag-nosis of Hodgkin lymphoma rests on the definitiveidentification of RS cells or their variants in the appro-priate background of reactive cells. Immunophenotyp-ing plays an important adjunct role in helping todistinguish Hodgkin lymphoma from reactive condi-tions and other forms of lymphoma.

In all forms, involvement of the spleen, liver, bonemarrow, and other organs may appear in due courseand take the form of irregular nodules that are com-posed of a mixture of RS cells and reactive cells similarto that observed in lymph nodes. In advanced disease,the spleen and the liver can be enlarged by tumor.

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in the RS cells in as many as 70% of cases of the mixed-cellularity type and a smaller fraction of the nodular scle-rosis type. More importantly, the integration of the EBVgenome is identical in all RS cells in a given tumor, indi-cating that infection precedes (and therefore may berelated to) transformation. Thus, as in Burkitt lymphomaand B-cell lymphomas in immunodeficient patients, EBVinfection is likely to be one of several steps contributingto the development of Hodgkin lymphoma, particularlythe mixed-cellularity type.

If EBV is playing a causative role, are there commononcogenic signals in EBV-positive and EBV-negativetumors? A possible lead stems from the observation thatthe RS cells in classical forms of Hodgkin lymphoma,regardless of their EBV status, contain high levels of activated NF-κB, a transcription factor that normallystimulates B-cell proliferation and protects B cells frompro-apoptotic signals. Several EBV proteins that areknown to activate NF-κB are expressed in EBV-positiveRS cells. Somatic mutations that abolish the function ofIκB, an important inhibitor of NF-κB, have been foundin EBV-negative RS cells. Thus, hyperactivation of NF-κBmay be a central event in the genesis, growth, and sur-vival of RS cells.

The characteristic non-neoplastic, inflammatory-cellinfiltrate seems to result from a number of cytokinessecreted by RS cells, including IL-5 (which attracts andactivates eosinophils), transforming growth factor β (afibrogenic factor), and IL-13 (which may stimulate RScells through an autocrine mechanism). Conversely, theresponding inflammatory cells, rather than being inno-cent bystanders, produce factors (such as CD30 ligand)that can aid the growth and survival of RS cells, and con-tribute further to the tissue reaction.

Clinical Course. Hodgkin lymphomas, like NHLs,usually present as a painless enlargement of the lymphnodes. Although a definitive distinction from NHL canbe made only by examination of a lymph node biopsyspecimen, several clinical features favor the diagnosis ofHodgkin lymphoma (Table 12–10). Younger patientswith the more favorable histologic types tend to present

Table 12–10 Clinical Differences Between Hodgkinand Non-Hodgkin Lymphomas

Hodgkin Lymphoma Non-Hodgkin Lymphoma

More often localized to More frequent involvement ofa single axial group of multiple peripheral nodesnodes (cervical, mediastinal, para-aortic)

Orderly spread by contiguity Noncontiguous spread

Mesenteric nodes and Mesenteric nodes and WaldeyerWaldeyer ring rarely ring commonly involvedinvolved

Extranodal involvement Extranodal involvement uncommon common

in clinical stages I or II and are usually free of systemicmanifestations. Patients with disseminated disease (stagesIII and IV) are more likely to have systemic complaintssuch as fever, unexplained weight loss, pruritus, andanemia. As mentioned earlier, these patients generallyhave the histologically less favorable variants. The out-look after aggressive radiotherapy and chemotherapy forpatients with this disease, including those with dissemi-nated disease, is generally very good. With current modal-ities of therapy, the clinical stage is the most importantprognostic indicator. The 5-year survival rate of patientswith stage I-A or II-A disease is close to 100%. Even withadvanced disease (stage IV-A or IV-B), the overall 5-yeardisease-free survival rate is around 50%. However, ther-apeutic successes have also brought problems. Long-termsurvivors of radiotherapy protocols are at much higherrisk of developing certain malignancies, including lungcancer, melanoma, and breast cancer. As a result, currentefforts are aimed at developing less genotoxic therapeu-tic regimens that decrease therapy-related complicationswhile preserving a high cure rate.

Miscellaneous Lymphoid Neoplasms

Of the many remaining forms of lymphoid neoplasiawithin the WHO classification, several with distinctive orclinically important features merit brief discussion.

Extranodal Marginal Zone Lymphoma. This is a specialcategory of low-grade mature B-cell tumors that arisemost commonly in mucosal-associated lymphoid tissue(MALT), such as salivary glands, small and large bowel,and lungs, and some nonmucosal sites such as the orbitand breast. Extranodal marginal zone lymphomas tendto develop in the setting of autoimmune disorders (suchas Sjögren syndrome and Hashimoto thyroiditis) orchronic infections with such organisms as Helicobacterpylori and Campylobacter jejuni), suggesting that sus-tained antigenic stimulation contributes to lymphomage-nesis. In the case of H. pylori–associated gastric MALTlymphoma, eradication of the organism with antibiotictherapy often leads to regression of the tumor cells, whichseem to depend on cytokines secreted by H. pylori–specific T cells for their growth and survival (Chapter 6).When arising at other sites, MALT tumors can often becured by local excision or radiotherapy. Two recurrentcytogenetic abnormalities are recognized: t(1;14), involv-ing the BCL10 and IgH genes; and t(11;18), involvingthe MALT1 and IAP2 genes.

Hairy Cell Leukemia. This uncommon, indolent B-cellneoplasm is distinguished by the presence of leukemiccells that have fine, hairlike cytoplasmic projections. Thetumor cells express pan–B-cell markers, including CD19and CD20, surface immunoglobulin, and, characteristi-cally, CD11c and CD103; these two antigens are notpresent on most other B-cell tumors, making them diag-nostically useful.

This tumor occurs mainly in older males, and its man-ifestations result largely from infiltration of bone marrow

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and spleen. Splenomegaly, which is often massive, is the most common and sometimes the only abnormalphysical finding. Pancytopenia, resulting from marrowinfiltration and splenic sequestration, is seen in more thanhalf the cases. Hepatomegaly is less common and not asmarked, and lymphadenopathy is distinctly rare. Leuko-cytosis is not a common feature, being present in only15% to 20% of patients, but hairy cells can be identifiedin the peripheral blood smear in most cases. The diseaseis indolent but progressive if untreated; pancytopenia andinfections are major problems. Unlike most other low-grade lymphoid neoplasms, this tumor is extremely sen-sitive to chemotherapeutic agents, particularly purinenucleosides. Complete durable responses are the rule, andthe overall prognosis is excellent.

Mycosis Fungoides and Sézary Syndrome. These arecomposed of neoplastic CD4+ T cells that home to theskin; as a result, they are often referred to as cutaneousT-cell lymphomas.

Mycosis fungoides usually presents as a nonspecificerythrodermic rash, which over time tends to progressthrough a plaque phase to a tumor phase. Histologically,there is infiltration of the epidermis and upper dermis by neoplastic T cells, which often have a cerebriformnucleus characterized by marked infolding of the nuclearmembrane. With progressive disease, both nodal and visceral dissemination appear. Sézary syndrome is a clin-ical variant characterized by the presence of (1) a gener-alized exfoliative erythroderma and (2) tumor cells(Sézary cells) in the peripheral blood. Circulating tumorcells are also present in as many as 25% of cases ofplaque- or tumor-phase mycosis fungoides. Patients witherythrodermic-phase mycosis fungoides often survive formany years, whereas survival is generally 1 to 3 years for patients with tumor-phase disease, visceral disease, orSézary syndrome.

Adult T-Cell Leukemia/Lymphoma. This T-cell neoplasmis caused by a retrovirus, human T-cell leukemia virustype 1 (HTLV-1). It is endemic in southern Japan, theCaribbean basin, and West Africa and occurs sporadicallyelsewhere, including in the southeastern United States.The pathogenesis of this tumor is discussed in Chapter 6.In addition to causing lymphoid malignancies, HTLV-1infection can also give rise to transverse myelitis, a pro-gressive demyelinating disease that affects the centralnervous system and the spinal cord.

Adult T-cell leukemia/lymphoma is characterized byskin lesions, generalized lymphadenopathy, hepatosp-lenomegaly, hypercalcemia, and variable numbers ofmalignant CD4+ lymphocytes in the peripheral blood.The leukemic cells express high levels of CD25, the IL-2receptor α chain. In most cases this is an extremelyaggressive disease, with a median survival time of about8 months. In 15% to 20% of patients the course of thedisease is chronic; their disease is clinically indistinguish-able from cutaneous T-cell lymphoma.

Peripheral T-Cell Lymphomas. This is a heterogeneousgroup of tumors that together make up about 15% ofadult NHLs. Although several rare distinctive subtypes

SUMMARY

Lymphoid Neoplasms

• Classified based on cell of origin and stage of dif-ferentiation• Most common types in children are acute lym-phoblastic leukemias and lymphomas, which arederived from B- and T-cell precursors.

� Highly aggressive tumors that present withsymptoms of bone marrow failure, or asrapidly growing masses

� Tumor cells contain genetic lesions that blockdifferentiation, leading to the accumulation ofimmature blasts that cannot function asimmune cells.

• Most common types in adults are non-Hodgkinlymphomas derived from germinal center B cells.

� May be indolent (e.g., follicular lymphoma) oraggressive (e.g., diffuse large B-cell lymphoma)

� Sometimes interfere with the immune system bydysregulating the function of normal B and Tcells (e.g., chronic lymphocytic leukemia, mul-tiple myeloma)

� Often contain chromosomal translocations ormutations involving genes (such as BCL2 andBCL6) that regulate normal mature B-celldevelopment and survival

• Precursor B- and T-Cell Lymphoblastic Leukemia/Lymphoma:

� Aggressive tumors of pre-B or pre-T cells thatare most common in childhood and youngadults, but which occur throughout life.

� Most patients present with bone marrow failurecaused by extensive marrow replacement byleukemic cells, resulting in pancytopenia.

• Small Lymphocytic Lymphoma/Chronic Lym-phocytic Leukemia:

� Tumor of mature B cells that usually presentswith involvement of the bone marrow and thelymph nodes.

� Follows an indolent course, commonly associ-ated with immune abnormalities, including anincreased susceptibility to infection and auto-immune disorders.

• Follicular Lymphoma:� Tumor cells recapitulate the growth pattern of

normal germinal center B cells; more than 80%of cases are associated with a t(14;18) translo-cation that results in the over-expression of theanti-apoptotic protein BCL2.

• Mantle Cell Lymphoma:� Tumor of mature B cells that usually presents

with advanced disease involving lymph nodes,

fall under this heading, most tumors in this group are unclassifiable. In general, they present as disse-minated disease, are aggressive, and respond poorly totherapy.

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Myeloid NeoplasmsMyeloid neoplasms arise from hematopoietic stem cellsand typically give rise to monoclonal proliferations thatreplace normal bone marrow cells. There are threegeneral categories of myeloid neoplasia. In the AMLs, theneoplastic cells are blocked at some early stage of myeloidcell development. Immature myeloid cells (blasts), whichcan exhibit evidence of granulocytic, erthroid, monocytic,or megakaryoctyic differentiation, accumulate in themarrow, replacing normal elements, and frequently cir-culate in the peripheral blood. In the chronic myelopro-liferative disorders, the neoplastic clone retains thecapacity to undergo terminal differentiation but exhibitsincreased or dysregulated growth. Commonly there is anincrease in one or more of the formed elements (red cells,platelets, and/or granulocytes) in the peripheral blood. Inthe myelodysplastic syndromes, terminal differentiationoccurs but in a disordered and ineffective fashion, leadingto the appearance of dysplastic marrow precursors andperipheral blood cytopenias.

