WBCs Disorders PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus 13 CHAPTER CONTENTS NORMAL HEMATOPOIESIS 584 Chronic Lymphocytic Leukemia/Small Myeloid Neoplasms 616 Lymphocytic Lymphoma 597 Acute Myeloid Leukemia 617 DISORDERS OF WHITE Follicular Lymphoma 599 Myelodysplastic Syndrome 620 CELLS 586 Diffuse Large B-Cell Lymphoma 600 Myeloproliferative Neoplasms 621 Leukopenia 586 Burkitt Lymphoma 601 Chronic Myeloid Leukemia 622 Neutropenia, Agranulocytosis 586 Mantle Cell Lymphoma 602 Polycythemia Vera 624 Reactive Proliferations of Marginal Zone Lymphomas 603 Essential Thrombocytosis 625 White Cells and Lymph Hairy Cell Leukemia 603 Primary Myelofibrosis 626 Nodes 587 Peripheral T- and NK-Cell Neoplasms 605 Langerhans Cell Histiocytosis 627 Leukocytosis 587 Peripheral T-Cell Lymphoma, Unspecified 605 Lymphadenitis 588 SPLEEN 628 Anaplastic Large-Cell Lymphoma (ALK Acute Nonspecific Lymphadenitis 588 Splenomegaly 629 Positive) 605 Chronic Nonspecific Lymphadenitis 589 Nonspecific Acute Splenitis 629 Adult T-Cell Leukemia/Lymphoma 605 Hemophagocytic Lymphohistiocytosis 590 Congestive Splenomegaly 630 Mycosis Fungoides/Sézary Syndrome 606 Neoplastic Proliferations of White Splenic Infarcts 630 Large Granular Lymphocytic Leukemia 606 Cells: Overview 590 Neoplasms 630 Extranodal NK/T-Cell Lymphoma 607 Etiologic and Pathogenetic Factors Congenital Anomalies 631 Plasma Cell Neoplasms and Related in White Cell Neoplasia 590 Rupture 631 Disorders 607 Lymphoid Neoplasms 592 Multiple Myeloma 607 THYMUS 631 Definitions and Classifications 592 Smoldering Myeloma 610 Developmental Disorders 631 Precursor B- and T-Cell Neoplasms 594 Solitary Osseous Plasmacytoma 610 Thymic Hyperplasia 632 Acute Lymphoblastic Leukemia/ Lymphoplasmacytic Lymphoma 610 Thymoma 632 Lymphoma 594 Hodgkin Lymphoma 611 Peripheral B-Cell Neoplasms 597 The components of the hematopoietic system have been nodes. Some red cell disorders (e.g., immunohemolytic anemia, traditionally divided into the myeloid tissues, which include discussed in Chapter 14) result from the formation of auto- the bone marrow and the cells derived from it (e.g., red cells, antibodies, indicating a primary disorder of lymphocytes. platelets, granulocytes, and monocytes), and the lymphoid Thus it is not possible to draw neat lines between diseases tissues, consisting of the thymus, lymph nodes, and spleen. involving the myeloid and lymphoid tissues. It is important to recognize, however, that this subdivision Recognizing this difficulty, we somewhat arbitrarily divide is artificial with respect to both the normal physiology of diseases of the hematopoietic tissues into two chapters. In hematopoietic cells and the diseases affecting them. For this chapter we discuss white cell diseases and disorders example, although bone marrow contains relatively few affecting the spleen and thymus. In Chapter 14 we consider lymphocytes, it is the source of all lymphoid progenitors and diseases of red cells and those affecting hemostasis. Before the home of long-lived plasma cells and memory lymphocytes. delving into specific diseases, we will briefly discuss the Similarly, neoplastic disorders of myeloid progenitor cells origins of hematopoietic cells, since many disorders of white (myeloid leukemias) originate in the bone marrow but sec- cells and red cells involve disturbances of their normal ondarily involve the spleen and (to a lesser degree) the lymph development and maturation. 583 584 C H A P T E R 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus Normal Hematopoiesis Blood cell progenitors first appear during the third week and appear in the peripheral blood. In fact, HSCs used in of embryonic development in the yolk sac. Cells derived transplantation are now mainly collected from the peripheral from the yolk sac are the source of long-lived tissue mac- blood of donors treated with granulocyte colony-stimulating rophages such as microglial cells in the brain and Kupffer factor (G-CSF), one of the factors that can mobilize marrow cells in the liver (Chapter 3), but the contribution of the HSCs from their stem cell niches. yolk sac to blood formation, mainly in the form of embryonic The marrow response to short-term physiologic needs red cells, is only transient. Definitive hematopoietic stem cells is regulated by hematopoietic growth factors through their (HSCs) arise several weeks later in the mesoderm of the effects on the committed progenitors. These growth factors intraembryonic aorta/gonad/mesonephros region. During are called colony-stimulating factors (CSFs) because they were the third month of embryogenesis, HSCs migrate to the discovered by their ability to support the growth of colonies liver, which becomes the chief site of blood cell formation of blood cells in vitro. Because mature blood elements are until shortly before birth. HSCs also take up residence in terminally differentiated cells with finite lifespans, their the fetal placenta; this pool of HSCs is of uncertain physi- numbers must be constantly replenished. In current models ologic relevance but has substantial clinical importance, as of hematopoiesis, some divisions of HSCs give rise to cells HSCs harvested at birth from umbilical cord blood are used referred to as multipotent progenitors, which are more pro- in therapeutic HSC transplantation. By the fourth month liferative than HSCs but have a lesser capacity for self- of development, HSCs shift in location yet again to the bone renewal (see Fig. 13.1). Division of multipotent progenitors marrow. By birth, marrow throughout the skeleton is gives rise to at least one daughter cell that leaves the stem hematopoietically active, and hepatic hematopoiesis dwindles cell pool and begins to differentiate. Once past this threshold, to a trickle, persisting only in scattered foci that become these newly committed cells lose the capacity for self-renewal inactive soon after birth. After puberty, hematopoiesis ceases and commence an inexorable journey down a road that in distal bones and becomes restricted to the axial skeleton. leads to terminal differentiation and death. However, as Thus in normal adults, only about half of the marrow space these progenitors differentiate, they also proliferate rapidly is hematopoietically active. in response to growth factors, expanding their numbers. The formed elements of blood—red cells, granulocytes, Some growth factors, such as stem cell factor (also called monocytes, platelets, and lymphocytes—have a common KIT ligand) and FLT3 ligand, act through receptors that are origin from HSCs, pluripotent cells that sit at the apex of expressed on very early committed progenitors. Others, a hierarchy of bone marrow progenitors (Fig. 13.1). Most such as erythropoietin, granulocyte-macrophage colony- evidence supporting this scheme comes from studies in mice, stimulating factor (GM-CSF), G-CSF, and thrombopoietin, but human hematopoiesis is believed to proceed in a similar act through receptors that are expressed only on committed way. The development of mature blood cells from HSCs progenitors with more restricted differentiation potentials. involves progressive commitment to increasingly specialized Feedback loops involving these lineage-specific growth cell populations. HSCs give rise to several kinds of early factors tune the marrow output, allowing the numbers of progenitor cells that have more restricted differentiation formed blood elements (red cells, white cells, and platelets) potential, such that they ultimately produce mainly myeloid to be maintained within appropriate ranges (Table 13.1). cells or lymphoid cells. The origins of lymphoid cells are Many diseases alter the production of blood cells. The revisited when tumors derived from these cells are discussed. marrow is the ultimate source of most cells of the innate These early progenitors in turn give “birth” to progenitors and adaptive immune system and responds to infectious that are further constrained in their differentiation potential. or inflammatory challenges by increasing its output of Some of these cells are referred to as colony-forming units granulocytes under the direction of specific growth factors (see Fig. 13.1) because they produce colonies composed of specific kinds of mature cells when grown in culture. Table 13.1 Adult Reference Ranges for Blood Cellsa From the various committed progenitors are derived the morphologically recognizable precursors, such as myelo- Cell Type Range blasts, proerythroblasts, and megakaryoblasts, which are 3 White cells (×10 /µL) 4.8–10.8 the immediate progenitors of mature granulocytes, red cells, Granulocytes (%) 40–70 and platelets. Neutrophils (×103/µL) 1.4–6.5 HSCs have two essential properties that are required for the maintenance of hematopoiesis: pluripotency and Lymphocytes (×103/µL) 1.2–3.4 the capacity for self-renewal. Pluripotency refers to the Monocytes (×103/µL) 0.1–0.6 ability of a single HSC to generate all mature blood cells. Eosinophils (×103/µL) 0–0.5 When an HSC divides, at least one daughter cell must self- 3 Basophils (×10 /µL) 0–0.2 renew to avoid stem cell depletion. Self-renewing divisions occur within a specialized marrow niche, in which stromal Red cells (×103/µL) Men 4.3–5 cells and secreted factors nurture and protect the HSCs. Women 3.5–5 As one might surmise from their ability to migrate during embryonic development, HSCs are not sessile. Particularly Platelets (×103/µL) 150–450 under conditions of stress, such as severe anemia or acute a Reference ranges vary among laboratories. The reference ranges for the laboratory providing the result should always be used. inflammation, HSCs are mobilized from the bone marrow  Normal hematopoiesis 585 Self- cKIT+ Hematopoietic stem cell renewal Sca-1+ STEM CELLS LIN– Multipotent progenitor Lineage-independent growth factor receptors Early progenitor with Early progenitor with lymphoid potential myeloid potential COMMITTED PRECURSORS Lineage-specific growth factor receptors (e.g., erythropoietin receptor) Pro- Pro- Pro- CFU-Mix CFU-b/M/E NK-cell B-cell T-cell Lymphopoiesis Cell division Pre- Pre- Pre- CFU-G CFU-M CFU-eo CFU-b CFU-Mg CFU-E NK cell B cell T cell Lineage-specific markers AND MATURE FORMS LATE PRECURSORS Myeloblast Monoblast Eosinophilo- Basophilo- Megakary- Erythroblast blast blast oblast NK cell B cell T cell Neutrophil Monocyte Eosinophil Basophil Platelets Erythrocyte Figure 13.1 Differentiation of blood cells. CFU, Colony forming unit; LIN−, negative for lineage-specific markers; NK, natural killer. and cytokines. By contrast, many other disorders are associ- In some instances these tumors originate from transformed ated with defects in hematopoiesis that lead to deficiencies HSCs that retain the ability to differentiate along multiple of one or more types of blood cells. Primary tumors of lineages, whereas in other instances the origin is a more hematopoietic cells are among the most important diseases differentiated progenitor that has acquired an abnormal that interfere with marrow function, but certain genetic capacity for self-renewal (Chapter 7). diseases, infections, toxins, and nutritional deficiencies, as well as chronic inflammation from any cause, may also decrease the production of blood cells by the marrow. MORPHOLOGY Tumors of hematopoietic origin are often associated The bone marrow is a unique microenvironment that supports with mutations that block progenitor cell maturation or the orderly proliferation, differentiation, and release of blood abrogate their growth factor dependence. The net effect of cells. It is filled with a network of thin-walled sinusoids lined by such derangements is an unregulated clonal expansion of a single layer of endothelial cells, which are underlaid by a dis- hematopoietic elements, which replace normal marrow continuous basement membrane and adventitial cells. Within the progenitors and often spread to other hematopoietic tissues. 586 C H A P T E R 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus interstitium lie clusters of hematopoietic cells and fat cells. Dif- precursors can be identified based on their morphology alone. ferentiated blood cells enter the circulation by transcellular Immature precursors (“blast” forms) of different types are migration through the endothelial cells. morphologically similar and must be identified definitively using The normal marrow is organized in subtle, but important, ways. lineage-specific antibodies and histochemical markers (described For example, normal megakaryocytes lie next to sinusoids and later under white cell neoplasms). Bone marrow biopsies are a extend cytoplasmic processes that bud off into the bloodstream good means for estimating marrow activity. In normal adults the to produce platelets, while red cell precursors often surround ratio of fat cells to hematopoietic elements is about 1:1. In macrophages that dispose of nuclear remnants produced when red hypoplastic states (e.g., aplastic anemia) the proportion of fat cells disgorge their nucleus prior to release into the bloodstream. cells is greatly increased; conversely, fat cells often disappear when Processes that distort the marrow architecture, such as deposits the marrow is involved by hematopoietic tumors and in diseases of metastatic cancer or granulomatous disorders, can cause the characterized by compensatory hyperplasias (e.g., hemolytic abnormal release of immature precursors into the peripheral anemias) and neoplastic proliferations such as leukemias. Other blood, a finding that is referred to as leukoerythroblastosis. disorders (e.g., metastatic cancers and granulomatous diseases) Marrow aspirate smears provide the best assessment of the induce local marrow fibrosis. In such cases the marrow usually morphology of hematopoietic cells. The most mature marrow cannot be aspirated and the lesions are best seen in biopsies. Disorders of White Cells Disorders of white blood cells can be classified into two Agranulocytosis, a marked reduction in neutrophils, has the broad categories: proliferative disorders, in which there serious consequence of making individuals susceptible to is an expansion of leukocytes, and leukopenias, which bacterial and fungal infections. are defined as a deficiency of leukocytes. Proliferations of white cells can be reactive or neoplastic. Reactive proliferations Pathogenesis in the setting of infections or inflammatory processes, when Neutropenia can be caused by (1) inadequate or ineffective large numbers of leukocytes are needed for an effective granulopoiesis or (2) increased destruction or sequestration host response, are fairly common. Neoplastic disorders, of neutrophils in the periphery. Inadequate or ineffective though less frequent, are much more important clinically. granulopoiesis is observed in the setting of: In the following discussion we will first describe the leu- Suppression of HSCs, as occurs in aplastic anemia (Chapter kopenic states and summarize the common reactive disorders 14) and a variety of infiltrative marrow disorders (e.g., and then consider in some detail the malignant proliferations tumors, granulomatous disease); in these conditions, of white cells. granulocytopenia is accompanied by anemia and thrombocytopenia. Suppression of committed granulocytic precursors by exposure LEUKOPENIA to certain drugs (discussed later). Disease states associated with ineffective hematopoiesis, The number of circulating white cells may be decreased in such as megaloblastic anemia (Chapter 14) and myelo- a variety of disorders. An abnormally low white cell count dysplastic syndrome, in which defective precursors die (leukopenia) usually results from reduced numbers of neu- in the marrow. trophils (neutropenia, granulocytopenia). Lymphopenia is less Rare congenital conditions (e.g., Kostmann syndrome), in common; in addition to congenital immunodeficiency which inherited defects in specific genes impair granu- diseases (Chapter 6), it is most commonly observed in locytic differentiation. advanced human immunodeficiency virus (HIV) infection, following therapy with glucocorticoids or cytotoxic drugs, Accelerated destruction or sequestration of neutrophils autoimmune disorders, malnutrition, and certain acute viral occurs with: infections. In the latter setting, lymphopenia actually stems Immunologically mediated injury to neutrophils, which can from lymphocyte redistribution rather than a decrease in be idiopathic, associated with a well-defined immunologic the number of lymphocytes in the body. Acute viral infections disorder (e.g., systemic lupus erythematosus), or caused induce production of type I interferons, which activate T by exposure to drugs. lymphocytes and change the expression of surface proteins Splenomegaly, in which splenic enlargement leads to that regulate T-cell migration. These changes result in the sequestration and destruction of neutrophils in the spleen sequestration of activated T cells in lymph nodes and and modest neutropenia, sometimes associated with increased adherence to endothelial cells, both of which anemia and