13 Heme Lymph Flashcards

Question

Neutrophils 10^3 range

Answer 1

4. 3-5 men | 3. 5-5 women

Answer 2

The marrow is the ultimate source of most cells of the innate and adaptive immune system and responds to infectious or inflammatory challenges by increasing its output of granulocytes under the direction of specific growth factors and cytokines. . By contrast, many other disorders are associated with defects in hematopoiesis that lead to deficiencies of one or more types of blood cells. Primary tumors of hematopoietic cells are among the most important diseases that interfere with marrow function, but certain genetic diseases, infections, toxins, and nutritional deficiencies, as well as chronic inflammation from any cause, can also decrease the production of blood cells by the marrow

Answer 3

The net effect of such derangements is an unregulated clonal expansion of hematopoietic elements, which replace normal marrow progenitors and often spread to other hematopoietic tissues. In some instances, these tumors originate from transformed HSCs that retain the ability to differentiate along multiple lineages, whereas in other instances the origin is a more differentiated progenitor that has acquired an abnormal capacity for self-renewal ( Chapter 7 ).

Answer 4

The bone marrow is a unique microenvironment that supports the orderly proliferation, differentiation, and release of blood cells. It is filled with a network of thin-walled sinusoids lined by a single layer of endothelial cells, which are underlaid by a discontinuous basement membrane and adventitial cells. Within the interstitium lie clusters of hematopoietic cells and fat cells. Differentiated blood cells enter the circulation by transcellular migration through the endothelial cells.

Answer 5

The normal marrow is organized in subtle, but important, ways. For example, normal megakaryocytes lie next to sinusoids and extend cytoplasmic processes that bud off into the bloodstream to produce platelets, while red cell precursors often surround macrophages (so-called nurse cells ) that provide some of the iron needed for the synthesis of hemoglobin

Answer 6

Processes that distort the marrow architecture, such as deposits of metastatic cancer or granulomatous disorders, can cause the abnormal release of immature precursors into the peripheral blood, a finding that is referred to as leukoerythroblastosis

Answer 7

Marrow aspirate

Answer 8

mmature precursors (“blast” forms) of different types are morphologically similar and must be identified definitively using lineage-specific antibodies and histochemical markers (described later under white cell neoplasms

Answer 9

Morphology alone

Answer 10

Fat decreased,

Answer 11

Fat cells disappear

Answer 12

Metastatic cancer and granulomatous

Answer 13

Disorders of white blood cells can be classified into two broad categories: proliferative disorders , in which there is an expansion of leukocytes, and leukopenias , which are defined as a deficiency of leukocytes.

Answer 14

Reactive or neoplastic

Answer 15

Reactive proliferations in the setting of infections or inflammatory processes, when leukocytes are needed for an effective host response, are fairly common

Answer 16

Neoplastic disorders, though less frequent, are much more important clinically

Answer 17

An abnormally low white cell count (leukopenia) ) usually results from reduced numbers of neutrophils (neutropenia, granulocytopenia) .

Answer 18

Lymphopenia is less common; in addition to congenital immunodeficiency diseases ( Chapter 6 ), it is most commonly observed in advanced human immunodeficiency virus (HIV) infection, following therapy with glucocorticoids or cytotoxic drugs, autoimmune disorders, malnutrition, and certain acute viral infections. Lymphopenia is less common; in addition to congenital immunodeficiency diseases ( Chapter 6 ), it is most commonly observed in advanced human immunodeficiency virus (HIV) infection, following therapy with glucocorticoids or cytotoxic drugs, autoimmune disorders, malnutrition, and certain acute viral infections. In the latter setting lymphopenia actually stems from lymphocyte redistribution rather than a decrease in the number of lymphocytes in the body.

Answer 19

cute viral infections induce production of type I interferons, which activate T lymphocytes and change the expression of surface proteins that regulate T cell migration. These changes result in the sequestration of activated T cells in lymph nodes and increased adherence to endothelial cells, both of which contribute to lymphopenia

Answer 20

Granulocytopenia is more common and is often associated with diminished granulocyte function, and thus merits further discussion

Answer 21

Neutropenia , a reduction in the number of neutrophils in the blood, occurs in a wide variety of circumstances

Answer 22

Agranulocytosis , a clinically significant reduction in neutrophils, has the serious consequence of making individuals susceptible to bacterial and fungal infections

Answer 23

(1) inadequate or ineffective granulopoiesis, or (2) increased destruction or sequestration of neutrophils in the periphery

Answer 24

, as occurs in aplastic anemia ( Chapter 14 ) and a variety of infiltrative marrow disorders (e.g., tumors, granulomatous disease); in these conditions granulocytopenia is accompanied by anemia and thrombocytopenia