Although these three categories provide a useful start-ing point when considering the myeloid neoplasms, thedivisions between them sometimes blur. Both myelodys-plastic syndromes and myeloproliferative disorders oftentransform to a picture identical to acute myelogenousleukemia, and some patients present with disorders thathave features of both myelodysplastic and myeloprolifer-ative disorders. Given that all arise from hematopoieticstem cells, the close relationship among these disorders isnot surprising.

Acute Myelogenous Leukemia

AML primarily affects older adults, with the median agebeing 50 years. It is an extremely heterogeneous disorder,as will be discussed below. The clinical signs and symp-toms, which closely resemble those produced by ALL, areusually related to marrow failure caused by the replace-ment of normal marrow elements by leukemic blasts.Fatigue and pallor, abnormal bleeding, and infections arecommon in newly diagnosed patients, who typicallypresent within a few weeks of the onset of symptoms.Splenomegaly and lymphadenopathy are in general lessprominent than in ALL, but, rarely, AML presents as adiscrete tissue mass (a so-called granulocytic sarcoma).Ideally the diagnosis and classification of AML are basedon the results of morphologic, histochemical, immuno-phenotypic, and karyotypic studies. Of these tests, kary-otyping is most predictive of outcome.

Pathophysiology. Most AMLs are associated withacquired mutations in transcription factors that inhibitnormal myeloid differentiation, leading to the accumula-tion of cells at earlier stages of development. Of particu-lar interest is the t(15;17) translocation in acutepromyelocytic leukemia. This translocation results in thefusion of the retinoic acid receptor α (RARA) gene onchromosome 17 with the PML gene on chromosome 15.The chimeric gene(s) produce abnormal PML/RARAfusion proteins that block myeloid differentiation at thepromyelocytic stage, probably by inhibiting the functionof normal RARA receptors. Remarkably, pharmacologicdoses of retinoic acid (Chapter 8), a vitamin A analogue,overcome this block and cause the neoplastic promyelo-cytes to terminally differentiate into neutrophils and die.Because neutrophils live, on average, for 6 hours, theresult is the rapid clearance of tumor cells and remissionin a high fraction of patients. The effect is very specific; AMLs without translocations involving RARA do notrespond to retinoic acid. Sufferers relapse if treated withretinoic acid alone, possibly because the neoplastic progenitor that gives rise to the promyelocytes is resistantto the pro-differentiative effects of retinoic acid.However, when combined with chemotherapy, the prog-nosis is excellent. Nonetheless, this is an importantexample of an effective therapy that is targeted at atumor-specific molecular defect.

Other work using transgenic or gene knock-in micehas generally suggested that the mutated transcriptionfactors found in AML are not sufficient, in and of them-selves, to cause the disease. Complementary mutations

bone marrow, and extranodal sites such as thegut.

� Highly associated with a t(11;14) translocationthat results in over-expression of cyclin D1, aregulator of cell cycle progression.

• Diffuse Large B-Cell Lymphoma:� Heterogeneous group of mature B cell tumors

that share a similar large-cell morphology andaggressive clinical behavior; the most commontype of lymphoma.

� Highly associated with rearrangements ormutations of BCL6 gene; one-third arise fromfollicular lymphomas and carry a t(14;18)translocation.

• Burkitt Lymphoma:� Very aggressive tumor of mature B cells that

usually arises at extranodal sites, is uniformlyassociated with translocations involving the c-MYC proto-oncogene, and is often associatedwith latent infection by Epstein-Barr virus(EBV).

• Multiple Myeloma:� Plasma cell tumor that usually presents as mul-

tiple lytic bone lesions with pathologic frac-tures and hypercalcemia.

� Neoplastic plasma cells may suppress normalhumoral immunity and secrete partialimmunoglobulins that are often nephrotoxic.

• Hodgkin Lymphoma:� Unusual tumor mostly comprised of reactive

lymphocytes, macrophages, and stromal cells;the malignant cell, the Reed-Sternberg cell(which is derived from B cells), typically makesup a minor fraction of the tumor mass.

See also Table 2–8 for features of different tumors.

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12–11B). The FAB categories are used within the WHOclassification for tumors that lack these strong prognos-tic factors.

Histochemistry. Cases with granulocytic differentiationare typically positive for the enzyme myeloperoxidase,which is detected by incubation of cells with peroxidasesubstrates. Auer rods are intensely peroxidase positive,which can help bring out their presence when they arerare. Monocytic differentiation is demonstrated by stain-ing for lysosomal nonspecific esterases.

Immunophenotype. The expression of immunologicmarkers is heterogeneous in AML. Most express somecombination of myeloid-associated antigens, such asCD13, CD14, CD15, CD64, or CD117 (cKIT). CD33 isexpressed on pluripotent stem cells but is retained onmyeloid progenitor cells. Such markers are helpful in dis-tinguishing AML from ALL (as shown in Fig. 12–14) andidentifying primitive AMLs (e.g., the M0 subtype). Inaddition, monoclonal antibodies reactive with platelet-associated antigens are very helpful in the diagnosis ofthe M7 subtype, acute megakaryocytic leukemia.

Prognosis. AML is a devastating disease. Tumors with“good-risk” karyotypic aberrations (t[8;21], inv[16]) areassociated with a 50% chance of long-term disease-freesurvival, but the overall long-term disease-free survival is only 15% to 30% with conventional chemotherapy. An increasing number of patients with AML are beingtreated with more aggressive approaches, such as allo-geneic bone marrow transplantation.

Myelodysplastic Syndromes

In patients with these disorders, the bone marrow ispartly or wholly replaced by the clonal progeny of atransformed multipotent stem cell that retains the capac-ity to differentiate into red cells, granulocytes, andplatelets, but in a manner that is both ineffective and disordered. As a result the bone marrow is usually hyper-cellular or normocellular, but the peripheral blood showsone or more cytopenias. The abnormal stem cell clone inthe bone marrow is genetically unstable, which leads toacquisiton of additional mutations and the eventualtransformation to AML. Most cases are idiopathic, butsome develop after chemotherapy with alkylating agentsor exposure to ionizing radiation therapy.

Cytogenetic studies reveal that a chromosomallyabnormal clone of cells is present in the marrow of asmany as 70% of individuals with this disease. Somecommon karyotypic abnormalities include loss of chro-mosomes 5 or 7, or deletions of 5q or 7q. Morphologi-cally, the marrow is populated by abnormal-appearinghematopoietic precursors. Some of the more commonabnormalities include megaloblastoid erythroid precur-sors resembling those seen in the megaloblastic anemias,erythroid forms with iron deposits within their mito-chondria (ringed sideroblasts), granulocyte precursorswith abnormal granules or nuclear maturation, and smallmegakaryocytes with single small nuclei.

Figure 12–25

Acute promyelocytic leukemia (M3 subtype). Bone marrow aspi-rate shows neoplastic promyelocytes with abnormally coarse andnumerous azurophilic granules. Other characteristic findingsinclude the presence of several cells with bilobed nuclei and a cellin the center of the field that contains multiple needle-like Auerrods. (Courtesy of Dr. Robert W. McKenna, Department of Pathol-ogy, University of Texas Southwestern Medical School, Dallas,Texas.)

Morphology

By definition, in AML myeloid blasts or promyelocytesmake up more than 20% of the bone marrow cellular-ity. Myeloblasts (precursors of granulocytes) have del-icate nuclear chromatin; three to five nucleoli; and fine,azurophilic granules in the cytoplasm (see Fig. 12–14B).Distinctive red-staining rodlike structures (Auer rods)may be present in myeloblasts or more differentiatedcells; they are particularly prevalent in the progranulo-cytes found in acute promyelocytic leukemia (Fig.12–25). Auer rods are found only in neoplasticmyeloblasts and are thus a helpful diagnostic cluewhen present. In other subtypes of AML, monoblasts,erythroblasts, or megakaryoblasts predominate.

have been described in a number of genes that have noeffect on maturation but instead promote enhanced pro-liferation and survivial. One example is gain-of-functionmutations in FLT3 (a surface receptor with tyrosinekinase activity), which are seen in a number of AML sub-types, including acute promyelocytic leukemia.

Classification. AMLs are diverse in terms of genetics, thepredominant line of differentiation, and the maturity ofcells. The latter two features serve as the basis for theRevised French-American-British (FAB) classification(Table 12–11A), which is still used widely. However,experience has shown that the FAB classification haslimited prognostic value, whereas certain recurrent chromosomal abnormalities, prior drug exposure, and ahistory of a myelodyplastic syndrome are predictive ofoutcome. As a result, a new WHO classification has beenproposed that takes these variables into account (Table

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Most individuals with this disease are between 50 and70 years of age. AML develops in 10% to 40%. Theothers suffer from infections, anemia, and hemorrhages,as a result of the defective bone marrow function. Theresponse to chemotherapy is usually poor, lendingsupport to the idea that myelodysplasia arises in a back-ground of stem cell failure. It is of interest in this regardthat some patients with aplastic anemia eventuallydevelop a myelodysplastic syndrome, and a significantminority of patients with myelodysplasia respond to T-cell immunosuppressants. In this subset of patients, it ispossible that the malignant clone “grows out” becausenormal stem cells are under attack by T cells. As dis-cussed earlier, a similar mechanism seems to underlieparoxysmal nocturnal hemoglobinuria. The prognosis isvariable; the median survival time varies from 9 to 29months and is worse in those with increased marrowblasts or cytogenetic abnormalities at the time of diagnosis.

Chronic Myeloproliferative Disorders

These disorders are marked by the hyperproliferation ofneoplastic myeloid progenitors that retain the capacityfor terminal differentiation; as a result, there is anincrease in one or more formed elements of the periph-eral blood. The neoplastic progenitors tend to seed sec-ondary hematopoietic organs (the spleen, liver, and

Table 12–11A Revised FAB Classification of Acute Myelogenous Leukemias (AML)

Class Definition Incidence (% of AML) Morphology/Comments

M0 Minimally 2–3 Blasts lack Auer rods and myeloperoxidase but express myeloid lineage surfacedifferentiated AML markers.

M1 AML without 20 Some blasts (≥3%) are myeloperoxidase positive; few granules or Auer rods maturation and very little maturation beyond the myeloblast stage of differentiation.

M2 AML with maturation 30–40 >20% of marrow cells are myeloblasts, but many cells are seen at later stages of granulocyte differentiation; Auer rods are usually present; oftenassociated with t(8;21).

M3 Acute promyelocytic 5–10 Most cells are abnormal promyelocytes, often containing many Auer rods perleukemia cell; patients are younger on average (median age 35–40yr); high

incidence of DIC; strongly associated with t(15;17).

M4 Acute myelomonocytic 15–20 Myelocytic and monocytic differentiation evident by cytochemical stains; leukemia monoblasts are positive for nonspecific esterase; myeloid cells show a

range of maturation; variable numbers of Auer rods; subset associated with inv(16).