often with thrombocytopenia. contribute to lymphopenia. Granulocytopenia is more Increased peripheral utilization, which can occur in over- common and is often associated with diminished granulocyte whelming bacterial, fungal, or rickettsial infections. function and thus merits further discussion. The most common cause of agranulocytosis is drug Neutropenia, Agranulocytosis toxicity. Certain drugs, such as alkylating agents and antimetabolites used in cancer treatment, produce agranu- Neutropenia, a reduction in the number of neutrophils in locytosis in a predictable, dose-related fashion. Because such the blood, occurs in a wide variety of circumstances. drugs cause a generalized suppression of hematopoiesis,  Disorders of white cells 587 production of red cells and platelets is also affected. Agranu- locytosis may also occur as an idiosyncratic reaction to a REACTIVE PROLIFERATIONS OF large variety of agents including certain antibiotics, anti- WHITE CELLS AND LYMPH NODES convulsants, antiinflammatory drugs, antipsychotic drugs, and diuretics. The neutropenia induced by antipsychotic Leukocytosis agents such as chlorpromazine and related phenothiazines results from a toxic effect on granulocytic precursors in the Leukocytosis refers to an increase in the number of white bone marrow. In contrast, agranulocytosis following admin- cells in the blood. It is a common reaction to a variety of istration of other drugs, such as sulfonamides, probably inflammatory states. stems from antibody-mediated destruction of neutrophils through mechanisms similar to those involved in drug- Pathogenesis induced immunohemolytic anemias (Chapter 14). The peripheral blood leukocyte count is influenced by several In some patients with acquired idiopathic neutropenia, factors, including: autoantibodies directed against neutrophil-specific antigens The size of the myeloid and lymphoid precursor and are detected. Severe neutropenia may also occur in associa- storage cell pools in the bone marrow, thymus, circulation, tion with monoclonal proliferations of large granular and peripheral tissues. lymphocytes (so-called LGL leukemia). The mechanism of The rate of release of cells from the storage pools into this neutropenia is not clear; suppression of granulocytic the circulation. progenitors by products of the neoplastic cell (usually a The proportion of cells that are adherent to blood vessel CD8+ cytotoxic T cell) is considered most likely. walls at any time (the marginal pool). The rate of extravasation of cells from the blood into tissues. MORPHOLOGY As discussed in Chapter 3, leukocyte homeostasis is The alterations in the bone marrow vary with cause. With maintained by cytokines, growth factors, and adhesion excessive destruction of neutrophils in the periphery, the marrow is molecules through their effects on the proliferation, dif- usually hypercellular due to a compensatory increase in granulocytic ferentiation, and extravasation of leukocytes and their precursors. Hypercellularity is also the rule with neutropenias progenitors. Table 13.2 summarizes the major mechanisms caused by ineffective granulopoiesis, as occurs in megaloblastic of neutrophilic leukocytosis and its causes, the most impor- anemia and myelodysplastic syndrome. Agranulocytosis caused tant of which is infection. In acute infection there is a rapid by agents that suppress or destroy granulocyte precursors is increase in the egress of mature granulocytes from the bone understandably associated with marrow hypocellularity. marrow pool, an alteration that may be mediated through Infections are a common consequence of agranulocytosis. the effects of tumor necrosis factor (TNF) and interleukin-1 Ulcerating necrotizing lesions of the gingiva, floor of the mouth, (IL-1). If the infection or an inflammatory process is pro- buccal mucosa, pharynx, or elsewhere in the oral cavity (agranu- longed, IL-1, TNF, and other inflammatory mediators locytic angina) are quite characteristic. These are typically deep, stimulate macrophages, bone marrow stromal cells, and T undermined, and covered by gray to green-black necrotic cells to produce increased amounts of hematopoietic growth membranes from which numerous bacteria or fungi can be isolated. factors. These factors enhance the proliferation and dif- Less frequently, similar ulcerative lesions occur in the skin, vagina, ferentiation of committed granulocytic progenitors and, over anus, or gastrointestinal tract. Severe life-threatening invasive several days, cause a sustained increase in neutrophil bacterial or fungal infections may occur in the lungs, urinary tract, production. and kidneys. The neutropenic patient is at particularly high risk Some growth factors preferentially stimulate the produc- for deep fungal infections caused by Candida and Aspergillus. Sites tion of a single type of leukocyte. For example, IL-5 mainly of infection often show a massive growth of organisms with little stimulates eosinophil production, while G-CSF induces leukocytic response. In the most dramatic instances, bacteria grow in colonies (botryomycosis) resembling those seen on agar plates. Table 13.2 Mechanisms and Causes of Leukocytosis Clinical Features Increased Marrow Production The symptoms and signs of neutropenia are related to Chronic infection or inflammation (growth factor–dependent) infection and include malaise, chills, and fever, often followed Paraneoplastic (e.g., Hodgkin lymphoma; growth factor–dependent) Myeloproliferative neoplasms (e.g., chronic myeloid leukemia; growth by marked weakness and fatigability. With agranulocytosis, factor–independent) infections are often overwhelming and may cause death within hours to days. Increased Release From Marrow Stores Serious infections are most likely when the neutrophil Acute inflammation (e.g., with infection) count falls below 500/mm3. Because infections are often Chronic inflammation (many causes) fulminant, broad-spectrum antibiotics must be given expedi- Decreased Margination tiously whenever signs or symptoms appear. In some Exercise instances, such as following myelosuppressive chemotherapy, Catecholamines neutropenia is treated with G-CSF, a growth factor that Decreased Extravasation Into Tissues stimulates the production of granulocytes from marrow Glucocorticoids precursors. 588 C H A P T E R 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus Table 13.3 Causes of Leukocytosis Type of Leukocytosis Causes Neutrophilic leukocytosis Acute bacterial infections, especially those caused by pyogenic organisms; sterile inflammation caused by, for example, tissue necrosis (myocardial infarction, burns) Eosinophilic leukocytosis (eosinophilia) Allergic disorders such as asthma, hay fever, parasitic infestations; drug reactions; certain malignancies (e.g., Hodgkin and some non-Hodgkin lymphomas); autoimmune disorders (e.g., pemphigus, dermatitis herpetiformis) and some vasculitides; atheroembolic disease (transient) Basophilic leukocytosis (basophilia) Rare, often indicative of a myeloproliferative neoplasm (e.g., chronic myeloid leukemia) Monocytosis Chronic infections (e.g., tuberculosis), bacterial endocarditis, rickettsiosis, and malaria; autoimmune disorders (e.g., systemic lupus erythematosus); 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-Barr virus); Bordetella pertussis infection neutrophilia. Such factors are differentially produced in Lymphadenitis response to various pathogenic stimuli, and, as a result, the five principal types of leukocytosis (neutrophilia, eosino- Following their initial development from precursors in the philia, basophilia, monocytosis, and lymphocytosis) tend central (also called primary) lymphoid organs—the bone to be observed in different clinical settings (Table 13.3). marrow for B cells and the thymus for T cells—lymphocytes In sepsis or severe inflammatory disorders (e.g., Kawasaki circulate through the blood and, under the influence of disease), leukocytosis is often accompanied by morphologic specific cytokines and chemokines, home to lymph nodes, changes in neutrophils, such as toxic granulations, Döhle spleen, tonsils, adenoids, and Peyer patches, which constitute bodies, and cytoplasmic vacuoles (Fig. 13.2). Toxic granules, the peripheral (secondary) lymphoid tissues. Lymph nodes, which are coarser and darker than normal neutrophilic the most widely distributed and easily accessible lymphoid granules, represent abnormal azurophilic (primary) granules. tissue, are frequently examined for diagnostic purposes. They Döhle bodies are