Answer 25

Exposure to certain drugs

Answer 26

, such as megaloblastic anemias ( Chapter 14 ) and myelodysplastic syndromes, in which defective precursors die in the marrow

Answer 27

e.g., Kostmann syndrome) in which inherited defects in specific genes impair granulocytic differentiation

Answer 28

Immunologically mediated injury to neutrophils Splenmegaly Increased peripheral utilization

Answer 29

• Immunologically mediated injury to neutrophils, which can be idiopathic, associated with a well-defined immunologic disorder (e.g., systemic lupus erythematosus), or caused by exposure to drugs

Answer 30

• Splenomegaly , in which splenic enlargement leads to sequestration of neutrophils and modest neutropenia, sometimes associated with anemia and often with thrombocytopenia

Answer 31

Increased peripheral utilization , which can occur in overwhelming bacterial, fungal, or rickettsial infections

Answer 32

Drug toxicity

Answer 33

Certain drugs, such as alkylating agents and antimetabolites used in cancer treatment, produce agranulocytosis in a predictable, dose-related fashion. Because such drugs cause a generalized suppression of hematopoiesis, production of red cells and platelets is also affected

Answer 34

The roster of implicated drugs includes aminopyrine, chloramphenicol, sulfonamides, chlorpromazine, thiouracil, and phenylbutazone. The neutropenia induced by chlorpromazine and related phenothiazines results from a toxic effect on granulocytic precursors in the bone marrow.

Answer 35

Severe neutropenia can also occur in association with monoclonal proliferations of large granular lymphocytes (so-called LGL leukemia ). The mechanism of this neutropenia is not clear; suppression of granulocytic progenitors by products of the neoplastic cell (usually a CD8+ cytotoxic T cell) is considered most likely.

Answer 36

With excessive destruction of neutrophils in the periphery, the marrow is usually hypercellular due to a compensatory increase in granulocytic precursors.

Answer 37

Hypercellularity is also the rule with neutropenias caused by ineffective granulopoiesis, as occurs in megaloblastic anemias and myelodysplastic syndromes.

Answer 38

Agranulocytosis caused by agents that suppress or destroy granulocytic precursors is understandably associated with marrow hypocellularity

Answer 39

Agranulocytosis Ulcerating necrotizing lesions of the gingiva, floor of the mouth, buccal mucosa, pharynx, or elsewhere in the oral cavity (agranulocytic angina) are quite characteristic. These are typically deep, undermined, and covered by gray to green-black necrotic membranes from which numerous bacteria or fungi can be isolated. Less frequently, similar ulcerative lesions occur in the skin, vagina, anus, or gastrointestinal tract. Severe life-threatening invasive bacterial or fungal infections may occur in the lungs, urinary tract, and kidneys. The neutropenic patient is at particularly high risk for deep fungal infections caused by Candida and Aspergillus . Sites of infection often show a massive growth of organisms with little leukocytic response. In the most dramatic instances, bacteria grow in colonies (botryomycosis) resembling those seen on agar plates.

Answer 40

The symptoms and signs of neutropenia are related to infection, and include malaise, chills, and fever, often followed by marked weakness and fatigability. With agranulocytosis, infections are often overwhelming and may cause death within hours to days.

Answer 41

Serious infections are most likely when the neutrophil count falls below 500 per mm 3 . Because infections are often fulminant, broad-spectrum antibiotics must be given expeditiously whenever signs or symptoms appear. In some instances, such as following myelosuppressive chemotherapy, neutropenia is treated with G-CSF, a growth factor that stimulates the production of granulocytes from marrow precursors.

Answer 42

Leukocytosis refers to an increase in the number of white cells in the blood . It is a common reaction to a variety of inflammatory states

Answer 43

* The size of the myeloid and lymphoid precursor and storage cell pools in the bone marrow, thymus, circulation, and peripheral tissues * The rate of release of cells from the storage pools into the circulation * The proportion of cells that are adherent to blood vessel walls at any time (the marginal pool) * The rate of extravasation of cells from the blood into tissues

Answer 44

As discussed in Chapter 3 , leukocyte homeostasis is maintained by cytokines, growth factors, and adhesion molecules through their effects on the commitment, proliferation, differentiation, and extravasation of leukocytes and their progenitors

Answer 45

. In acute infection there is a rapid increase in the egress of mature granulocytes from the bone marrow pool, an alteration that may be mediated through the effects of tumor necrosis factor (TNF) and interleukin-1 (IL-1). If the infection or an inflammatory process is prolonged, IL-1, TNF, and other inflammatory mediators stimulate macrophages, bone marrow stromal cells and T cells to produce increased amounts of hematopoietic growth factors. These factors enhance the proliferation and differentiation of committed granulocytic progenitors and, over several days, cause a sustained increase in neutrophil production