M5 Acute monocytic 10 Monoblasts and immature monocytic cells (myeloperoxidase negative, leukemia nonspecific esterase positive) predominate; Auer rods are usually absent;

older patients; more likely to be associated with organomegaly, lymphadenopathy, and tissue infiltration; the M5b subtype is defined by thepredominance of mature-appearing monocytes in the peripheral blood, whereas only immature cells are seen in the M5a subtype.

M6 Acute erythroleukemia 5 Most commonly associated with abundant dysplastic erythroid progenitors; >20% of cells of the marrow nonerythroid cells are myeloblasts, which maycontain Auer rods; usually occurs in advanced age or following exposureto mutagens (e.g., chemotherapy).

M7 Acute megakaryocytic 1 Blasts of megakaryocytic lineage predominate, as judged by expression of leukemia platelet-specific antigens; myelofibrosis or increased marrow reticulin often

present; Auer rods are absent.

DIC, disseminated intravascular coagulation.

Table 12–11B Proposed WHO Classification of AcuteMyelogenous Leukemia (AML)

Class Prognosis

I. AML with Recurrent Chromosomal Translocations

AML with t(8;21)(q22;q22); CBFa/ETO fusion Favorablegene

AML with inv(16)(p13;q22); CBFb/MYH11 Favorablefusion gene

AML with t(15;17)(q22;q21.1); PML/RARa Favorable

AML with t(11q23;variant) Poor

II. AML with Multilineage Dysplasia

With prior myelodysplastic syndrome Very poor

Without prior myelodysplastic syndrome Poor

III. AML, Therapy-Related

Alkylating agent related Very poor

Epipodophyllotoxin related Very poor

IV. AML, Not Otherwise Classified

Subclasses defined by extent and type of Intermediatedifferentiation (M0–M7)

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lymph nodes), resulting in hepatosplenomegaly (causedby neoplastic extramedullary hematopoiesis) and mildlymphadenopathy. A common theme is the association ofthese disorders with mutated tyrosine kinases, which gen-erate high-intensity constitutive signals that mimic thosethat regulate the growth and survival of normal myeloidcells. This insight provides a satisfying explanation forthe observed overproduction of myeloid cells and isimportant therapeutically because of the availability oftyrosine kinase inhibitors.

Most patients with this disease subgroup fall into oneof four diagnostic entities: chronic myelogenous leukemia(CML), polycythemia vera (PCV), primary myelofibrosis,and essential thrombocythemia. CML is clearly separatedfrom the other disorders by being associated with a char-acteristic abnormality, the presence of a BCR-ABL fusiongene. In contrast, the other myeloproliferative disordersshow considerable overlap clinically and genetically.Mutations of the JAK2 kinase are the single mostcommon genetic abnormality in this group. It is seen in>90% of cases of polycythemia vera, 50% of primarymyelofibrosis, and 30% of essential thrombocythemias.Additional rarer types of myeloproliferative disorders areassociated with activating mutations in still other tyro-sine kinases, such as platelet derived growth factor recep-tor alpha and beta. Thus, an evolving theme is that most,if not all, myeloproliferative disorders are associated withan abnormal increase in the activity of one or anothertyrosine kinase, which appears to stimulate the same sig-naling pathways that are normally activated byhematopoietic growth factors. Only CML, PCV, andprimary myelofibrosis are presented here. Essentialthrombocythemia and other myeloproliferative disordersoccur too infrequently to merit discussion.

Chronic Myelogenous Leukemia

CML principally affects adults between 25 and 60 yearsof age and accounts for 15% to 20% of all cases ofleukemia. The peak incidence is in the fourth and fifthdecades of life.

Pathophysiology. CML is uniformly associated with thepresence of an acquired genetic abnormality, a BCR-ABLfusion gene. In about 95% of cases the BCR-ABL fusiongene is the product of a (9;22) translocation that movesthe ABL gene from chromosome 9 to a position on chro-mosome 22 adjacent to the BCR gene. The derivativechromosome 22 is often referred to as the Philadelphia(Ph) chromosome, because it was discovered in Philadel-phia. In the remaining 5% of patients, the BCR-ABLfusion gene is created by rearrangements that are cyto-genetically cryptic or obscured by the involvement ofmore than two chromosomes. In individuals with CMLthe BCR-ABL fusion gene is present in granulocytic, ery-throid, megakaryocytic, and B-cell precursors, and insome cases T-cell precursors as well. This finding is firmevidence for the origin of CML from a pluripotent stemcell. As you recall from Chapter 6, the BCR-ABL geneencodes a fusion protein consisting of portions of BCRand the tyrosine kinase domain of ABL that is critical forneoplastic transformation. Although the Ph chromosomeis highly characteristic of CML, it should be remembered

that it is also present in 25% of adults with ALL and rarecases of adults with AML.

Normal myeloid progenitors depend on signals gener-ated by growth factors and their receptors for growth andsurvival, but CML progenitors have much decreasedrequirements. This altered growth-factor dependence isdue to the presence of the BCR-ABL tyrosine kinase,which generates constitutive signals that mimic the effectsof growth-factor receptor activation. Although the BCR-ABL fusion gene is present in multiple lineages, forunclear reasons the granulocyte precursors are mostaffected. As is evident from the markedly elevatednumber of granulocytes in the bone marrow and periph-eral blood, the proliferating CML progenitors retain thecapacity for terminal differentiation.

Figure 12–26

Chronic myelogenous leukemia. Peripheral blood smear showsmany mature neutrophils, some metamyelocytes, and a myelocyte.(Courtesy of Dr. Robert W. McKenna, Department of Pathology,University of Texas Southwestern Medical School, Dallas, Texas.)

Morphology

The peripheral blood findings are highly characteristic.The leukocyte count is elevated, often exceeding100,000 cells/μL. The circulating cells are predomi-nantly neutrophils, metamyelocytes, and myelocytes(Fig. 12–26), but basophils and eosinophils are alsoprominent. A small proportion of myeloblasts, usuallyless than 5%, can be seen in the peripheral blood. Anincreased number of platelets (thrombocytosis) is alsotypical. The bone marrow is hypercellular as a result ofa hyperplasia of granulocytic and megakaryocytic pre-cursors. Myeloblasts are usually only slightlyincreased, and there is frequently an increase in thenumber of phagocytes. The red pulp of the enlargedspleen has an appearance that resembles bone marrowbecause of the extensive extramedullary hemato-poiesis. This burgeoning mass of hematopoietic cellsoften compromises the local blood supply, leading tosplenic infarcts.

Clinical Features. The onset of CML is usually slow, andthe initial symptoms are often nonspecific (e.g., easy fati-gability, weakness, and weight loss). Sometimes the first

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symptom is a dragging sensation in the abdomen, causedby the extreme splenomegaly that is characteristic of thiscondition. On occasion it may be necessary to distinguishCML from a “leukemoid reaction,” a dramatic elevationof the granulocyte count in response to infection, stress,chronic inflammation, and certain neoplasms. The pres-ence of the Ph chromosome is the most definitive way ofdistinguishing CML from leukemoid reactions (and theother chronic myeloproliferative diseases). Measurementof leukocyte alkaline phosphatase can also be helpful,because the granulocytes in CML are almost completelydevoid of this enzyme, whereas it is increased in leuke-moid reactions and other myeloproliferative disorders(such as PCV).

The course of CML is one of slow progression. Evenwithout treatment, the median survival is 3 years. Aftera variable (and unpredictable) period, approximately50% of individuals with CML enter an accelerated phase,during which there is a gradual failure in the response totreatment; increasing anemia and new thrombocytope-nia; the appearance of additional cytogenetic abnormali-ties; and, finally, transformation into a picture resemblingacute leukemia (i.e., blast crisis). In the remaining 50%blast crisis occurs abruptly, without an intermediateaccelerated phase. Notably, in 30% of patients, the blastcrisis is of a pre–B-cell type, further attesting to the originof CML from a pluripotent stem cell. In the remaining70% of patients, the blast crisis resembles AML. Lesscommonly, CML progresses to a phase of extensive bonemarrow fibrosis resembling that seen in other myelopro-liferative disorders, most notably myeloid metaplasiawith myelofibrosis.

Treatment of CML is evolving rapidly. Most patientswere formerly treated with palliative “gentle” chemother-apy, which unfortunately did not prevent the develop-ment of blast crisis. Bone marrow transplantation was(and remains) a definitive form of therapy, being curativein 70% of patients, but it carries a high risk of death inpatients without a matched donor and in the aged. Aninhibitor of the BCR-ABL tyrosine kinase, Gleevec (iman-tinib mesylate), induces complete remission in a high frac-tion of individuals with stable-phase CML with little ofthe toxicity associated with nonspecific chemotherapeu-tic agents. When CML sufferers on imantinib mesylaterelapse, they often have new mutations in the active siteof BCR-ABL that prevent the binding of imantinib mesy-late; this proves that the drug is working by “hitting thetarget.” Further work is needed to determine whetherimantinib mesylate is curative, but it is an excellenttherapy for persons who cannot undergo bone marrowtransplantation and has stimulated great interest in thedevelopment of other targeted cancer therapies.

Polycythemia Vera

The hallmark of PCV is the excessive neoplastic pro-liferation and maturation of erythroid, granulocytic, and megakaryocytic elements, producing a panmyelosis.Although platelet and granulocyte numbers are increased,the most obvious clinical signs and symptoms are relatedto the absolute increase in red cell mass. This must be dis-tinguished from relative polycythemia, which resultsfrom hemoconcentration. Unlike reactive forms of

absolute polycythemia, PCV is associated with low levelsof erythropoietin in the serum, which is a reflection of thehypersensitivity of the neoplastic clone to erythropoietinand other growth factors. Recently it was observed thatin nearly all cases, PCV cells carry a particular mutationin JAK2, a tyrosine kinase that acts in the signaling pathways downstream of the erythropoietin receptor andother growth factor receptors. This mutation, whichresults in a valine-to-phenylalanine substitution at residue617, is sufficient to render cells expressing the erythro-poietic receptor hypersensitive to erythropoietin, sug-gesting that it is probably an important part of thepathogenesis of PCV.

Morphology

The major anatomic changes in PCV stem from theincrease in blood volume and viscosity brought aboutby the polycythemia. Plethoric congestion of all tissuesand organs is characteristic. The liver is enlarged andfrequently contains foci of extramedullary hemato-poiesis. The spleen is slightly enlarged (250–300gm) inabout 75% of patients, because of the vascular con-gestion. As a result of the increased viscosity and vascular stasis, thromboses and infarctions arecommon, particularly in the heart, spleen, and kidneys.Hemorrhages occur in about a third of these individu-als, probably as a result of excessive distention of bloodvessels and abnormal platelet function. They usuallyaffect the gastrointestinal tract, oropharynx, or brain.Although these hemorrhages may occasionally bespontaneous, they more often follow some minortrauma or surgical procedure. Platelets produced fromthe neoplastic clone are often dysfunctional. Depend-ing on their nature, the platelet defects can either exac-erbate the tendency for thrombosis or lead to abnormalbleeding. As in CML, the peripheral blood often showsincreased basophils.

The bone marrow is hypercellular due to the hyper-plasia of erythroid, myeloid, and megakaryocyticforms. In addition, some degree of marrow fibrosis ispresent in 10% of patients at the time of diagnosis. Ina subset of patients, the disease progresses to myelofi-brosis, where the marrow space is largely replaced byfibroblasts and collagen.