patches of dilated endoplasmic reticulum are discrete encapsulated structures that contain separate that appear as sky-blue cytoplasmic “puddles.” B-cell and T-cell zones, each richly invested with phagocytes In most instances it is not difficult to distinguish reactive and antigen-presenting cells (see Fig. 6.8, Chapter 6). and neoplastic leukocytoses, but uncertainties may arise in The activation of resident immune cells leads to mor- two settings. Acute viral infections, particularly in children, phologic changes in lymph nodes. Within several days of can cause the appearance of large numbers of activated antigenic stimulation, the primary follicles enlarge and lymphocytes that resemble neoplastic lymphoid cells. At develop pale-staining germinal centers, highly dynamic other times, particularly in severe infections, many immature structures in which B cells acquire the capacity to make granulocytes appear in the blood, mimicking a myeloid high-affinity antibodies against specific antigens. Paracortical leukemia (leukemoid reaction). Special laboratory studies T-cell zones may also undergo hyperplasia. The degree and (discussed later) are helpful in distinguishing reactive and pattern of morphologic change are dependent on the inciting neoplastic leukocytoses. stimulus and the intensity of the response. Trivial injuries and infections induce subtle changes, while more significant infections inevitably produce nodal enlargement and sometimes leave residual scarring. For this reason, lymph nodes in adults are almost never “normal” or “resting,” and it is often necessary to distinguish morphologic changes secondary to past experience from those related to present disease. Infections and inflammatory stimuli often elicit regional or systemic immune reactions within lymph nodes. Some that produce distinctive morphologic patterns are described in other chapters. Most, however, cause stereotypi- cal patterns of lymph node reaction designated acute and chronic nonspecific lymphadenitis. Acute Nonspecific Lymphadenitis Acute lymphadenitis in the cervical region is most often due to drainage of microbes or microbial products from infections of the teeth or tonsils, while in the axillary or inguinal regions it is most often caused by infections in the extremities. Acute lymphadenitis also occurs in mesenteric Figure 13.2 Reactive changes in neutrophils. Neutrophils containing coarse purple cytoplasmic granules (toxic granulations) and blue lymph nodes in the setting of acute appendicitis and other cytoplasmic patches of dilated endoplasmic reticulum (Döhle bodies) inflammatory conditions involving the gut (including self- (arrow) are observed in this peripheral blood smear prepared from a limiting viral infections), a differential diagnosis that plagues patient with bacterial sepsis. the surgeon. Systemic viral infections (particularly in  Disorders of white cells 589 children) and bacteremia often produce acute generalized lymphadenopathy. MORPHOLOGY The nodes are swollen, gray-red, and engorged. Microscopically, there is prominence of large reactive germinal centers containing numerous mitotic figures. Macrophages often contain particulate debris derived from dead bacteria or necrotic cells.When pyogenic organisms are the cause, neutrophils are prominent, and the centers of the follicles may undergo necrosis; sometimes the entire node is converted to pus. With less severe reactions, scattered neu- trophils infiltrate about the follicles and accumulate within the lymphoid sinuses. The endothelial cells lining the sinuses become activated and enlarge in size. Nodes involved by acute lymphadenitis are swollen and painful. When abscess formation is extensive the nodes become fluctuant. The overlying skin is red. Sometimes, suppurative infections penetrate through the capsule of the node and track to the skin to produce draining sinuses. Healing of such lesions is associated with scarring. Chronic Nonspecific Lymphadenitis A wide variety of chronic immunologic stimuli may produce nonspecific lymphadenitis. Several different patterns of morphologic change are seen, often within the same lymph node. MORPHOLOGY Figure 13.3 Follicular hyperplasia. (A) Low-power view showing a reactive follicle and surrounding mantle zone. The dark-staining mantle Follicular hyperplasia is caused by stimuli that activate humoral zone is more prominent adjacent to the germinal center light zone in the immune responses. It is defined by the presence of large oblong left half of the follicle. The right half of the follicle consists of the dark germinal centers (secondary follicles), which are surrounded by zone. (B) High-power view of the dark zone shows several mitotic figures a collar of small resting naive B cells (the mantle zone) (Fig. 13.3). and numerous macrophages containing phagocytosed apoptotic cells (tingible bodies). Germinal centers are polarized, consisting of two distinct regions: (1) a dark zone with proliferating blast-like B cells (centroblasts) and (2) a light zone composed of B cells with irregular or cleaved The expanded T-cell zones encroach on and, in particularly exuber- nuclear contours (centrocytes). Interspersed among the germinal ant reactions, may efface the B-cell follicles. In such cases, center B cells is an inconspicuous network of antigen-presenting immunoblasts are so numerous that special studies may be needed follicular dendritic cells and macrophages (often referred to as to exclude a lymphoid neoplasm. In addition, there is often tingible-body macrophages) containing the nuclear debris of hypertrophy of sinusoidal and vascular endothelial cells, sometimes B cells, which undergo apoptosis if they fail to produce an antibody accompanied by infiltrating macrophages and eosinophils. with a high affinity for antigen. Sinus histiocytosis (also called reticular hyperplasia) is marked Causes of follicular hyperplasia include rheumatoid arthritis, by an increase in the number and size of the endothelial cells toxoplasmosis, and early HIV infection. This form of hyperplasia that line lymphatic sinusoids and increased numbers of intrasinu- is morphologically similar to follicular lymphoma (discussed later). soidal macrophages, which expand and distort the sinusoids. This Features favoring a reactive (nonneoplastic) hyperplasia include form of hyperplasia may be particularly prominent in lymph nodes (1) preservation of the lymph node architecture, including the draining cancers such as carcinoma of the breast. interfollicular T-cell zones and the sinusoids, (2) marked variation in the shape and size of the follicles, and (3) the presence of frequent mitotic figures, phagocytic macrophages, and recognizable Characteristically, lymph nodes in chronic reactions are light and dark zones, all of which tend to be absent from neoplastic nontender, as enlargement occurs slowly over time and follicles. acute inflammation with associated tissue damage is absent. Paracortical hyperplasia is caused by stimuli that trigger Chronic lymphadenitis is particularly common in inguinal T-cell–mediated immune responses, such as acute viral infections and axillary nodes, which drain relatively large areas of the (e.g., infectious mononucleosis). The T-cell regions typically contain body and are frequently stimulated by immune reactions immunoblasts, activated T cells three to four times the size of to trivial injuries and infections of the extremities. resting lymphocytes that have round nuclei, open chromatin, several Chronic immune reactions also can promote the appear- prominent nucleoli, and moderate amounts of pale cytoplasm. ance of organized collections of immune cells in nonlymphoid 590 C H A P T E R 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus tissues. These collections are sometimes called tertiary Treatment involves the use of immunosuppressive drugs, lymphoid organs. A classic example is that of chronic gastritis “mild” chemotherapy, and administration of an antibody caused by Helicobacter pylori, in which aggregates of mucosal that neutralizes the activity of interferon-γ. Patients with lymphocytes are seen that simulate the appearance of Peyer germline mutations that cause HLH or who have persistent/ patches. A similar phenomenon occurs in rheumatoid resistant disease are candidates for HSC transplantation. arthritis, in which B-cell follicles often appear in the inflamed Without treatment, the prognosis is grim, particularly in synovium. Lymphotoxin, a cytokine required for the forma- those with familial forms of the disease, who typically survive tion of normal Peyer patches, is probably involved in the for less than 2 months. With prompt treatment, with or establishment of these “extranodal” inflammation-induced without subsequent HSC transplantation, roughly half of collections of lymphoid cells. patients survive, though many do so with significant sequelae, such as renal damage in adults and growth retarda- tion and intellectual disability in children. Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) is a reactive condi- NEOPLASTIC PROLIFERATIONS OF tion marked by cytopenias and signs and symptoms of WHITE CELLS: OVERVIEW systemic inflammation related to macrophage activation. For this reason, it is also sometimes referred to as macrophage Malignancies are clinically the most important disorders of activation syndrome. Some forms are familial and may appear white cells. These diseases fall into three broad categories: early in life, even in infants, while other forms are sporadic Lymphoid neoplasms include a diverse group of tumors and may affect people of any age. of B-cell, T-cell, and NK-cell origin. In many instances the phenotype of the neoplastic cell closely resembles Pathogenesis that of a particular lymphocyte class or stage of matura- The common feature of all forms of HLH is systemic activa- tion, a feature that is used in the diagnosis and classifica- tion of macrophages and CD8+ cytotoxic T cells. The activated tion of these disorders. macrophages phagocytose blood cell progenitors in the Myeloid neoplasms arise from early hematopoietic progeni- marrow and formed elements in the peripheral tissues, while tors. Three categories of myeloid neoplasia are recognized: the “stew” of mediators released from macrophages and acute myeloid leukemias (AMLs), in which immature lymphocytes suppress hematopoiesis and produce symptoms progenitor cells accumulate in the bone marrow; myelo- of systemic inflammation. These effects lead to cytopenias dysplastic syndromes (MDSs), which are associated with and a shock-like picture, sometimes referred to as “cytokine ineffective hematopoiesis and resultant peripheral blood storm” or the systemic inflammatory response syndrome cytopenias; and myeloproliferative neoplasms, in which (Chapter 4). increased production of one or more terminally differenti- Familial forms of HLH are associated with several dif- ated myeloid elements (e.g., granulocytes) usually leads ferent mutations, all of which impact the ability of cytotoxic to elevated peripheral blood counts. T cells (CTLs) and natural killer (NK) cells to properly The histiocytoses are uncommon proliferative lesions of form or deploy cytotoxic granules. How these defects lead macrophages and dendritic cells. Although “histiocyte” to HLH is not known. One common trigger for HLH is (literally, “tissue cell”) is an archaic morphologic term, Epstein-Barr virus infection, suggesting that in some instances it is still often used. A special type of immature dendritic HLH stems from a defect in the ability of CD8+ CTLs to kill cell, the Langerhans cell, gives rise to a spectrum of infected cells. As a result of the persistent infection, the CTLs neoplastic disorders referred to as the Langerhans cell continue to make cytokines, leading to excessive macrophage histiocytoses. activation. HLH is also a common complication of peripheral T-cell lymphoma (discussed later), a tumor of mature T cells Etiologic and Pathogenetic Factors in White that is marked by immune dysregulation. Regardless of the Cell Neoplasia trigger, HLH is uniformly associated with extremely high levels of inflammatory mediators such as interferon-γ, TNF-α, As in other cancers, the development of white blood cell IL-6, and IL-12. neoplasms involves genetic alterations, infections, and sometimes a background of chronic inflammation. Different Clinical Features types of tumors show different abnormalities and are, Most patients present with an acute febrile illness associated therefore, responsive to different therapies. Before delving with splenomegaly and hepatomegaly. Hemophagocytosis into this complexity, we consider themes of general relevance is usually seen on bone marrow examination, but is neither to their etiology and pathogenesis. sufficient nor required to make the diagnosis. Laboratory studies typically reveal anemia, thrombocytopenia, and Chromosomal Translocations and Other Acquired Muta- very high levels of plasma ferritin and soluble IL-2 receptor, tions. Nonrandom chromosomal abnormalities, most both indicative of severe inflammation, as well as elevated commonly translocations, are present in the majority of liver function tests and triglyceride levels, both related white cell neoplasms. Many of these alterations are specifi- to hepatitis. Coagulation studies may show evidence of cally associated with particular neoplasms and have a critical disseminated intravascular coagulation. If untreated, this role in their genesis (Chapter 7). picture can progress rapidly to multiorgan failure, shock, and Recurrently affected genes are often those that play crucial death. roles in the development, growth, or survival of the normal  Disorders of white cells 591 different constant segment (e.g., IgG3), leading to a switch Pro-growth mutations (tyrosine kinase mutations, in the class (isotype) of antibody produced, and somatic MYC translocation) hypermutation, which creates point mutations within Ig genes that may increase antibody affinity for antigen Increased cell division (Chapter 6). Certain proto-oncogenes, such as MYC, are Warburg metabolism activated in germinal center B-cell lymphomas by trans- locations to the transcriptionally active Ig locus. Remark- ably, AID expression induces MYC/Ig translocations in Increased self-renewal a small fraction of normal germinal center B cells, Decreased apparently because AID creates lesions in DNA that lead apoptosis to chromosomal breaks. “Mistargeting” of AID also is Mutations in transcription implicated in point mutations that upregulate the expres- factors that influence Pro-survival self-renewal mutations sion and activity of BCL6, an oncogenic transcription (KMT2A translocation, (BCL2 translocation) factor with an important role in several B-cell malignan- PML-RARA fusion gene) cies. Another type of regulated genomic instability that is unique to precursor B and T cells is attributable to Figure 13.4 Pathogenesis of white cell malignancies. Various tumors V(D)J recombinase, which cuts DNA at specific sites harbor mutations that principally effect maturation or enhance self- within the Ig and T-cell receptor loci, respectively. This renewal, drive growth, or prevent apoptosis. Examples of each type of process is essential for generating diversity in assembled mutation are listed; details are provided later under specific tumor types. antigen receptor genes but sometimes goes awry, leading to the joining of proto-oncogenes to antigen receptor gene regulatory elements. The resulting overexpression of the counterpart of the malignant cell. Mutations in certain genes involved proto-oncogene converts it to an oncogene. This are so strongly associated with specific tumor types that mechanism is particularly prevalent in tumors of precursor in some instances they are required for particular diag- T cells but is observed in other types of lymphoid neo- noses. Some of these mutations produce a “dominant- plasms as well. negative” protein that interferes with a normal function (a loss of function); in others the result is an inappropriate Inherited Genetic Factors. As discussed in Chapter 7, increase in some normal activity (a gain of function). individuals with genetic diseases that promote genomic Oncoproteins created by genomic aberrations often block normal instability, such as Bloom syndrome, Fanconi anemia, and maturation, turn on pro-growth signaling pathways, or protect ataxia telangiectasia, are at increased risk of acute leukemia. cells from apoptotic cell death. Fig. 13.4 highlights several In addition, both Down syndrome (trisomy 21) and type I well-characterized driver mutations and their pathogenic neurofibromatosis are associated with an increased incidence consequences in particular white cell neoplasms. of childhood leukemia. Many oncoproteins cause an arrest in differentiation, often at a stage when cells are proliferating rapidly. Viruses. Three lymphotropic viruses—human T-cell leu- The importance of this mechanism is most evident in kemia virus-1 (HTLV-1), EBV, and human herpesvirus-8 the acute leukemias, in