Answer 46

Chronic infection or inflammation (growth factor-dependent) Paraneoplastic (e.g., Hodgkin lymphoma; growth factor-dependent) Myeloproliferative disorders (e.g., chronic myeloid leukemia; growth factor-independent)

Answer 47

Endotoxemia Infection Hypoxia

Answer 48

Exercise | Catecholamines

Answer 49

Glucocorticoids

Answer 50

For example, IL-5 mainly stimulates eosinophil production, while G-CSF induces neutrophilia. Such factors are differentially produced in response to various pathogenic stimuli and, as a result, the five principal types of leukocytosis (neutrophilia, eosinophilia, basophilia, monocytosis, and lymphocytosis) tend to be observed in different clinical settings

Answer 51

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

Answer 52

Allergic disorders such as asthma, hay fever, parasitic infestations; drug reactions; certain malignancies (e.g., Hodgkin and some non-Hodgkin lymphomas); automimmune disorders (e.g., pemphigus, dermatitis herpetiformis) and some vasculitides; atheroembolic disease (transient

Answer 53

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

Answer 54

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

Answer 55

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

Answer 56

In sepsis or severe inflammatory disorders (e.g., Kawasaki disease), leukocytosis is often accompanied by morphologic changes in the neutrophils, such as toxic granulations, Döhle bodies, and cytoplasmic vacuoles ( Fig. 13-2 ). Toxic granules , which are coarser and darker than the normal neutrophilic granules, represent abnormal azurophilic (primary) granules. Döhle bodies are patches of dilated endoplasmic reticulum that appear as sky-blue cytoplasmic “puddles

Answer 57

Acute viral infections, particularly in children, can cause the appearance of large numbers of activated lymphocytes that resemble neoplastic lymphoid cells. At other times, particularly in severe infections, many immature granulocytes appear in the blood, mimicking a myeloid leukemia (leukemoid reaction) . Special laboratory studies (discussed later) are helpful in distinguishing reactive and neoplastic leukocytoses

Answer 58

CD34: Antigen/marker of HSC cells

Answer 59

leukocyte common antigen -- found on all white cells

Answer 60

circulate through the blood and, under the influence of specific cytokines and chemokines, home to lymph nodes, spleen, tonsils, adenoids, and Peyer's patches, which constitute the peripheral (secondary) lymphoid tissues. Lymph nodes, the most widely distributed and easily accessible lymphoid tissue, are frequently examined for diagnostic purposes. They are discrete encapsulated structures that contain well-organized B-cell and T-cell zones, which are richly invested with phagocytes and antigen-presenting cells

Answer 61

morphologic changes in lymph nodes

Answer 62

, highly dynamic structures in which B cells acquire the capacity to make high-affinity antibodies against specific antigens. Paracortical T-cell zones may also undergo hyperplasia.

Answer 63

Trivial injuries and infections induce subtle changes, while more significant infections inevitably produce nodal enlargement and sometimes leave residual scarring.

Answer 64

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 stereotypical patterns of lymph node reaction designated acute and chronic nonspecific lymphadenitis.

Answer 65

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 lymph nodes draining acute appendicitis. Other self-limited infections may also cause acute mesenteric adenitis and induce symptoms mimicking acute appendicitis, a differential diagnosis that plagues the surgeon. Systemic viral infections (particularly in children) and bacteremia often produce acute generalized lymphadenopathy

Answer 66

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 a bag of pus. With less severe reactions, scattered neutrophils infiltrate about the follicles and accumulate within the lymphoid sinuses. The endothelial cells lining the sinuses undergo hyperplasia

Answer 67

Nodes involved by acute lymphadenitis are enlarged 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

Answer 68

Chronic immunologic stimuli produce several different patterns of lymph node reaction, as described later

Answer 69

s caused by stimuli that activate humoral immune responses. It is defined by the presence of large oblong germinal centers (secondary follicles), which are surrounded by a collar of small resting naive B cells (the mantle zone) ( Fig. 13-3 ). Germinal centers are normally polarized, consisting of two distinct regions: (1) a dark zone containing proliferating blastlike B cells (centroblasts) and (2) a light zone composed of B cells with irregular or cleaved nuclear contours (centrocytes). Interspersed between the germinal B centers is an inconspicuous network of antigen-presenting follicular dendritic cells and macrophages (often referred to as tingible-body macrophages ) containing the nuclear debris of B cells, which undergo apoptosis if they fail to produce an antibody with a high affinity for antigen