Clinical Course. PCV appears insidiously, usually in latemiddle age. Patients are plethoric and often somewhatcyanotic. Histamine release from the neoplastic basophilsmay contribute to pruritus, which can be intense. Exces-sive histamine release may also account for the pepticulceration seen in these individuals. Other complaints arereferable to the thrombotic and hemorrhagic tendenciesand to hypertension. Headache, dizziness, gastrointesti-nal symptoms, hematemesis, and melena are common.Because of the high rate of cell turnover, symptomaticgout is seen in 5% to 10% of cases, and many morepatients have asymptomatic hyperuricemia.

The diagnosis is usually made in the laboratory. Redcell counts range from 6 to 10 million per microliter, andthe hematocrit often approaches 60%. The other myeloidlineages are also hyperproliferative: the granulocyte

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count can be as high as 50,000 cells/mm3, and the plateletcount is often greater than 400,000 cells/mm3. Thebasophil count is also frequently elevated. The plateletsare functionally abnormal in most cases, and giant formsand megakaryocyte fragments are seen in the blood.About 30% of patients develop thrombotic complica-tions, usually affecting the brain or heart. Hepatic vein thrombosis, giving rise to the Budd-Chiari syn-drome (Chapter 16), is an uncommon but grave compli-cation. Minor hemorrhages (e.g., epistaxis and bleed-ing from gums) are common, and life-threatening hemorrhages occur in 5% to 10% of patients. In thosereceiving no treatment, death occurs from vascular complications within months after diagnosis; however, if the red cell mass is maintained at near normal levels by phlebotomies, the median survival is around 10 years.

Prolonged survival with treatment has revealed thatPCV tends to evolve to a “spent phase,” during whichthe clinical and anatomic features of primary myelofi-brosis develop. After an average interval of 10 years,15% to 20% of tumors undergo such a transformation.This transition is marked by creeping fibrosis in the bonemarrow and a shift of hematopoiesis to the spleen, whichenlarges markedly. Transformation to a “blast crisis”identical to AML also occurs but much less frequentlythan in CML. Targeted molecular therapy with JAK2inhibitors is presently under consideration.

Myeloid Metaplasia with Primary Myelofibrosis

In this chronic myeloproliferative disorder, a “spentphase” of marrow fibrosis supervenes early in the disease course, often following a brief period in which the peripheral blood white cell and platelet counts are elevated. As hematopoiesis shifts from the fibroticmarrow to the spleen, liver, and lymph nodes, extremesplenomegaly and hepatomegaly develop. Hematopoiesisin these extramedullary sites tends to be disordered andinefficient and, together with the marrow fibrosis, leadsto moderate-to-severe anemia and thrombocytopenia inmost patients.

Although marrow fibrosis is characteristic, the fibrob-lasts that lay down the collagen are not clonal descen-dants of the transformed stem cells. Instead, marrowfibrosis is secondary to derangements confined to thehematopoietic cells, particularly the megakaryocytes. It is believed that marrow fibroblasts are stimulated to proliferate by platelet-derived growth factor and transforming growth factor b released from neoplasticmegakaryocytes. These two growth factors are known tobe mitogenic for fibroblasts. By the time patients come to clinical attention, marrow fibrosis and markedextramedullary hematopoiesis are usually evident. Moreuncommonly, marrow fibrosis is less advanced at diag-nosis, and the clinical picture resembles that seen in other“hyperproliferative” myeloproliferative disorders.

It is of pathogenic and possibly therapeutic importancethat the same JAK2 mutation that is found in PCV (avaline-to-phenylalanine mutation at amino residue 617)is present in around half of the cases of primary myelofi-brosis (as well as a similar proportion of individuals withessential thrombocytosis), findings that emphasize the

Morphology

The principal site of the extramedullary hematopoiesisin myeloid metaplasia with primary myelofibrosis is thespleen, which is usually markedly enlarged, sometimesweighing as much as 4000gm. As is always true whensplenomegaly is massive, multiple subcapsular infarctsare often present. Histologically the spleen containsnormoblasts, granulocyte precursors, and megakary-ocytes, which are often prominent in terms of theirnumbers and bizarre morphology. Sometimes dispro-portional activity of any one of the three major cell linesis seen.

The liver is often moderately enlarged, with foci ofextramedullary hematopoiesis. Microscopically, thelymph nodes also contain foci of extramedullaryhematopoiesis, but these are insufficient to causeappreciable enlargement.

The bone marrow in a typical case is hypocellularand diffusely fibrotic. However, early in the course themarrow can be hypercellular, with equal representationof the three major cell lines. Both early and late in thedisease, megakaryocytes are often prominent and areusually dysplastic.

extent of the overlap between these entities. It is not yet known why tumors with the same mutation have such varied clinical pictures. Perhaps the JAK2 mutationoccurs in a different stem cell population in primarymyelofibrosis, or the unknown mutations that promoteprogression to the spent phase occur much earlier in someindividuals by chance.

Clinical Course. Primary myelofibrosis can begin with ablood picture suggestive of PCV or CML, but it morecommonly has progressed to marrow fibrosis by the timeit comes to clinical attention. Most patients have moder-ate-to-severe anemia. The white cell count can be normal,reduced, or markedly elevated. Early in the diseasecourse, the platelet count is normal or elevated, but even-tually patients develop thrombocytopenia. The peripheralblood smear appears markedly abnormal (Fig. 12–27).Red cell abnormalities include bizarre shapes (poikilo-cytes, teardrop cells). Nucleated erythroid precursors areoften found in the peripheral blood as well. Immaturewhite cells (myelocytes and metamyelocytes) are alsoseen, and basophils are sometimes increased as well. Thepresence of nucleated red cell precursors and immaturewhite cells is referred to as leukoerythrocytosis. Plateletsare often abnormal in size and shape and defective infunction. In some cases the clinical and blood pictureresembles CML, but the Ph chromosome is absent.Because of a high rate of cell turnover, hyperuricemia andgout may also complicate the picture.

The outcome of this disease is variable, but the mediansurvival time is 4 to 5 years. There is a constant threat of infections, as well as thrombotic and hemorrhagicepisodes stemming from platelet abnormalities. Splenicinfarctions are common. In 5% to 15% of individuals,there is eventually a blast crisis resembling AML.

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Figure 12–27

Myelofibrosis with myeloid metaplasia (peripheral blood smear).Two nucleated erythroid precursors and several teardrop-shapedred cells (dacryocytes) are evident. Immature myeloid cells werepresent in other fields. An identical picture can be seen in otherdiseases producing marrow distortion and fibrosis.

SUMMARY

Myeloid Neoplasms

Myeloid tumors are mainly tumors of adults thatfall into three groups.• Acute Myelogenous Leukemias (AML):

� Collection of aggressive tumors that are comprised of immature myeloid lineage cells(myeloblasts), which replace the marrow andsuppress normal hematopoiesis.

� AML cells contain diverse genetic lesions thatoften lead to the expression of abnormal transcription factors that block myeloid celldifferentiation.

• Chronic Myeloproliferative Disorders:� Indolent tumors in which production of cells is

initially increased, leading to high blood countsand extramedullary hematopoiesis

� Commonly associated with acquired geneticlesions that lead to constitutive activation oftyrosine kinases, which mimic signals fromnormal growth factors; treated with kinaseinhibitors.

� Two main types are:� Chronic Myelogenous Leukemia (CML):

myeloid tumor arising from a pluripotentstem cell; associated with chromosomerearrangements that cause the formation ofa BCR-ABL fusion gene, which encodes aconstitutively active tyrosine kinase; causesincreased hematopoiesis, particularly in thegranulocytic and thrombocytic lineages; ifuntreated, inevitably progresses to a blastcrisis phase that can resemble either AML orlymphoblastic leukemia.

� Polycythemia Vera: myeloid tumor associ-ated with point mutations that activate

JAK2, a tyrosine kinase; causes increasedhematopoiesis with high white cell, platelet,and red cell counts; the latter is responsiblefor most of the clinical symptoms.

• Myelodysplastic Syndromes: group of myeloidtumors characterized by disordered and ineffectivehematopoiesis. Most patients present with pancy-topenia, and many progress to a disease state thatis identical to AML.

� Myeloid Metaplasia with Myelofibrosis is themost common myelodysplastic syndrome. It isa myeloid tumor in which abnormal megakary-ocytes release growth factors that stimulatereactive marrow fibroblasts to deposit collagen,and the resulting fibrosis slowly replaces themarrow space, leading to pancytopenia andextramedullary hematopoiesis, which canproduce massive splenomegaly.

Histiocytic NeoplasmsLangerhans Cell Histiocytoses

The term histiocytosis is an “umbrella” designation for a variety of proliferative disorders of histiocytes, ormacrophages. Some, such as very rare histiocytic lym-phomas, are clearly malignant neoplasms. Others, suchas most histiocytic proliferations in lymph nodes, arecompletely benign and reactive. Between these twoextremes lies a group of relatively rare tumors, theLangerhans cell histiocytoses, which are derived fromLangerhans cells. You will recall that the Langerhans cellis an immature dendritic cell that is found normally inmany organs, most prominently the skin (Chapter 5).

These proliferations take on different clinical forms,but all are believed to be variations of the same basic dis-order. The proliferating Langerhans cells are humanleukocyte antigen DR (HLA-DR) positive and express theCD1 antigen. Characteristically, these cells have HXbodies (Birbeck granules) in their cytoplasm. Under theelectron microscope these are seen to have a pentalami-nar, rodlike, tubular structure, with characteristic peri-odicity and sometimes a dilated terminal end (“tennisracket” appearance). Under the light microscope the pro-liferating Langerhans cells in these disorders do notresemble their normal dendritic counterparts. Instead,they have abundant, often vacuolated, cytoplasm withvesicular nuclei. This appearance is more akin to that oftissue histiocytes (macrophages), hence the term Langer-hans cell histiocytosis.

Acute disseminated Langerhans cell histiocytosis (Letterer-Siwe disease) usually occurs in children youngerthan 2 years of age but may occasionally been seen inadults. The dominant clinical feature is the developmentof multifocal cutaneous lesions composed of Langerhanscells that grossly resemble seborrheic skin eruptions.Most of those affected have concurrent hepatosp-lenomegaly, lymphadenopathy, pulmonary lesions, and,eventually, destructive osteolytic bone lesions. Extensiveinfiltration of the marrow often leads to anemia, throm-

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bocytopenia, and predisposition to recurrent infectionssuch as otitis media and mastoiditis. Thus, the clinicalpicture may resemble that of an acute leukemia. Thecourse of untreated disease is rapidly fatal. With inten-sive chemotherapy, 50% of patients survive 5 years.

Both unifocal and multifocal Langerhans cell histio-cytosis (unifocal and multifocal eosinophilic granuloma)are characterized by expanding, erosive accumulations ofLangerhans cells, usually within the medullary cavities of bones. Histiocytes are variably admixed witheosinophils, lymphocytes, plasma cells, and neutrophils.The eosinophilic component ranges from scatteredmature cells to sheetlike masses of cells. Virtually anybone in the skeletal system may be involved; the calvar-ium, ribs, and femur are most commonly affected. Similarlesions may be found in the skin, lungs, or stomach, eitheras unifocal lesions or as components of the multifocaldisease.

Unifocal lesions usually affect the skeletal system.They may be asymptomatic or cause pain and tendernessand, in some instances, pathologic fractures. This is anindolent disorder that may heal spontaneously or becured by local excision or irradiation.