which dominant-negative (HHV-8; also known as Kaposi sarcoma herpesvirus)—have oncogenic mutations involving transcription factors been implicated as causative agents in particular lymphomas. interfere with early stages of lymphoid or myeloid The possible mechanisms of transformation by viruses are cell differentiation. discussed in Chapter 7. HTLV-1 is associated with adult Other mutations in transcriptional regulators directly T-cell leukemia/lymphoma. EBV is found in a subset of enhance the self-renewal of tumors cells, giving them Burkitt lymphoma, 30% to 40% of Hodgkin lymphoma (HL), stem cell–like properties. These types of mutations many B-cell lymphomas arising in the setting of T-cell often collaborate with mutations that constitutively immunodeficiency, and rare NK-cell lymphomas. In addition activate tyrosine kinases, which in turn activate RAS to Kaposi sarcoma (Chapter 11), HHV-8 is associated with and its two downstream signaling arms, the PI3K/ an unusual B-cell lymphoma that presents as a malignant AKT and MAPK pathways (Chapter 7), thereby driving effusion, often in the pleural cavity. cell growth. Finally, mutations that inhibit apoptosis are prevalent Chronic Inflammation. Several agents that cause localized in certain hematologic malignancies. chronic inflammation predispose to lymphoid neoplasia, Proto-oncogenes are often activated in lymphoid cells by which almost always arises within the inflamed tissue. errors that occur during attempted antigen receptor gene Examples include the associations between H. pylori infection diversification. Among lymphoid cells, potentially onco- and gastric B-cell lymphomas (Chapter 17); gluten-sensitive genic mutations occur most frequently in germinal center enteropathy and intestinal T-cell lymphomas; and even B cells. After antigen stimulation, B cells enter germinal breast implants, which are associated with an unusual centers and upregulate the expression of activation- subtype of T-cell lymphoma. This can be contrasted with induced cytosine deaminase (AID), a specialized DNA- HIV infection, which is associated with an increased risk modifying enzyme that is essential for two types of of B-cell lymphomas that may arise within virtually any immunoglobulin (Ig) gene modifications: class switching, organ. Early in the course, T-cell dysregulation by HIV an intragenic recombination event in which the IgM infection causes a systemic hyperplasia of germinal center heavy-chain constant gene segment is replaced with a B cells that is associated with an increased incidence of 592 C H A P T E R 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus germinal center B-cell lymphomas. In advanced infection examples include the plasma cell tumors, in which much (acquired immunodeficiency syndrome [AIDS]), severe T-cell of the pathophysiology is related to the secretion of whole immunodeficiency further elevates the risk for B-cell lym- antibodies or Ig fragments; Hodgkin lymphoma, which is phomas, particularly those associated with EBV and KSHV/ often associated with fever related to the release of cytokines HHV-8. These relationships are discussed in more detail in from nonneoplastic inflammatory cells; and peripheral T-cell Chapter 6. lymphomas, tumors of functional T cells that often release pro-inflammatory cytokines and chemokines. Iatrogenic Factors. Ironically, radiation therapy and certain Historically, few areas of pathology evoked as much forms of chemotherapy used to treat cancer increase the controversy as the classification of lymphoid neoplasms, risk of subsequent myeloid and lymphoid neoplasms. This but consensus has been reached through use of objective association stems from the mutagenic effects of ionizing molecular diagnostic tools. The current World Health radiation and chemotherapeutic drugs on hematolymphoid Organization (WHO) classification scheme (Table 13.4) uses progenitor cells. morphologic, immunophenotypic, genotypic, and clinical features to sort the lymphoid neoplasms into five broad Smoking. The incidence of AML is increased 1.3- to 2-fold categories, separated according to the cell of origin: in smokers, presumably because of exposure to carcinogens, 1. Precursor B-cell neoplasms (neoplasms of immature such as benzene, in tobacco smoke. B cells) 2. Peripheral B-cell neoplasms (neoplasms of mature B cells) 3. Precursor T-cell neoplasms (neoplasms of immature T LYMPHOID NEOPLASMS cells) Taken together, the diverse lymphoid neoplasms constitute a complex, clinically important group of cancers, with about 100,000 new cases being diagnosed each year in the United Table 13.4 World Health Organization Classification of States. Lymphoid Neoplasms I. Precursor B-Cell Neoplasms Definitions and Classifications B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) Neoplasms that present with widespread involvement of the II. Peripheral B-Cell Neoplasms bone marrow and (usually, but not always) the peripheral blood are called leukemias. Proliferations of white cells, Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia typically lymphocytes, that usually present as discrete Lymphoplasmacytic lymphoma tissue masses are called lymphomas. Originally these terms Splenic and nodal marginal zone lymphomas were attached to what were considered distinct entities, but Extranodal marginal zone lymphoma with time and increased understanding these divisions have Mantle cell lymphoma blurred. Many entities called “lymphoma” occasionally have Follicular lymphoma leukemic presentations, and evolution to “leukemia” is not Marginal zone lymphoma Hairy cell leukemia unusual during the progression of incurable “lymphomas.” Plasmacytoma/plasma cell myeloma Conversely, tumors identical to “leukemias” sometimes arise Diffuse large B-cell lymphoma as soft tissue masses without detectable bone marrow disease. Burkitt lymphoma Hence the terms leukemia and lymphoma merely reflect III. Precursor T-Cell Neoplasms the usual tissue distribution of each disease at presentation. Within the large group of lymphomas, Hodgkin lymphoma T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is segregated from other forms, which constitute the non- IV. Peripheral T-Cell and NK-Cell Neoplasms Hodgkin lymphomas (NHLs). Hodgkin lymphoma has distinc- T-cell prolymphocytic leukemia tive pathologic features and is treated in a unique fashion. Large granular lymphocytic leukemia Another special group of tumors includes plasma cell neo- Mycosis fungoides/Sézary syndrome plasms. These most often arise in the bone marrow and only Peripheral T-cell lymphoma, unspecified Anaplastic large-cell lymphoma infrequently involve lymph nodes or the peripheral blood. Angioimmunoblastic T-cell lymphoma The clinical presentation of lymphoid neoplasms is most Enteropathy-associated T-cell lymphoma often determined by the anatomic distribution of disease. Panniculitis-like T-cell lymphoma Two-thirds of NHLs and virtually all Hodgkin lymphomas Hepatosplenic γδ T-cell lymphoma present as enlarged nontender lymph nodes (often >2 cm). Adult T-cell leukemia/lymphoma The remaining NHLs present with symptoms related to the Extranodal NK/T-cell lymphoma NK-cell leukemia involvement of extranodal sites (e.g., skin, stomach, or brain). Lymphocytic leukemias most often come to attention because V. Hodgkin Lymphoma of signs and symptoms related to the suppression of normal Classic subtypes hematopoiesis by tumor cells in the bone marrow, whereas Nodular sclerosis the most common plasma cell neoplasm, multiple myeloma, Mixed cellularity causes bony destruction of the skeleton and often presents Lymphocyte-rich Lymphocyte depletion with pain due to pathologic fractures. Other symptoms are Nodular lymphocyte predominant frequently caused by proteins secreted from tumor cells NK, Natural killer. or from immune cells responding to the tumor. Specific  Disorders of white cells 593 4. Peripheral T-cell and NK-cell neoplasms (neoplasms of Table 13.5 Some Immune Cell Antigens Detected by mature T cells and NK cells) Monoclonal Antibodies 5. Hodgkin lymphomas (neoplasms of Reed-Sternberg cells Antigen and variants) Designation Normal Cellular Distribution Primarily T-Cell Associated Before discussing the specific entities, some important CD1 Thymocytes and Langerhans cells principles relevant to lymphoid neoplasms should be emphasized. CD3 Thymocytes, mature T cells Lymphoid neoplasia can be suspected based on clinical features, CD4 Helper T cells, subset of thymocytes but histologic examination of lymph nodes or other involved