Answer 70

Follicular hyperplasia. A, Low-power view showing a reactive follicle and surrounding mantle zone. The dark-staining mantle zone is more prominent adjacent to the germinal-center light zone in the left half of the follicle. The right half of the follicle consists of the dark zone. B, High-power view of the dark zone shows several mitotic figures and numerous macrophages containing phagocytosed apoptotic cells (tingible bodies

Answer 71

Causes of follicular hyperplasia include rheumatoid arthritis, toxoplasmosis, and early stages of infection with HIV. This form of hyperplasia is morphologically similar to follicular lymphoma (discussed later). Features favoring a reactive (nonneoplastic) hyperplasia include (1) preservation of the lymph node architecture, including the 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 light and dark zones, all of which tend to be absent from neoplastic follicles

Answer 72

a is caused by stimuli that trigger T-cell–mediated immune responses, such as acute viral infections (e.g., infectious mononucleosis). The T-cell regions typically contain immunoblasts, activated T cells three to four times the size of resting lymphocytes that have round nuclei, open chromatin, several prominent nucleoli, and moderate amounts of pale cytoplasm. The expanded T-cell zones encroach on and, in particularly exuberant reactions, efface the B-cell follicles. In such cases immunoblasts may be so numerous that special studies are needed to exclude a lymphoid neoplasm. In addition, there is often a hypertrophy of sinusoidal and vascular endothelial cells, sometimes accompanied by infiltrating macrophages and eosinophils

Answer 73

Sinus histiocytosis (also called reticular hyperplasia ) refers to an increase in the number and size of the cells that line lymphatic sinusoids. Although nonspecific, this form of hyperplasia may be particularly prominent in lymph nodes draining cancers such as carcinoma of the breast. The lining lymphatic endothelial cells are markedly hypertrophied and macrophages are greatly increased in numbers, resulting in the expansion and distension of the sinuses

Answer 74

reactions are nontender, as nodal enlargement occurs slowly over time and acute inflammation with associated tissue damage is absent. Chronic lymphadenitis is particularly common in inguinal and axillary nodes, which drain relatively large areas of the body and are frequently stimulated by immune reactions to trivial injuries and infections of the extremities.

Answer 75

These collections are sometimes called tertiary lymphoid organs. A classic example is that of chronic gastritis caused by Helicobacter pylori , in which aggregates of mucosal lymphocytes are seen that simulate the appearance of Peyer patches. A similar phenomenon occurs in rheumatoid arthritis, in which B-cell follicles often appear in the inflamed synovium. Lymphotoxin, a cytokine required for the formation of normal Peyer patches, is probably involved in the establishment of these “extranodal” inflammation-induced collections of lymphoid cells.

Answer 76

Hemophagocytic lymphohistiocytosis (HLH) is a reactive condition marked by cytopenias and signs and symptoms of systemic inflammation related to macrophage activation. For this reason, it is also sometimes referred to as macrophage activation syndrome . Some forms are familial and may appear early in life, even in infants, while other forms are sporadic and may affect people of any age

Answer 77

. The activated macrophages phagocytose blood cell progenitors in the marrow and formed elements in the peripheral tissues, while the “stew” of mediators released from macrophages and lymphocytes suppress hematopoiesis and produce symptoms of systemic inflammation. These effects lead to cytopenias and a shock-like picture, sometimes referred to as “cytokine storm” or the systemic inflammatory response syndrome ( Chapter 4 ).

Answer 78

How these defects lead to HLH is not known. One idea with some experimental support is based on the premise that cytotoxic T cells keep immune responses in check by lysing antigen-bearing dendritic cells or activated macrophages; if this regulatory mechanism fails, hyperactivation of the immune system and the clinical syndrome of HLH ensue. Unbridled HLH is associated with extremely high levels of inflammatory mediators such as interferon-γ, TNFα, IL-6, and IL-12, as well as soluble IL-2 receptor. Some “sporadic” cases in adults also prove to have mutations in the same set of genes, while in other adult-onset patients the cause is unknown. The most common trigger for HLH is infection, particularly with Epstein-Barr virus (EBV).