Multifocal Langerhans cell histiocytosis usually affectschildren, who present with fever; diffuse eruptions, particularly on the scalp and in the ear canals; and fre-quent bouts of otitis media, mastoiditis, and upper respiratory tract infections. The proliferation may some-times cause mild lymphadenopathy, hepatomegaly, andsplenomegaly. In about 50% of patients, involvement ofthe posterior pituitary stalk of the hypothalamus leads todiabetes insipidus. The combination of calvarial bonedefects, diabetes insipidus, and exophthalmos is referredto as the Hand-Schüller-Christian triad. Many patientsexperience spontaneous regressions; others are treatedeffectively with chemotherapy.

BLEEDING DISORDERS

These disorders are characterized clinically by abnormalbleeding, which can either be spontaneous or becomeevident after some inciting event (e.g., trauma or surgery).It should be recalled from the discussion in Chapter 4 thatthe normal hemostatic response involves the blood vesselwall, the platelets, and the clotting cascade, and abnor-malities in any of these three components can be associ-ated with clinically significant bleeding. Before embarkingon a discussion of disorders of coagulation, we should firstreview normal hemostasis and the common laboratorytests used in the evaluation of a bleeding diathesis. Thevarious tests used in the initial evaluation of patients withbleeding disorders are as follows:

• Bleeding time. This represents the time taken for astandardized skin puncture to stop bleeding. Measuredin minutes, this procedure provides an in vivo assess-ment of platelet response to limited vascular injury. Thereference range depends on the actual method used andvaries from 2 to 9 minutes. It is abnormal when thereis a defect in platelet numbers or function. Bleedingtime is fraught with variability and poor reproducibil-ity. Hence, new instrument-based assays that providequantitative measures of platelet function are beingintroduced.• Platelet counts. These are obtained on anticoagu-lated blood by using an electronic particle counter. The reference range is 150×103 to 450×103 cells/mm3.Counts outside this range must be confirmed by avisual inspection of a peripheral blood smear.• Prothrombin time (PT). This procedure tests the ade-quacy of the extrinsic and common coagulation path-ways. It represents the time needed for plasma to clotin the presence of an exogenously added source of tissue thromboplastin (e.g., brain extract) and Ca2+

ions. A prolonged PT can result from a deficiency offactors V, VII, or X, prothrombin, or fibrinogen.• Partial thromboplastin time (PTT). This test isdesigned to assess the integrity of the intrinsic andcommon clotting pathways. In this test the time neededfor the plasma to clot in the presence of kaolin,cephalin, and calcium is measured. Kaolin serves toactivate the contact-dependent factor XII, and cephalinsubstitutes for platelet phospholipids. Prolongation ofPTT can be caused by a deficiency of factors V, VIII,IX, X, XI, or XII or prothrombin or fibrinogen or anacquired inhibitor (typically an antibody) that inter-feres with the intrinsic pathway.

Additional, more specialized tests are available thatmeasure the levels of specific clotting factors, fibrinogen,and fibrin split products; assess the presence of circulat-ing anticoagulants; and evaluate platelet function. Withthis overview we can return to the three important cate-gories of bleeding disorders.

Abnormalities of vessels can contribute to bleeding inseveral ways. Increased fragility of the vessels is associ-ated with severe vitamin C deficiency (scurvy) (Chapter8), systemic amyloidosis (Chapter 5), chronic glucocorti-coid use, rare inherited conditions affecting the connectivetissues, and a large number of infectious and hypersensi-tivity vasculitides. The latter include meningococcemia,infective endocarditis, the rickettsial diseases, typhoid,and Henoch-Schönlein purpura. Some of these conditionsare discussed in other chapters; others are beyond thescope of this book. A hemorrhagic diathesis that is purelythe result of vascular fragility is characterized by theapparently spontaneous appearance of petechiae andecchymoses in the skin and mucous membranes (proba-bly resulting from minor trauma). In most instances, the

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laboratory tests of coagulation are normal. Bleeding canalso be triggered by systemic conditions that activate ordamage endothelial cells. If severe enough, such insultsconvert the vascular lining to a prothrombotic surfacethat activates coagulation throughout the circulatorysystem. Paradoxically, in such consumptive coagu-lopathies platelets and coagulation factors are used upfaster than they can be replaced, and the resulting defi-ciencies (which are readily identified in laboratory tests ofcoagulation) often lead to severe bleeding.

Deficiencies of platelets (thrombocytopenia) areimportant causes of hemorrhage. They can occur in avariety of clinical settings that are discussed later. Otherdisorders are characterized by qualitative defects inplatelet function. These include defects that are acquired,as in uremia, after aspirin ingestion, and in certain myelo-proliferative disorders, or inherited, as in von Willebranddisease and other rare congenital disorders. The clinicalsigns of inadequate platelet function include easy bruis-ing, nosebleeds, excessive bleeding from minor trauma,and menorrhagia. The PT and PTT are normal, but thebleeding time is prolonged.

Bleeding diatheses based purely on a derangement ofblood clotting differ in several respects from those result-ing from defects in the vessel walls or in platelets. ThePT, PTT, or both, are prolonged, whereas the bleedingtime is normal. Petechiae and other evidence of bleedingfrom very minor surface trauma are usually absent.However, massive hemorrhage can occur subsequent tooperative or dental procedures or severe trauma. More-over, hemorrhages into areas of the body subject totrauma, such as the joints of the lower extremities, arecharacteristic. This category includes the hemophilias, animportant group of inherited coagulation disorders.

Disseminated intravascular coagulation, one of themost common consumptive coagulopathies, presentswith laboratory and clinical features related to boththrombocytopenia and coagulation factor deficiencies.Von Willebrand disease is a fairly common inherited disorder in which both platelet and (to a lesser degree)coagulation factor function are abnormal. With this as an overview, we will now turn to specific bleeding disorders.

DISSEMINATED INTRAVASCULARCOAGULATION

An acute, subacute, or chronic thrombohemorrhagic disorder, disseminated intravascular coagulation (DIC)occurs as a secondary complication in a variety of diseases. It is caused by the systemic activation of thecoagulation pathways, leading to the formation ofthrombi throughout the microcirculation. As a conse-quence of the widespread thromboses, there is consump-tion of platelets and coagulation factors and, secondarily,activation of fibrinolysis. Thus, DIC can give rise to eithertissue hypoxia and microinfarcts caused by myriadmicrothrombi or to a bleeding disorder related to patho-logic activation of fibrinolysis and the depletion of theelements required for hemostasis (hence the term con-sumptive coagulopathy). This entity is probably a more

common cause of bleeding than all of the congenitalcoagulation disorders combined.

Etiology and Pathogenesis. Before presenting the specificdisorders associated with DIC, we will discuss in ageneral way the pathogenetic mechanisms by whichintravascular clotting can occur. Reference to earlier com-ments on normal blood coagulation (Chapter 4) may behelpful at this point. It suffices here to recall that clottingcan be initiated by either of two pathways: the extrinsicpathway, which is triggered by the release of tissue factor(tissue thromboplastin), or the intrinsic pathway, whichinvolves the activation of factor XII by surface contact,collagen, or other negatively charged substances. Bothpathways lead to the generation of thrombin. Clot-inhibiting influences include the rapid clearance of acti-vated clotting factors by the mononuclear phagocyticsystem or by the liver, activation of endogenous antico-agulants (e.g., protein C), and activation of fibrinolysis.

Two major mechanisms can trigger DIC: (1) the releaseof tissue factor or thromboplastic substances into the circulation, and (2) widespread endothelial cell damage(Fig. 12–28). Thromboplastic substances can be releasedinto the circulation from a variety of sources—forexample, the placenta in obstetric complications, thecytoplasmic granules of acute promyelocytic leukemiacells, or mucin-secreting adenocarcinoma cells. Carcino-mas can also release other procoagulant substances, suchas proteolytic enzymes, and other still-undefined tumorproducts. Some tumors express tissue factor on the cellmembrane. In gram-negative and gram-positive sepsis(important causes of DIC), endotoxins or exotoxins causeincreased synthesis, surface expression, and release oftissue factor from monocytes. Furthermore, activatedmonocytes release IL-1 and tumor necrosis factor, bothof which increase the expression of tissue factor onendothelial cells and simultaneously decrease the expres-sion of thrombomodulin. The latter, you may recall, acti-vates protein C, an anticoagulant (Chapter 4). The netresult is the enhanced activation of the extrinsic clottingsystem and the blunting of inhibitory pathways that tendto prevent coagulation.

Severe endothelial cell injury can initiate DIC bycausing the release of tissue factor and by exposingsubendothelial collagen and von Willebrand factor(vWF), which act together to promote platelet aggrega-tion and the activation of the intrinsic coagulationcascade. Even subtle endothelial damage can unleash pro-coagulant activity by stimulating the increased expressionof tissue factor on endothelial cell surfaces. Widespreadendothelial injury can be produced by the deposition ofantigen-antibody complexes (e.g., in SLE), by tempera-ture extremes (e.g., following heat stroke or burns), or byinfections (e.g., meningococci and rickettsiae). As dis-cussed in Chapter 4, endothelial injury is an importantconsequence of endotoxemia, and, not surprisingly, DICis a frequent complication of gram-negative sepsis.

Several additional disorders associated with DIC arelisted in Table 12–12. Of these, DIC is most likely tooccur after sepsis, obstetric complications, malignancy,and major trauma (especially trauma to the brain). Theinitiating events in these conditions are multiple and often

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interrelated. For example, in obstetric conditions, tissuefactor derived from the placenta, retained dead fetus, oramniotic fluid enters the circulation; however, shock,hypoxia, and acidosis often coexist and can lead to wide-spread endothelial injury. Trauma to the brain releases fat

and phospholipids, which can act as contact factors andthereby activate the intrinsic arm of the coagulationcascade.

Whatever the pathogenetic mechanism, DIC has twoconsequences. First, there is widespread fibrin depositionwithin the microcirculation. This leads to ischemia in themore severely affected or vulnerable organs and tohemolysis as red cells are traumatized while passingthrough vessels narrowed by fibrin thrombi (microangio-pathic hemolytic anemia). Second, a bleeding diathesisresults from the depletion of platelets and clotting factors and the secondary release of plasminogen activators. Plasmin cleaves not only fibrin (fibrinolysis)but also factors V and VIII, thereby reducing their con-centration further. In addition, fibrinolysis creates fibrindegradation products, which inhibit platelet aggregation,have antithrombin activity, and impair fibrin polymer-ization, all of which contribute to the hemostatic failure(see Fig. 12–28).