CD5 T cells and small subset of B cells tissues is required for diagnosis. Analysis of lineage-specific CD8 Cytotoxic T cells, subset of thymocytes, and protein (marker) expression and genetic alterations is an some NK cells important complement to the morphologic studies. Primarily B-Cell Associated Markers recognized by antibodies that are helpful in the CD10 Pre-B cells and germinal center B cells characterization of lymphomas and leukemias are listed in Table 13.5. CD19 Pre-B cells and mature B cells but not plasma Antigen receptor gene rearrangement generally precedes cells transformation of lymphoid cells; hence all daughter cells CD20 Pre-B cells after CD19 and mature B cells but derived from the malignant progenitor share the same antigen not plasma cells receptor gene configuration and sequence and synthesize identi- CD21 EBV receptor; mature B cells and follicular cal antigen receptor proteins (either Igs or T-cell receptors). dendritic cells In contrast, normal immune responses are comprised CD23 Activated mature B cells of polyclonal populations of lymphocytes that express CD79a Marrow pre-B cells and mature B cells many different antigen receptors. Thus, analyses of Primarily Monocyte or Macrophage Associated antigen receptor genes and their protein products can be used to distinguish reactive (polyclonal) and malig- CD11c Granulocytes, monocytes, and macrophages; also expressed by hairy cell leukemias nant (monoclonal) lymphoid proliferations. In addition, each antigen receptor gene rearrangement produces a CD13 Immature and mature monocytes and granulocytes unique DNA sequence that constitutes a highly spe- cific clonal marker, which can be used to detect small CD14 Monocytes numbers of residual malignant lymphoid cells after CD15 Granulocytes; Reed-Sternberg cells and variants therapy. CD33 Myeloid progenitors and monocytes Most lymphoid neoplasms resemble some recognizable stage CD64 Mature myeloid cells of B- or T-cell differentiation (Fig. 13.5), a feature that is used in their classification. The vast majority (85% to Primarily NK-Cell Associated 90%) of lymphoid neoplasms are of B-cell origin, with CD16 NK cells and granulocytes most of the remainder being T-cell tumors; tumors of CD56 NK cells and a subset of T cells NK-cell origin are rare. Primarily Stem Cell and Progenitor Cell Associated Lymphoid neoplasms are often associated with immune CD34 Pluripotent hematopoietic stem cells and abnormalities. Both a loss of protective immunity (sus- progenitor cells of many lineages ceptibility to infection) and a breakdown of tolerance (autoimmunity) may be seen, sometimes in the same Activation Markers patient. In a further ironic twist, individuals with inherited CD30 Activated B cells, T cells, and monocytes; or acquired immunodeficiency are themselves at high Reed-Sternberg cells and variants risk of developing certain lymphoid neoplasms, particu- Present on All Leukocytes larly those caused by oncogenic viruses (e.g., EBV). CD45 All leukocytes; also known as leukocyte Neoplastic B and T cells tend to recapitulate the behavior of common antigen (LCA) their normal counterparts. Like normal lymphocytes, CD, Cluster designation; EBV, Epstein-Barr virus; NK, natural killer. neoplastic B and T cells express adhesion molecules and chemokine receptors that govern their homing to certain tissue sites, leading to characteristic patterns of involve- Hodgkin lymphoma spreads in an orderly stepwise fashion, ment. For example, follicular lymphomas home to ger- whereas most forms of NHL disseminate widely and somewhat minal centers in lymph nodes, whereas cutaneous T-cell unpredictably early in their course. Hence, while lymphoma lymphomas home to the skin. Variable numbers of staging provides useful prognostic information, it is of neoplastic B and T lymphoid cells also recirculate through most utility in guiding therapy in Hodgkin lymphoma. the lymphatics and peripheral blood to distant sites; as a result, most lymphoid tumors are widely disseminated We begin our discussion of specific entities with neo- at the time of diagnosis. Notable exceptions to this rule plasms of immature lymphoid cells and then move to mature include Hodgkin lymphomas, which are sometimes B-cell tumors, plasma cell neoplasms, and tumors of T-cells restricted to one group of lymph nodes, and marginal and NK-cells. Some of the salient molecular and clinical zone B-cell lymphomas, which are often restricted to features of these neoplasms are summarized in Table 13.6. sites of chronic inflammation. We will finish by discussing Hodgkin lymphoma. 594 C H A P T E R 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus B cell neoplasms T cell neoplasms BONE MARROW THYMUS CLP DN Precursor T Precursor B lymphoblastic lymphoblastic lymphoma/ lymphoma/ BLB leukemias leukemias DP Small lymphocytic lymphoma NBC Chronic lymphocytic CD4 CD8 leukemia Multiple myeloma PC Mantle cell lymphoma MC Peripheral Follicular lymphoma PTC T cell Burkitt lymphoma lymphomas Diffuse large B cell GC MZ lymphoma Hodgkin lymphoma Diffuse large B cell lymphoma Marginal zone lymphoma Small lymphocytic lymphoma LYMPH NODE Chronic lymphocytic leukemia Figure 13.5 Origin of lymphoid neoplasms. Stages of B- and T-cell differentiation from which specific lymphoid tumors emerge are shown. BLB, Pre-B lymphoblast; CLP, common lymphoid precursor; DN, CD4/CD8 double-negative pro-T cell; DP, CD4/CD8 double-positive pre-T cell; GC, germinal center B cell; MC, mantle B cell; MZ, marginal zone B cell; NBC, naive B cell; PTC, peripheral T cell. Precursor B- and T-Cell Neoplasms age of 3, perhaps because the number of normal bone marrow pre-B cells (the cell of origin) is greatest very early in life. Acute Lymphoblastic Leukemia/Lymphoma Similarly the peak incidence of T-ALL is in adolescence, Acute lymphoblastic leukemia/lymphomas (ALLs) are the age when the thymus reaches maximum size. B-ALL neoplasms composed of immature B (pre-B) or T (pre-T) and T-ALL also occur less frequently in adults of all ages. cells, which are referred to as lymphoblasts. About 85% are B-ALLs, which typically manifest as childhood acute Pathogenesis leukemias. The less common T-ALLs tend to present in Many of the chromosomal aberrations seen in ALL dys- adolescent males as thymic lymphomas. There is, however, regulate the expression and function of transcription factors considerable overlap in the clinical behavior of B-ALL and required for normal B- and T-cell development. Most T-ALLs T-ALL; for example, B-ALL uncommonly presents as a mass have mutations in NOTCH1, a gene that is essential for in the skin or a bone, and many T-ALLs present with or T-cell development, while a high fraction of B-ALLs have evolve to a leukemic picture. Because of their morphologic mutations affecting genes such as PAX5, TCF3, ETV6, and and clinical similarities, the various forms of ALL are dis- RUNX1, all of which are required for the proper differentia- cussed here together. tion of early hematopoietic precursors. By disturbing the ALL is the most common cancer of children. Approxi- expression and function of “master” regulatory factors, these mately 2500 new cases are diagnosed each year in the United mutations promote maturation arrest and increased self- States, most occurring in individuals younger than 15 years renewal, a stem cell–like phenotype. Similar themes are of age. ALL is almost three times more common in Cauca- relevant in the genesis of AML (discussed later). sians than in African-Americans and is slightly more frequent In keeping with the multistep origin of cancer (Chapter in boys than in girls. Hispanics have the highest incidence 7), mutations in transcription factor genes are not sufficient of any ethnic group. B-ALL peaks in incidence at about the to produce ALL. The identity of other driver mutations is  Disorders of white cells 595 Table 13.6 Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin Lymphomas Diagnosis Cell of Origin Genotype Salient Clinical Features Neoplasms of Immature B and T Cells B-cell acute lymphoblastic Bone marrow Diverse chromosomal translocations; Predominantly children; symptoms relating to leukemia/lymphomaa precursor B cell t(12;21) involving RUNX1 and ETV6 marrow replacement and pancytopenia; present in 25% aggressive T-cell acute lymphoblastic Precursor T cell (often Diverse chromosomal translocations; Predominantly adolescent males; thymic masses and leukemia/lymphoma of thymic origin) NOTCH1 mutations (50%–70%) variable bone marrow involvement; aggressive