Answer 79

Most patients present with an acute febrile illness associated with splenomegaly and hepatomegaly. Hemophagocytosis is usually seen on bone marrow examination, but is neither sufficient nor required to make the diagnosis. Laboratory studies typically reveal anemia, thrombocytopenia, and very high levels of plasma ferritin and soluble IL-2 receptor, both indicative of severe inflammation, as well as elevated liver function tests and triglyceride levels, both related to hepatitis. Coagulation studies may show evidence of disseminated intravascular coagulation. If untreated, this picture can progress rapidly to multiorgan failure, shock, and death

Answer 80

Treatment involves the use of immunosuppressive drugs and “mild” chemotherapy. Patients with germline mutations that cause HLH or who have persistent/resistant disease are candidates for hematopoietic stem cell transplantation. Without treatment, the prognosis is grim, particularly in those with familial forms of the disease, who typically survive for less than 2 months. With prompt treatment, with or without subsequent hematopoietic stem cell transplantation, roughly half of patients survive, though many do so with significant sequelae, such as renal damage in adults and growth and mental retardation in children

Answer 81

Malignancies are clinically the most important disorders of white cells. These diseases fall into several broad categories

Answer 82

s include a diverse group of tumors of B-cell, T-cell, and NK-cell origin. In many instances the phenotype of the neoplastic cell closely resembles that of a particular stage of normal lymphocyte maturation, a feature that is used in the diagnosis and classification of these disorders

Answer 83

arise from early hematopoietic progenitors. Three categories of myeloid neoplasia are recognized: acute myeloid leukemias , in which immature progenitor cells accumulate in the bone marrow;

Answer 84

myelodysplastic syndromes , which are associated with ineffective hematopoiesis and resultant peripheral blood cytopenias

Answer 85

chronic myeloproliferative disorders , in which increased production of one or more terminally differentiated myeloid elements (e.g., granulocytes) usually leads to elevated peripheral blood counts

Answer 86

• The histiocytoses are uncommon proliferative lesions of macrophages and dendritic cells. Although “histiocyte” (literally, “tissue cell”) is an archaic morphologic term, it is still often used. A special type of immature dendritic cell, the Langerhans cell, gives rise to a spectrum of neoplastic disorders referred to as the Langerhans cell histiocytoses

Answer 87

. Many specific rearrangements are associated with particular neoplasms, suggesting a critical role in their genesis ( Chapter 7 ).

Answer 88

As a consequence, certain mutations are strongly associated with specific tumor types, so much so that in some instances they are required for particular diagnoses. In some instances, the mutation produces a “dominant-negative” protein that interferes with a normal function (a loss of function); in others the result is an inappropriate increase in some normal activity (a gain of function).

Answer 89

Figure 13-4 highlights some of the more common or better characterized oncogenic events that serve as oncogenic driver mutations in particular kinds of white cell malignancies.

Answer 90

The importance of this block in maturation is most evident in the acute leukemias, in which dominant-negative oncogenic mutations involving transcription factors are often present that interfere with early stages of lymphoid or myeloid cell differentiation.

Answer 91

These types of mutations often collaborate with mutations that produce a constitutively active tyrosine kinase; oncogenic tyrosine kinases activate RAS and its two downstream signaling arms, the PI3K/AKT and MAPK pathways ( Chapter 7 ), and thereby drive cell growth and Warburg metabolism.

Answer 92

Pathogenesis of white cell malignancies. Various tumors harbor mutations that principally effect maturation or enhance self-renewal, drive growth, or prevent apoptosis. Exemplary examples of each type of mutation are listed; details are provided later under specific tumor types

Answer 93

Among lymphoid cells, potentially oncogenic mutations occur most frequently in germinal center B cells during attempted antibody diversification . After antigen stimulation, B cells enter germinal centers and upregulate the expression of activation-induced cytosine deaminase (AID), a specialized DNA-modifying enzyme that is essential for two types of immunoglobulin (Ig) gene modifications: class switching , an intragenic recombination event in which the IgM heavy-chain constant gene segment is replaced with a different constant segment (e.g., IgG 3 ), leading to a switch in the class (isotype) of antibody produced; and somatic hypermutation , which creates point mutations within Ig genes that may increase antibody affinity for antigen

Answer 94

Certain proto-oncogenes, such as MYC , are activated in germinal center B-cell lymphomas by translocations to the transcriptionally active Ig locus. Remarkably, AID expression is sufficient to induce MYC/Ig translocations in normal germinal center B cells, apparently because AID creates lesions in DNA that lead to chromosomal breaks. Other proto-oncogenes, such as BCL6 , a transcription factor that has an important role in many B cell malignancies, are frequently activated in germinal center B-cell lymphomas by point mutations that also seem to stem from “mistargeted” DNA breaks induced by AID. A different type of regulated genomic instability is unique to precursor B and T cells, which express a V(D)J recombinase that cuts DNA at specific sites within the Ig and T-cell receptor loci, respectively. This process is essential for the assembly of productive antigen receptor genes, but sometimes goes awry, leading to the joining of portions of other genes to antigen receptor gene regulatory elements. Particularly in tumors of precursor T cells, proto-oncogenes are often deregulated by their involvement in such aberrant recombination events