Table 12–12 Major Disorders Associated with Disseminated Intravascular Coagulation

Obstetric Complications

Abruptio placentaeRetained dead fetusSeptic abortionAmniotic fluid embolismToxemia

Infections

Sepsis (gram-negative and gram-positive)MeningococcemiaRocky Mountain spotted feverHistoplasmosisAspergillosisMalaria

Neoplasms

Carcinomas of pancreas, prostate, lung, and stomachAcute promyelocytic leukemia

Massive Tissue Injury

TraumaBurnsExtensive surgery

Miscellaneous

Acute intravascular hemolysis, snakebite, giant hemangioma,shock, heat stroke, vasculitis, aortic aneurysm, liver disease

Morphology

In DIC microthrombi are found principally in the arteri-oles and capillaries of the kidneys, adrenals, brain, andheart, but no organ is spared, and the lungs, liver, andgastrointestinal mucosa can be prominently involved.The glomeruli contain small fibrin thrombi. These maybe associated with only a subtle, reactive swelling ofthe endothelial cells, or varying degrees of focalglomerulitis. The microvascular occlusions lead tosmall infarcts in the renal cortex. In severe cases, theischemia can destroy the entire cortex and cause bilat-eral renal cortical necrosis. Involvement of the adrenalglands can produce the Waterhouse-Friderichsen

Massive tissuedestruction Sepsis

Endothelialinjury

Plateletaggregation

Consumption ofclotting factorsand platelets

Release of tissue factor

Widespreadmicrovascular

thrombosis

Activation ofplasmin

Microangiopathichemolytic anemia

Vascularocclusion

Ischemic tissuedamage

BLEEDING

Proteolysis ofclotting factors

Fibrinolysis

Fibrin splitproducts

Inhibition of thrombin, plateletaggregation, and fibrin polymerization

Figure 12–28

Pathophysiology of disseminated intravascular coagulation.

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Clinical Course. As might be imagined, depending on thebalance between clotting and bleeding tendencies, therange of possible clinical manifestations is enormous. Ingeneral, acute DIC (e.g., that associated with obstetriccomplications) is dominated by a bleeding diathesis,whereas chronic DIC (e.g., as occurs in an individualwith cancer) tends to present with symptoms related to thrombosis. Typically, the abnormal clotting occursonly in the microcirculation, although large vessels are involved occasionally. The manifestations may beminimal, or there may be shock, with acute renal failure,dyspnea, cyanosis, convulsions, and coma. Most often,attention is called to the presence of DIC by prolongedand copious postpartum bleeding or by the presence ofpetechiae and ecchymoses on the skin. These may be theonly manifestations, or there may be severe hemorrhageinto the gut or urinary tract. Laboratory evaluationreveals thrombocytopenia and prolongation of PT andPTT (resulting from depletion of platelets, clottingfactors, and fibrinogen). Fibrin split products areincreased in the plasma.

The prognosis for patients with DIC is highly variable,and depends on the nature of the underlying disorder andthe severity of the intravascular clotting and fibrinolysis.In some acute cases it can be life-threatening and must betreated aggressively with anticoagulants such as heparinor the coagulants contained in fresh-frozen plasma. Con-versely, in more chronic forms DIC is sometimes identi-fied as a laboratory abnormality. In either circumstance,definitive treatment must be directed at the cause of theDIC, not at its hemostatic consequences.

THROMBOCYTOPENIA

Thrombocytopenia is characterized by spontaneousbleeding, a prolonged bleeding time, and a normal PTand PTT. A platelet count of 100,000 cells/μL or less isgenerally considered to constitute thrombocytopenia.Platelet counts in the range of 20,000 to 50,000 cells/μLare associated with an increased risk of post-traumaticbleeding, and spontaneous bleeding becomes evident

when counts fall below 20,000 cells/μL. Most bleedingtends to occur from small, superficial blood vessels andproduces petechiae or large ecchymoses in the skin, themucous membranes of the gastrointestinal and urinarytracts, and other sites. Larger hemorrhages into thecentral nervous system are a major hazard in patientswith markedly depressed platelet counts.

The major causes of thrombocytopenia are listed inTable 12–13. Clinically important thrombocytopenias areconfined to those disorders in which there is reduced pro-duction or increased destruction of platelets. In mostcases in which the cause is accelerated destruction, thebone marrow reveals a compensatory increase in thenumber of megakaryocytes. Hence, bone marrow exam-ination can help to distinguish the two major categoriesof thrombocytopenia. It is also worth emphasizing thatthrombocytopenia is one of the most common hemato-logic manifestations of AIDS. It can occur early in thecourse of HIV infection and has multifactorial bases,including immune complex–mediated platelet destruc-tion, antiplatelet autoantibodies, and HIV-mediated sup-pression of megakaryocyte development and survival.

Immune Thrombocytopenic PurpuraImmune thrombocytopenic purpura (ITP), also calledidiopathic thrombocytopenic purpura, can occur in thesetting of a variety of conditions and exposures (sec-ondary ITP) or in the absence of any known risk factors(primary or idiopathic ITP). There are two clinical sub-

syndrome (Chapter 20). Microinfarcts are also com-monly encountered in the brain, surrounded by micro-scopic or gross foci of hemorrhage. These can give riseto bizarre neurologic signs. Similar changes are seen inthe heart and often in the anterior pituitary. It has beensuggested that DIC contributes to Sheehan postpartumpituitary necrosis (Chapter 20).

When the underlying disorder is toxemia of preg-nancy, the placenta is the site of capillary thrombosesand, occasionally, florid degeneration of the vesselwalls. Such changes are in all likelihood responsible forthe premature loss of cytotrophoblasts and syncy-tiotrophoblasts that characterizes this condition.

The bleeding tendency associated with DIC is mani-fested not only by larger than expected hemorrhagesnear foci of infarction but also by diffuse petechiae andecchymoses, which can be found on the skin, serosallinings of the body cavities, epicardium, endocardium,lungs, and mucosal lining of the urinary tract.

Table 12–13 Causes of Thrombocytopenia

Decreased Production of Platelets

Generalized disease of bone marrowAplastic anemia: congenital and acquiredMarrow infiltration: leukemia, disseminated cancer

Selective impairment of platelet productionDrug-induced: alcohol, thiazides, cytotoxic drugsInfections: measles, HIV infection

Ineffective megakaryopoiesisMegaloblastic anemiaParoxysmal nocturnal hemoglobinuria

Decreased Platelet Survival

Immunologic destructionAutoimmune: immune thrombocytopenic purpura, systemic

lupus erythematosusIsoimmune: post-transfusion and neonatalDrug-associated: quinidine, heparin, sulfa compoundsInfections: infectious mononucleosis, HIV infection,

cytomegalovirus infection

Nonimmunologic destructionDisseminated intravascular coagulationThrombotic thrombocytopenic purpuraGiant hemangiomasMicroangiopathic hemolytic anemias

Sequestration

Hypersplenism

Dilutional

HIV, human immunodeficiency virus.

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types of primary ITP: chronic primary ITP, a relativelycommon disorder that tends to affect adult femalesbetween the ages of 20 and 40 years; and acute ITP, aself-limited form that is most commonly seen in childrensubsequent to viral infections.

Antiplatelet immunoglobulins directed against plateletmembrane glycoproteins IIb/IIIa or Ib/IX complexes canbe identified in 80% of patients with chronic ITP. Thespleen is an important site of antiplatelet antibody pro-duction and the major site of destruction of the IgG-coated platelets. It is usually normal in size and showsonly subtle evidence of increased platelet destruction;thus, splenic enlargement or lymphadenopathy shouldlead one to consider other possible diagnoses. Nonethe-less, the importance of the spleen in this disorder is confirmed by the clinical benefits produced by splenec-tomy, which normalizes the platelet count and induces acomplete remission in more than two-thirds of patients.The bone marrow usually contains increased numbers of megakaryocytes, a finding that is common to all formsof thrombocytopenia that are caused by acceleratedplatelet destruction. A marrow examination can behelpful in excluding marrow failure as a cause of thethrombocytopenia.

The onset of chronic ITP is insidious. Common find-ings include petechiae, easy bruisability, epistaxis, gumbleeding, and hemorrhages after minor trauma. Fortu-nately, more serious intracerebral or subarachnoid hem-orrhages occur much less commonly. The diagnosis restson the clinical features, the presence of thrombocytope-nia, examination of the marrow, and the exclusion of sec-ondary ITP. Reliable clinical tests for antiplateletantibodies are not widely available.

Heparin-Induced ThrombocytopeniaThis special type of drug-induced thrombocytopeniamerits brief mention because of its clinical importance.Moderate to severe thrombocytopenia develops in 3% to5% of individuals treated with unfractionated heparinafter 1 to 2 weeks of therapy. The disorder is caused byIgG antibodies that bind to platelet factor IV on plateletsurfaces in a heparin-dependent fashion. This activatesplatelets and induces their aggregation, thus exacerbatingthe condition that heparin is used to treat—thrombosis.Both venous and arterial thromboses occur, even in the setting of marked thrombocytopenia, and can cause severe morbidity (e.g., loss of limbs because of vascular insufficiency) and death. Cessation of heparintherapy breaks the cycle of platelet activation and consumption.

Thrombotic Microangiopathies:Thrombotic Thrombocytopenic Purpuraand Hemolytic-Uremic SyndromeThe term thrombotic microangiopathies encompasses aspectrum of clinical syndromes that include thromboticthrombocytopenic purpura (TTP) and hemolytic-uremicsyndrome (HUS). As originally defined, TTP is associatedwith the pentad of fever, thrombocytopenia, microangio-pathic hemolytic anemia, transient neurologic deficits,and renal failure. HUS is also associated with microan-giopathic hemolytic anemia and thrombocytopenia but is

distinguished from TTP by the absence of neurologicsymptoms, the dominance of acute renal failure, and anonset in childhood (Chapter 14). Clinical experience hasblurred these distinctions, because many adults with TTPlack one or more of the five criteria, and some patientswith HUS have fever and neurologic dysfunction. Fun-damental to both of these conditions is the widespreadformation of hyaline thrombi in the microcirculation thatare composed primarily of dense aggregates of plateletssurrounded by fibrin. The consumption of platelets leadsto thrombocytopenia, and the narrowing of blood vesselsby the platelet-rich thrombi results in a microangiopathichemolytic anemia.

For many years the pathogenesis of TTP was enig-matic, although treatment with plasma exchange (initi-ated in the early 1970s) converted it from a disease thatwas almost uniformly fatal to one that is successfullytreated in more than 80% of individuals. Recently, theunderlying cause of most cases of TTP has been eluci-dated. In brief, symptomatic patients are deficient in ametalloprotease called ADAMTS13. This enzymedegrades very-high-molecular-weight multimer of vWF,and hence the absence of ADAMTS13 activity allowsmultimers of vWF to accumulate in plasma. Under somecircumstances, these colossal vWF multimers promoteplatelet microaggregate formation throughout the circu-lation. The superimposition of an endothelial cell injury(caused by some other condition) can further promotemicroaggregate formation, thus initiating or exacerbatingclinically evident TTP.

The deficiency of ADAMTS13 activity can be an inher-ited condition, but it is more commonly caused by anacquired autoantibody that binds and inhibits the metal-loprotease. TTP must be considered in any individualwho presents with unexplained thrombocytopenia andmicroangiopathic hemolytic anemia, because the failureto make an early diagnosis can be fatal.

Although clinically similar to TTP, HUS has a differ-ent basis, because ADAMTS13 levels are normal in thisdisorder. HUS in children and the elderly usually occurssubsequent to infectious gastroenteritis caused by E. colistrain O157:H7. This organism elaborates a Shiga-like toxin that damages endothelial cells, which initiatesplatelet activation and aggregation. Affected individualsoften present with bloody diarrhea, which is followed afew days later by HUS. With supportive care and plasmaexchange, recovery is possible, but irreversible renaldamage and death can occur in more severe cases. About10% of cases in children are not preceded by infectionwith Shiga toxin-producing bacteria. Some of thesepatients have mutations in the gene encoding complementregulatory proteins, notably factor H. Deficiency of thisprotein leads to uncontrolled complement activation afterminor endothelial injury, resulting in thrombosis. HUScan also be seen after exposures to other factors (e.g.,certain drugs, radiation therapy) that damage endothe-lial cells. Here the prognosis is more guarded, in partbecause the underlying conditions are often chronic orlife-threatening.