Neoplasms of Mature B Cells Burkitt lymphomaa Germinal center B cell Translocations involving MYC and Ig Adolescents or young adults with extranodal loci, usually t(8;14); subset masses; uncommonly presents as “leukemia”; EBV-associated aggressive Diffuse large B-cell Germinal center or Diverse chromosomal rearrangements, All ages, but most common in older adults; often lymphomab post–germinal most often of BCL6 (30%), BCL2 appears as a rapidly growing mass; 30% center B cell (10%), or MYC (5%) extranodal; aggressive Extranodal marginal zone Memory B cell t(11;18), t(1;14), and t(14;18) creating Arises at extranodal sites in adults with chronic lymphoma MALT1-IAP2, BCL10-IGH, and inflammatory diseases; may remain localized; MALT1-IGH fusion genes, respectively indolent Follicular lymphomab Germinal center B cell t(14;18) creating BCL2-IGH fusion gene Older adults with generalized lymphadenopathy and marrow involvement; indolent Hairy cell leukemia Memory B cell Activating BRAF mutations Older men with pancytopenia and splenomegaly; indolent Mantle cell lymphoma Naive B cell t(11;14) creating cyclin D1–IGH fusion Older men with disseminated disease; moderately gene aggressive Multiple myeloma/solitary Post–germinal center Diverse rearrangements involving IGH; Myeloma: older adults with lytic bone lesions, plasmacytomab bone marrow 13q deletions pathologic fractures, hypercalcemia, and renal homing plasma cell failure; moderately aggressive Plasmacytoma: isolated plasma cell masses in bone or soft tissue; indolent Small lymphocytic Naive B cell or Trisomy 12, deletions of 11q, 13q, and Older adults with bone marrow, lymph node, lymphoma/chronic memory B cell 17p; NOTCH1 mutations; splicing spleen, and liver disease; autoimmune hemolysis lymphocytic leukemia factor mutations and thrombocytopenia in a minority; indolent Neoplasms of Mature T Cells or NK Cells Adult T-cell leukemia/ Helper T cell HTLV-1 provirus present in tumor cells Adults with cutaneous lesions, marrow involvement, lymphoma and hypercalcemia; occurs mainly in Japan, West Africa, and the Caribbean; aggressive Peripheral T-cell Helper or cytotoxic T No specific chromosomal abnormality Mainly older adults; usually presents with lymphoma, unspecified cell lymphadenopathy; aggressive Anaplastic large-cell Cytotoxic T cell Rearrangements of ALK (anaplastic large Children and young adults, usually with lymph node lymphoma cell lymphoma kinase) in a subset and soft tissue disease; aggressive Extranodal NK/T-cell NK-cell (common) or EBV-associated; no specific Adults with destructive extranodal masses, most lymphoma cytotoxic T cell chromosomal abnormality commonly sinonasal; aggressive (rare) Mycosis fungoides/Sézary Helper T cell No specific chromosomal abnormality Adult patients with cutaneous patches, plaques, syndrome nodules, or generalized erythema; indolent Large granular Two types: cytotoxic T Point mutations in STAT3 Adult patients with splenomegaly, neutropenia, and lymphocytic leukemia cell and NK cell anemia, sometimes accompanied by autoimmune disease a Most common tumors in children. b Most common tumors in adults. EBV, Epstein-Barr virus; HTLV-1, human T-cell leukemia virus-1; Ig, immunoglobulin; NK, natural killer. incomplete, but aberrations that promote cell growth, such chromosomes), but hypoploidy and a variety of balanced as mutations that increase tyrosine kinase activity and RAS chromosomal translocations also are seen. Changes in chro- signaling, are commonly present. Emerging data from deep mosome numbers are of uncertain pathogenic significance sequencing of ALL genomes suggest that fewer than 10 but are important because they frequently correlate with mutations are sufficient to produce full-blown ALL; hence immunophenotype and sometimes prognosis. For example, compared to solid tumors, ALL is genetically simple. hyperdiploidy and hypodiploidy are seen only in B-ALL and Approximately 90% of ALLs have numerical or structural are associated with better and worse prognoses, respectively. chromosomal changes. Most common is hyperploidy (>50 In addition, B-ALL and T-ALL are associated with completely 596 C H A P T E R 13 Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus different sets of translocations; thus, while morphologically identical, they are genetically quite distinct. MORPHOLOGY In leukemic presentations, the marrow is hypercellular and packed with lymphoblasts, which replace normal marrow elements. Mediastinal thymic masses occur in 50% to 70% of T-ALLs, which are also more likely than B-ALL to be associated with lymphadenopathy and splenomegaly. In both B-ALL and T-ALL, the tumor cells have scant basophilic cytoplasm and nuclei somewhat larger than those of small lymphocytes (Fig. 13.6A). The nuclear chromatin is delicate and finely stippled, and nucleoli are usually small and often demarcated by a rim of condensed A chromatin. The nuclear membrane is often deeply subdivided, imparting a convoluted appearance. In keeping with the aggressive clinical behavior, the mitotic rate is high. As with other rapidly growing lymphoid tumors, interspersed macrophages ingesting apoptotic tumor cells may impart a “starry sky” appearance (shown CD22 CD19 in Fig. 13.15). Because of their different responses to chemotherapy, ALL must be distinguished from AML, a neoplasm of immature myeloid cells that can cause identical signs and symptoms. Compared with myeloblasts, lymphoblasts have more condensed chromatin, less conspicuous nucleoli, and smaller amounts Intracellular TdT CD10 of cytoplasm that usually lacks granules. However, these B C morphologic distinctions are not absolute, and definitive diagnosis Figure 13.6 (A) Acute lymphoblastic leukemia/lymphoma (ALL). relies on stains performed with antibodies specific for B- and Lymphoblasts with condensed nuclear chromatin, small nucleoli, and scant T-cell antigens (Fig. 13.6B and C). Histochemical stains are also agranular cytoplasm. (B and C) Phenotype of ALL shown in (A) analyzed helpful, in that (in contrast to myeloblasts) lymphoblasts are by flow cytometry. (B) The lymphoblasts represented by the red dots myeloperoxidase-negative and often contain periodic acid–Schiff– express terminal deoxynucleotidyl transferase (TdT) and the B-cell marker positive cytoplasmic material. CD22. (C) The same cells are positive for two other markers, CD10 and CD19, commonly expressed on pre-B lymphoblasts. Thus this is a B-ALL. (A, Courtesy Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Tex.; B and C, courtesy Dr. Immunophenotype. Immunostaining for terminal deoxy- Louis Picker, Oregon Health Science Center, Portland, Ore.) nucleotidyl transferase (TdT), a specialized DNA polymerase that is expressed only in pre-B and pre-T lymphoblasts, is positive in more than 95% of cases (Fig. 13.6B). B-ALLs are Symptoms related to depression of marrow function, including arrested at various stages of pre–B-cell development, which fatigue due to anemia; fever, reflecting infections second- correlate with the expression of certain proteins. The lym- ary to neutropenia; and bleeding due to thrombocytopenia. phoblasts usually express the pan B-cell marker CD19 and Mass effects caused by neoplastic infiltration (which are more the transcription factor PAX5 as well as CD10. In very common in ALL), including bone pain resulting from immature B-ALLs, CD10 is negative. Alternatively, more marrow expansion and infiltration of the subperiosteum; mature “late pre-B” ALLs express CD10, CD19, CD20, and generalized lymphadenopathy, splenomegaly, and cytoplasmic IgM heavy chain (µ chain). Similarly, T-ALLs hepatomegaly; testicular enlargement; and, in T-ALL, are arrested at various stages of pre–T-cell development. complications related to compression of large vessels and In most cases the cells are positive for CD1, CD2, CD5, and airways in the mediastinum. CD7. The more immature tumors are usually negative for Central nervous system manifestations such as headache, surface CD3, CD4, and CD8, whereas “late” pre–T-cell tumors vomiting, and nerve palsies resulting from meningeal are positive for these markers. spread, all of which are also more common in ALL. Clinical Features Treatment of pediatric ALL is one of the great success Although ALLs and AMLs are genetically and immuno- stories of oncology. With aggressive chemotherapy about phenotypically distinct, they are clinically very similar. In 95% of children with ALL obtain a complete remission, and both, the accumulation of neoplastic “blasts” in the bone 75% to 85% are