Answer 95

As discussed in Chapter 7 , individuals with genetic diseases that promote genomic instability, such as Bloom syndrome, Fanconi anemia, and ataxia telangiectasia, are at increased risk of acute leukemia. In addition, both Down syndrome (trisomy 21) and type I neurofibromatosis are associated with an increased incidence of childhood leukemia

Answer 96

human T-cell leukemia virus-1 (HTLV-1), Epstein-Barr virus (EBV), and Kaposi sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV-8) — have been implicated as causative agents in particular lymphomas. The possible mechanisms of transformation by viruses are discussed in Chapter 7 . HTLV-1 is associated with adult T-cell leukemia/lymphoma. EBV is found in a subset of Burkitt lymphoma, 30% to 40% of Hodgkin lymphoma (HL), many B-cell lymphomas arising in the setting of T-cell immunodeficiency, and rare NK-cell lymphomas. In addition to Kaposi sarcoma ( Chapter 11 ), KSHV is associated with an unusual B-cell lymphoma that presents as a malignant effusion, often in the pleural cavity

Answer 97

Several agents that cause localized chronic inflammation predispose to lymphoid neoplasia, which almost always arises within the inflamed tissue. Examples include the associations between H. pylori infection and gastric B-cell lymphomas ( Chapter 17 ), gluten-sensitive enteropathy and intestinal T-cell lymphomas, and even breast implants, which are associated with an unusual subtype of T cell lymphoma. This can be contrasted with HIV infection, which is associated with an increased risk of B-cell lymphomas that may arise within virtually any organ. Early in the course, T-cell dysregulation by HIV infection causes a systemic hyperplasia of germinal center B cells that is associated with an increased incidence of germinal center B-cell lymphomas. In advanced infection (acquired immunodeficiency syndrome), severe T-cell immunodeficiency further elevates the risk for B-cell lymphomas, particularly those associated with EBV and KSHV/HHV-8. These relationships are discussed in more detail in

Answer 98

Ironically, radiation therapy and certain forms of chemotherapy used to treat cancer increase the risk of subsequent myeloid and lymphoid neoplasms. This association stems from the mutagenic effects of ionizing radiation and chemotherapeutic drugs on hematolymphoid progenitor cells

Answer 99

The incidence of acute myeloid leukemia is increased 1.3- to 2-fold in smokers, presumably because of exposure to carcinogens, such as benzene, in tobacco smoke

Answer 100

is used for neoplasms that present with widespread involvement of the bone marrow and (usually, but not always) the peripheral blood

Answer 101

Lymphoma is used for proliferations that arise as discrete tissue masses. Originally these terms were attached to what were considered distinct entities, but with time and increased understanding these divisions have blurred

Answer 102

Hodgkin lymphoma has distinctive pathologic features and is treated in a unique fashion.

Answer 103

Another special group of B cell tumors, which differs from most lymphomas, is the plasma cell neoplasms . These most often arise in the bone marrow and only infrequently involve lymph nodes or the peripheral blood

Answer 104

is most often determined by the anatomic distribution of disease

Answer 105

The lymphocytic leukemias most often come to attention because of signs and symptoms related to the suppression of normal hematopoiesis by tumor cells in the bone marrow

Answer 106

multiple myeloma, causes bony destruction of the skeleton and often presents with pain due to pathologic fractures.

Answer 107

ther symptoms related to lymphoid tumors are frequently caused by proteins secreted from the tumor cells or from immune cells that are responding to the tumor

Answer 108

Hodgkin lymphoma, which is often associated with fever related to the release of cytokines from inflammatory cells responding to the tumor cells; and peripheral T-cell lymphomas, tumors of functional T cells that often release a number of inflammatory cytokines and chemokin

Answer 109

Neoplasms of immature B cells

Answer 110

Neoplasms of mature B cells

Answer 111

Neoplasms of immature T cells

Answer 112

Neoplasms of mature T cells and NK cells

Answer 113

Neoplasms of reed stern berg cells and variants

Answer 114

B-cell acute lymphoblastic leukemia/lymphoma (B-ALL

Answer 115

``` Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic and nodal marginal zone lymphomas Extranodal marginal zone lymphoma Mantle cell lymphoma Follicular lymphoma Marginal zone lymphoma Hairy cell leukemia Plasmacytoma/plasma cell myeloma Diffuse large B-cell lymphoma Burkitt lymphoma ```

Answer 116

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL

Answer 117