Although DIC and the thrombotic microangiopathiesshare features such as microvascular occlusion andmicroangiopathic hemolytic anemia, they are patho-genetically distinct. In TTP and HUS, unlike in DIC,

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activation of the coagulation cascade is not of primaryimportance, and thus the laboratory tests of coagulation(such as the PT and the PTT) are usually normal.

COAGULATION DISORDERS

These disorders result from either congenital or acquireddeficiencies of clotting factors. Most common are theacquired coagulation factor deficiencies, which typicallyaffect many factors simultaneously. As was discussed inChapter 8, vitamin K is essential for the synthesis of pro-thrombin and clotting factors VII, IX, and X, and its defi-ciency causes a severe coagulation defect. The liver is thesite of both the synthesis of several coagulation factorsand the removal of many activated coagulation factors;thus, parenchymal diseases of the liver are commoncauses of complex hemorrhagic diatheses.

Hereditary deficiencies have been identified for each of the coagulation factors. These deficiencies charac-teristically occur singly. Hemophilia A, resulting fromdeficiency of factor VIII, and hemophilia B (Christmasdisease), resulting from deficiency of factor IX, are trans-mitted as X-linked recessive disorders, whereas mostothers are autosomal disorders. These inherited deficien-cies are rare; only von Willebrand disease, hemophilia A,and hemophilia B are sufficiently common to warrantfurther consideration here.

Deficiencies of Factor VIII–vWF ComplexHemophilia A and von Willebrand disease, two of themost common inherited disorders of bleeding, are causedby qualitative or quantitative defects involving the factorVIII–vWF complex. Before we can discuss these disor-ders, it is useful to review the structure and function ofthese proteins.

Plasma factor VIII–vWF complex is made up of twoproteins (Fig. 12–29). One, which is required for the acti-vation of factor X in the intrinsic coagulation pathway,is called factor VIII procoagulant protein, or factor VIII.Deficiency of factor VIII gives rise to hemophilia A.Factor VIII is associated noncovalently with a muchlarger protein, vWF, that forms high-molecular-weightmultimers of sizes that range as high as 20 megadaltons.vWF is found normally in the plasma (in association withfactor VIII), in platelet granules, in endothelial cells inunusual cytoplasmic vesicles called Weibel-Palade bodies,and in the subendothelium, where it binds to collagen.

When endothelial cells are stripped away by trauma orinjury, subendothelial vWF becomes exposed and bindsto platelets through the receptors glycoproteins Ib andIIb/IIIa (see Fig. 12–29). The most important function ofvWF is to facilitate the adhesion of platelets to damagedblood vessel walls, which is a crucial early event in theformation of a hemostatic plug. It is this activity that isbelieved to be deficient in von Willebrand disease. Inaddition to its function in platelet adhesion, vWF alsoserves as a carrier for factor VIII.

The various forms of von Willebrand disease can becharacterized by immunologic techniques and the so-called ristocetin agglutination test. Ristocetin (developedas an antibiotic) binds platelets and promotes the inter-action between vWF and platelet membrane glycoproteinIb. The binding of vWF creates interplatelet “bridges”that lead to the formation of platelet clumps (aggluti-nation), an event that can be measured easily. Thus, ristocetin-dependent platelet agglutination serves as auseful bioassay for vWF.

The two components of the factor VIII–vWF complexare encoded by separate genes and are synthesized by dif-ferent cells. vWF is produced by both megakaryocytesand endothelial cells. The latter are the major source of

Factor VIII

Clottingcascade

Activated, aggregatedplatelets

X Xa

Endothelium

vWF

GpIb

GpIIb/IIIa

Fibrinogen

Collagen

Circulating vWFwith Factor VIII

Subendothelial vWF

Platelet

Endothelial defect

Platelet

Figure 12–29

Structure and function of factor VIII–von Willebrand factor (vWF) complex. Factor VIII and vWF are synthesized in the liver and in endothe-lial cells, respectively. The two circulate as a complex in the circulation. vWF is also present in the subendothelial matrix of normal bloodvessels. Factor VIII takes part in the coagulation cascade by activating factor X. vWF causes adhesion of platelets to subendothelial col-lagen, primarily through the glycoprotein Ib (GpIb) platelet receptor. Ristocetin activates GpIb receptors in vitro and causes platelet aggre-gation if vWF is present.

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plasma vWF, whereas most factor VIII is synthesized in the liver. To summarize, the two components of factor VIII–vWF complex, synthesized separately, cometogether and circulate in the plasma as a unit that servesto promote clotting as well as the platelet-vessel wallinteractions necessary to ensure hemostasis.

With this background we can turn to the discussion ofdiseases resulting from deficiencies of factor VIII–vWFcomplex.

von Willebrand Disease

von Willebrand disease is marked by spontaneous bleed-ing from mucous membranes, excessive bleeding fromwounds, menorrhagia, and a prolonged bleeding time inthe presence of a normal platelet count. In most cases itis transmitted as an autosomal dominant disorder. Itsprecise incidence is difficult to estimate, because in manyinstances the clinical manifestations are mild and thediagnosis requires sophisticated tests; it may well be themost common inherited bleeding disorder.

Individuals with von Willebrand disease have a com-pound defect involving platelet function and the coagu-lation pathway. The amounts of factor VIII are onlymoderately depressed, and it is the defect in platelet func-tion that dominates the clinical picture. Except for rarehomozygous patients with type III von Willebranddisease, the effects of factor VIII deficiency that charac-terize hemophilia are not seen.

The classic and most common variant of von Wille-brand disease (type I) is an autosomal dominant disordercharacterized by a reduced quantity of circulating vWF.Because vWF stabilizes factor VIII by binding to it, itsdeficiency causes a secondary decrease in factor VIIIlevels, but not to levels that are clinically significant. Theother, less common, varieties of von Willebrand diseasetend to show both qualitative and quantitative defects invWF. Type II is divided into several subtypes that are allcharacterized by a selective loss of high-molecular-weightmultimers of vWF. Because these multimers are the mostactive form, there is a functional deficiency of vWF. Intype IIA, the high-molecular-weight multimers are notsynthesized, leading to a true deficiency. In type IIB, func-tionally abnormal high-molecular-weight multimers aresynthesized that are rapidly removed from the circula-tion. These high-molecular-weight multimers cause spon-taneous platelet aggregation (a situation reminiscent of the very-high-molecular-weight multimer aggregatesthat are seen in TTP), and indeed some individuals with type IIB von Willebrand disease have chronic mild thrombocytopenia that is presumably caused byplatelet consumption.

Factor VIII Deficiency (Hemophilia A,Classic Hemophilia)

Hemophilia A is the most common hereditary diseaseassociated with serious bleeding. It is an X-linked reces-sive disorder that is caused by reduction in factor VIII

activity. It primarily affects males, but much less com-monly excessive bleeding also occurs in heterozygousfemales, presumably as a result of extremely unfavorablelyonization (inactivation of the normal X chromosome inmost of the cells). Approximately 30% of cases arecaused by new mutations; in the remainder, there is a pos-itive family history. Severe hemophilia A is observed inindividuals with a marked degree of factor VIII deficiency(activity levels of <1% of normal). Milder deficienciesmay only become apparent when a major hemodynamicstress supervenes, such as trauma. The varying degrees offactor VIII deficiency are for the most part explained bythe existence of many different causative mutations. Asin the thalassemias, several types of genetic lesions (e.g.,deletions, splice junction mutations, nonsense mutations)have been identified. In about 10% of patients, the factorVIII concentration is normal by immunoassay, but thecoagulant activity detected by bioassay is low because ofa mutation that causes the synthesis of functionallyabnormal protein.

In all symptomatic cases there is a tendency towardeasy bruising and massive hemorrhage after trauma oroperative procedures. In addition, “spontaneous” hem-orrhages are frequently encountered in regions of thebody that are normally subject to trauma, particularly the joints, where recurrent bleeds into the joints(hemarthroses) lead to progressive deformities that canbe crippling. Petechiae are characteristically absent. Typ-ically, patients with hemophilia A have a prolonged PTTthat is corrected by mixing the patient’s plasma withnormal plasma. In approximately 15% of the mostseverely affected patients, replacement therapy is compli-cated by the development of neutralizing antibodiesagainst factor VIII, perhaps because factor VIII is seen asforeign in severely deficient individuals. In these personsthe PTT fails to correct in mixing studies. Specific factorVIII assays are required to confirm the diagnosis onhemophilia A.

Treatment involves infusion of factor VIII. Histori-cally, factor VIII was prepared from human plasma, car-rying with it the risk of transmission of viral diseases. Aswas mentioned in Chapter 5, before 1985 thousands ofhemophiliacs received factor VIII preparations contami-nated with HIV. Subsequently, many became seropositiveand developed AIDS. The availability and widespread useof recombinant factor VIII and more highly purifiedfactor VIII concentrates has now eliminated the infectiousrisk of factor VIII replacement therapy.

Factor IX Deficiency (Hemophilia B,Christmas Disease)

Severe factor IX deficiency is an X-linked disorder that isindistinguishable clinically from hemophilia A but ismuch less common. The PTT is prolonged, and the bleed-ing time is normal. The diagnosis of Christmas disease(named after the first patient with this condition) is madewith specific assays of factor IX. It is treated by infusionof recombinant factor IX.

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SPLENOMEGALY

The spleen is frequently secondarily involved in a widevariety of systemic diseases. In virtually all instances, the response of the spleen causes its enlargement(splenomegaly), which produces a set of stereotypicalsigns and symptoms. Evaluation of splenomegaly is acommon clinical problem that is aided considerably byknowledge of the usual limits of the splenic enlargementthat is seen in the context of specific disorders. It wouldbe erroneous to attribute enlargement of the spleen intothe pelvis to vitamin B12 deficiency, or to entertain a diag-nosis of CML in the absence of significant splenomegaly.As an aid to diagnosis, then, we present the following list of disorders, classified according to the degree ofsplenomegaly that is characteristically produced:

A. Massive splenomegaly (weight more than 1000gm)1. Chronic myeloproliferative disorders (chronic

myeloid leukemia, myeloid metaplasia withmyelofibrosis)

2. Chronic lymphocytic leukemia3. Hairy cell leukemia

SUMMARY

Bleeding Disorders

• Disseminated Intravascular Coagulation:� Syndrome in which systemic activation of the

coagulation cascade by various stimuli, includ-ing sepsis, massive tissue injury, and release ofprocoagulant factors from tumor cells, leads to consumption of coagulation factors andplatelets.

� The clinical picture can be dominated by bleed-ing, vascular occlusion and tissue hypoxemia,or both. Common stimuli include sepsis, majortrauma, certain cancers, and obstetric compli-cations.

• Immune Thrombocytopenia Purpura (ITP): iscaused by autoantibodies against platelet antigens;may be triggered by drugs, infections, or lym-phomas, or be idiopathic.• Thrombotic Thromobocytopenia Purpura (TTP):

� Caused most commonly by acquired or inher-ited deficiencies of ADAMTS13, a plasma metalloprotease that normally prevents theaccumulation of very high molecular weightmultimers of von Willebrand factor (vWF).Deficiency of ADAMTS13 results in abnor-mally large vWF multimers, which lead to theformation of platelet-rich thrombi, particularlyin the kidney and the central nervous system.