``` T-cell prolymphocytic leukemia Large granular lymphocytic leukemia Mycosis fungoides/Sézary syndrome Peripheral T-cell lymphoma, unspecified Anaplastic large-cell lymphoma Angioimmunoblastic T-cell lymphoma Enteropathy-associated T-cell lymphoma Panniculitis-like T-cell lymphoma Hepatosplenic γδT-cell lymphoma Adult T-cell leukemia/lymphoma Extranodal NK/T-cell lymphoma NK-cell leukemia ```

Answer 118

``` Classical subtypes Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depletion Lymphocyte predominance ```

Answer 119

In contrast, normal immune responses are comprised of polyclonal populations of lymphocytes that express many different antigen receptors. Thus, analyses of antigen receptor genes and their protein products can be used to distinguish reactive (polyclonal) and malignant (monoclonal) lymphoid proliferations. In addition, each antigen receptor gene rearrangement produces a unique DNA sequence that constitutes a highly specific clonal marker, which can be used to detect small numbers of residual malignant lymphoid cells after therapy

Answer 120

( Fig. 13-5 ), a feature that is used in their classification. The vast majority (85% to 90%) of lymphoid neoplasms are of B-cell origin, with most of the remainder being T-cell tumors; only rarely are tumors of NK cell origin encountered. Markers recognized by antibodies that are helpful in the characterization of lymphomas and leukemias are listed in Table 13-5

Answer 121

Stages of B- and T-cell differentiation from which specific lymphoid tumors emerge are shown. CLP, Common lymphoid precursor; BLB, pre-B lymphoblast; 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.

Answer 122

Thymocytes and Langerhans cells

Answer 123

Thymocytes, mature T cells

Answer 124

Helper T cells, subset of thymocytes

Answer 125

T cells and a small subset of B cells

Answer 126

Cytotoxic T cells, subset of thymocytes, and some NK cells

Answer 127

Pre-B cells and germinal-center B cells

Answer 128

Pre-B cells and mature B cells but not plasma cells

Answer 129

Pre-B cells after CD19 and mature B cells but not plasma cells

Answer 130

EBV receptor; mature B cells and follicular dendritic cells

Answer 131

Activated mature B cells

Answer 132

Marrow pre-B cells and mature B cells

Answer 133

Granulocytes, monocytes, and macrophages; also expressed by hairy cell leukemias

Answer 134

Immature and mature monocytes and granulocytes

Answer 135

Granulocytes; Reed-Sternberg cells and variants

Answer 136

Myeloid progenitors and monocytes

Answer 137

Mature myeloid cells

Answer 138

NK cells and granulocytes

Answer 139

NK cells and a subset of T cells

Answer 140

Pluripotent hematopoietic stem cells and progenitor cells of many lineages

Answer 141

Activated B cells, T cells, and monocytes; Reed-Sternberg cells and variants

Answer 142

All leukocytes; also known as leukocyte common antigen (LCA)

Answer 143

Both a loss of protective immunity (susceptibility to infection) and a breakdown of tolerance (autoimmunity) can be seen, sometimes in the same patient. In a further ironic twist, individuals with inherited or acquired immunodeficiency are themselves at high risk of developing certain lymphoid neoplasms, particularly those caused by oncogenic viruses (e.g., EBV

Answer 144

s. Like normal lymphocytes, neoplastic B and T cells home to certain tissue sites, leading to characteristic patterns of involvement. For example, follicular lymphomas home to germinal centers in lymph nodes, whereas cutaneous T-cell lymphomas home to the skin. Like their normal counterparts, particular adhesion molecules and chemokine receptors govern the homing of the neoplastic lymphoid cells. Variable numbers of neoplastic B and T lymphoid cells also recirculate through the lymphatics and peripheral blood to distant sites; as a result most lymphoid tumors are widely disseminated at the time of diagnosis. Notable exceptions to this rule include Hodgkin lymphomas, which are sometimes restricted to one group of lymph nodes, and marginal zone B-cell lymphomas, which are often restricted to sites of chronic inflammation

Answer 145

Hence, while lymphoma staging provides generally useful prognostic information, it is of most utility in guiding therapy in Hodgkin lymphoma

Answer 146

Bone marrow precursor B cell Diverse chromosomal translocations; t(12;21) involving RUNX1 and ETV 6 present in 25% Predominantly children; symptoms relating to marrow replacement and pancytopenia; aggressive

Answer 147

Precursor T cell (often of thymic origin) Diverse chromosomal translocations, NOTCH1 mutations (50%-70%) Predominantly adolescent males; thymic masses and variable bone marrow involvement; aggressive

Answer 148