� Manifested as thrombocytopenia and micro-angiopathic hemolytic anemia.

� Hemolytic Uremic Syndrome resembles TTPclinically, but is caused by deficiencies of com-plement regulatory protein factor H, or agentsthat damage endothelial cells, such as a Shiga-like toxin elaborated by E. coli strain O157:H7. The endothelial injury initiates plateletactivation, platelet aggregation, and microvas-culature thrombosis.

• von Willebrand Disease:� Autosomal dominant disorder caused by muta-

tions in vWF, which normally functions as abridging molecule between platelets and suben-dothelial collagen.

� Typically causes a mild to moderate bleedingdisorder that mimics that caused by thrombo-cytopenia.

• Hemophilia A is an X-linked disorder caused bymutations in coagulation factor VIII. Affected malestypically present with severe bleeding into softtissues and joints, and have a prolonged partialthromboplastin time (PTT).• Hemophilia B is an X-linked disorder caused bymutations in coagulation factor IX; clinically, it isidentical to hemophilia A.

DISORDERS THAT AFFECT THE SPLEEN AND THYMUS

4. Lymphomas5. Malaria6. Gaucher disease7. Primary tumors of the spleen (rare)

B. Moderate splenomegaly (weight 500–1000gm)1. Chronic congestive splenomegaly (portal hyper-

tension or splenic vein obstruction)2. Acute leukemias (inconstant)3. Hereditary spherocytosis4. Thalassemia major5. Autoimmune hemolytic anemia6. Amyloidosis7. Niemann-Pick disease8. Langerhans histiocytosis9. Chronic splenitis (especially with infective endo-

carditis)10. Tuberculosis, sarcoidosis, typhoid11. Metastatic carcinoma or sarcoma

C. Mild splenomegaly (weight <500gm)1. Acute splenitis2. Acute splenic congestion3. Infectious mononucleosis

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4. Miscellaneous acute febrile disorders, includingsepticemia, SLE, and intra-abdominal infections

The microscopic changes associated with these dis-eases need not be described here, because they have beendiscussed in the relevant sections of this and other chapters.

An enlarged spleen often removes excessive numbersof one or more of the formed elements of blood, result-ing in anemia, leukopenia, or thrombocytopenia. This isreferred to as hypersplenism, a state that can be associ-ated with many of the diseases affecting the spleen listedpreviously. In addition, platelets are particularly suscep-tible to sequestration in the interstices of the red pulp; asa result, thrombocytopenia is more prevalent and severe in individuals with splenomegaly than are anemia or neutropenia.

DISORDERS OF THE THYMUS

As is well known, the thymus is a central lymphoid organthat has a crucial role in T-cell differentiation. It is notsurprising, therefore, that the thymus can be involved bylymphomas, particularly those of T-cell lineage, whichwere discussed earlier in this chapter. Here we will focuson the two most frequent (albeit uncommon) disordersof the thymus: thymic hyperplasia and thymoma.

Thymic HyperplasiaHyperplasia of the thymus is often associated with theappearance of lymphoid follicles, or germinal centers,within the medulla. These germinal centers contain reac-tive B cells, which are normally present in only lownumbers in the thymus. Thymic follicular hyperplasia ispresent in most patients with myasthenia gravis and issometimes also found in other autoimmune diseases, such as SLE and rheumatoid arthritis. The relationshipbetween the thymus and myasthenia gravis is discussedin Chapter 21. Significantly, removal of the hyperplasticthymus is often beneficial early in the disease.

ThymomaThe term thymoma is restricted to tumors in whichepithelial cells constitute the neoplastic element. Scant orabundant precursor T cells (thymocytes) are present inthese tumors, but these are non-neoplastic. Several clas-sification systems for thymoma have been proposed onthe basis of cytologic and biologic criteria. One simpleand clinically useful classification is as follows:

• Benign or encapsulated thymoma: cytologically andbiologically benign• Malignant thymoma

Type I: cytologically benign but biologicallyaggressive and capable of local invasionand, rarely, distant spread

Type II, also called thymic carcinoma: cyto-logically malignant with all of the featuresof cancer and comparable behavior

Clinical Features. All thymomas are rarities, the malig-nant more so than the benign. They may arise at any agebut typically occur in middle adult life. In a large series,about 30% were asymptomatic; 30% to 40% producedlocal manifestations such as a mass demonstrable oncomputed tomography in the anterosuperior medi-astinum associated with cough, dyspnea, and superiorvena caval syndrome; and the remainder were associatedwith some systemic disease, principally myastheniagravis. Fifteen to 20% of patients with this disorder havea thymoma. Removal of the tumor often leads toimprovement in the neuromuscular disorder. Additionalassociations with thymomas include hypogammaglobu-linemia, SLE, pure red cell aplasia, and nonthymiccancers.

Morphology

Macroscopically, thymomas are lobulated, firm, gray-white masses up to 15 to 20cm in longest dimension.Most appear encapsulated, but in 20% to 25% there isapparent penetration of the capsule and infiltration ofperithymic tissues and structures.

Microscopically, virtually all thymomas are made upof a mixture of epithelial cells and a variable infiltrateof non-neoplastic thymocytes. The relative proportionsof the epithelial and lymphocytic components are oflittle significance. In benign thymomas the epithelialcells are spindled or elongated and resemble those thatnormally populate the medulla. As a result, these aresometimes referred to as medullary thymomas. Inother tumors there is an admixture of the plumper,rounder, cortical-type epithelial cells; this pattern issometimes referred to as a mixed thymoma. Themedullary and mixed patterns account for 60% to 70%of all thymomas.

Malignant thymoma type I is a tumor that is cyto-logically bland but locally invasive. These tumors occa-sionally (and unpredictably) metastasize and accountfor 20% to 25% of all thymomas. They are composedof varying proportions of epithelial cells and reactivethymocytes; the epithelial cells usually resemble thosethat are normally found in the cortex, in that they haveabundant cytoplasm and rounded vesicular nuclei. Theneoplastic epithelial cells often form palisades aroundblood vessels. Sometimes spindled epithelial cells arepresent as well. The critical distinguishing feature isthe penetration of the capsule and the invasion of sur-rounding structures.

Malignant thymoma type II is perhaps better thoughtof as a form of thymic carcinoma. These representabout 5% of thymomas and, in contrast to the type Imalignant thymomas, are malignant cytologically.Macroscopically, they are usually fleshy, obviouslyinvasive masses sometimes accompanied by metas-tases to such sites as the lungs. Most resemble eitherpoorly or well-differentiated squamous cell carcino-mas. The next most common malignant pattern is lym-phoepithelioma-like carcinoma, which is composed ofanaplastic cortical-type epithelial cells mixed with largenumbers of benign thymocytes. Tumors of this type aremore common in Asian populations and sometimescontain the EBV genome.

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Red Cell Disorders

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Stuart MJ, Nagel RL: Sickle-cell disease. Lancet 363:1343, 2004. [Areview focused on recent pathogenic insights and their translationinto new therapies.]

Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med352:1011, 2005. [An excellent update on the anemia of chronicdisease, with a particular focus on the role of perturbed iron metab-olism.]

Young NS, Maciejewski JP: Genetic and environmental effects in parox-ysmal nocturnal hemoglobinuria: this little PIG-A goes “Why? Why?Why?.” J Clin Invest 106:637, 2000. [Discussion of the dual role ofsomatic mutation and autoimmunity in PNH.]

White Cell Disorders

Harris NL, et al.: World Health Organization classification of neoplas-tic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting, Airlie House, Virginia,November 1997. J Clin Oncol 17:3835, 1999. [A progress reportconfirming the utility of the WHO classification for lymphoid neo-plasms.]

Harris NL, Brunning RD: The World Health Organization (WHO) clas-sification of the myeloid neoplasms. Blood 100:2292, 2002. [A proposed updated classification system for acute myelogenousleukemias, myeloproliferative disorders, and myelodysplastic syndromes.]

Kantargian H, et al.: Hematologic and cytogenetic responses to ima-tinib mesylate in chronic myelogenous leukemia. N Engl J Med346:645, 2002. [An elegant example of how understanding the mol-ecular biology of CML has led to improved treatment.]

Krause DS, Van Etten RA: Tyrosine kinases as targets for cancertherapy. N Engl J Med 353:172, 2005. [A timely and thoroughreview of the increasing number of mutations that activate tyrosinekinases in cancer, many of which occur in acute leukemia and myelo-proliferative disorders.]

Kuppers R: Mechanisms of B-cell lymphoma pathogenesis. Nat RevCancer 5:251, 2005. [A lucid discussion of the origin of diverse B-cell malignancies.]

Mitsiades CS, Mitsiades N, Munshi NC, Anderson KC. Focus on multi-ple myeloma. Cancer Cell 6:439, 2004. [A review of recent advancesin understanding the molecular pathogenesis of multiple myeloma.]

Pui CH, Relling MV, Downing JR: Acute lymphoblastic leukemia. NEngl J Med 350:1535, 2004. [A recent review of the molecularpathogenesis, diagnosis, and treatment of ALL.]

Re D, Thomas, RK, Behringer K, Diehl V: From Hodgkin disease toHodgkin lymphoma: biologic insights and therapeutic potential.Blood 105:4553, 2005. [A current concise review of Hodgkin lym-phoma pathogenesis and therapy.]

Reilly JT: Pathogenesis of acute myeloid leukaemia andinv(16)(p13;q22): a paradigm for understanding leukaemogene-sis? Br J Haematol 128:18, 2005. [A review discussing the evidencesupporting the idea that mutations of two types, one anti-differentiative and the second pro-proliferative, collaborate toinduce and maintain AML.]

Coagulation Disorders

Levi GG, Motto DG, Ginsberg D: ADAMTS13 turns 3. Blood 106:11,2005. [An excellent review of ADAM-TS13 and its deficiency inTTP.]

Levi M, Cate HT: Disseminated intravascular coagulation. N Engl JMed 341:586, 1999. [A clinically oriented review of the causes,pathogenesis, and treatment of this disorder.]

Jang IK, Hursting MJ: When heparins promote thrombosis: review ofthe pathogenesis of heparin-induced thrombocytopenia. Circulation111:2671, 2005. [A discussion of the role of autoantibodies againstplatelet factor 4 and heparin in heparin-induced thrombocytopenia.]

Schneppenheim R, Budde U: Phenotypic and genotypic diagnosis of vonWillebrand disease: a 2004 update. Semin Hematol 42:12, 2005.[An update on this disorder.]

Siegler R, Oakes R: Hemolytic uremic syndrome; pathogenesis, treat-ment, and outcome. Curr Opin Pediatr 17:200, 2005. [An article onthe etiology and pathogenesis of the hemolytic-uremic syndrome.]

Disorders That Affect the Spleen and Thymus

Choi SS, Kim KD, Chung KY: Prognostic and clinical relevance of theWorld Health Organization schema for the classification of thymicepithelial tumors: a clinicopathologic study of 108 patients and lit-erature review. Chest 127:755, 2005. [A large clinicopathologicseries that shows that stage is the best predictor of outcome inthymoma.]

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