Germinal-center B cell Translocations involving MYC and lg loci, usually t(8;14); subset EBV-associated Adolescents or young adults with extranodal masses; uncommonly presents as “leukemia”; aggressive

Answer 149

erminal-center or postgerminal center B cell Diverse chromosomal rearrangements, most often of BCL6 (30%), BCL2 (10%), or MYC (5%) All ages, but most common in older adults; often appears as a rapidly growing mass; 30% extranodal; aggressive

Answer 150

Memory B cell t(11;18), t(1;14), and t(14;18) creating MALT1-IAP2, BCL10-IgH , and MALT1-IgH fusion genes, respectively Arises at extranodal sites in adults with chronic inflammatory diseases; may remain localized; indolent

Answer 151

Germinal-center B cell t(14;18) creating BCL2-IgH fusion gene Older adults with generalized lymphadenopathy and marrow involvement; indolent

Answer 152

Memory B cell Activating BRAF mutations Older males with pancytopenia and splenomegaly; indolent

Answer 153

Naive B cell t(11;14) creating CyclinD1 - IgH fusion gene Older males with disseminated disease; moderately aggressive

Answer 154

Post-germinal-center bone marrow homing plasma cell Diverse rearrangements involving IgH ; 13q deletions Myeloma: older adults with lytic bone lesions, pathologic fractures, hypercalcemia, and renal failure; moderately aggressive Plasmacytoma: isolated plasma cell masses in bone or soft tissue; indolent

Answer 155

Naive B cell or memory B cell Trisomy 12, deletions of 11q, 13q, and 17p Older adults with bone marrow, lymph node, spleen, and liver disease; autoimmune hemolysis and thrombocytopenia in a minority; indolent

Answer 156

Helper T cell HTLV-1 provirus present in tumor cells Adults with cutaneous lesions, marrow involvement, and hypercalcemia; occurs mainly in Japan, West Africa, and the Caribbean; aggressive

Answer 157

Helper or cytotoxic T cell No specific chromosomal abnormality Mainly older adults; usually presents with lymphadenopathy; aggressive

Answer 158

Cytotoxic T cell Rearrangements of ALK (anaplastic large cell lymphoma kinase) in a subset Children and young adults, usually with lymph node and soft-tissue disease; aggressive

Answer 159

NK-cell (common) or cytotoxic T cell (rare) EBV-associated; no specific chromosomal abnormality Adults with destructive extranodal masses, most commonly sinonasal; aggressive

Answer 160

Helper T cell No specific chromosomal abnormality Adult patients with cutaneous patches, plaques, nodules, or generalized erythema; indolent

Answer 161

Two types: cytotoxic T cell and NK cell Point mutations in STAT3 Adult patients with splenomegaly, neutropenia, and anemia, sometimes, accompanied by autoimmune disease

Answer 162

. About 85% are B-ALLs, which typically manifest as childhood acute “leukemias.” The less common T-ALLs tend to present in adolescent males as thymic “lymphomas.” There is, however, considerable overlap in the clinical behavior of B- and T-ALL; for example, B-ALL uncommonly presents as a mass in the skin or a bone, and many T-ALLs present with or evolve to a leukemic picture. Because of their morphologic and clinical similarities, the various forms of ALL will be considered here together

Answer 163

Approximately 2500 new cases are diagnosed each year in the United States, most occurring in individuals younger than 15 years of age. ALL is almost three times as common in whites as in blacks and is slightly more frequent in boys than in girls. Hispanics have the highest incidence of any ethnic group. B-ALL peaks in incidence at about the age of 3, perhaps because the number of normal bone marrow pre-B cells (the cell of origin) is greatest very early in life. Similarly the peak incidence of T-ALL is in adolescence, the age when the thymus reaches maximum size. B- and T-ALL also occur less frequently in adults of all ages

Answer 164

Up to 70% of T-ALLs have gain-of-function mutations in NOTCH1 , a gene that is essential for T-cell development. On the other hand, a high fraction of B-ALLs have loss-of-function mutations in genes that are required for B-cell development, such as PAX5 , E2A , and EBF , or a balanced t(12;21) involving the genes ETV6 and RUNX1 , two genes that are needed in very early hematopoietic precursors. All of these varied mutations disturb the differentiation of lymphoid precursors and promote maturation arrest, and in doing they induce increased self-renewal, a stem cell–like phenotype. Similar themes are relevant in the genesis of AML (discussed later

Answer 165

The identity of these complementary mutations is incomplete, but aberrations that drive cell growth, such as mutations that increase tyrosine kinase activity and RAS signaling, are commonly present. Emerging data from deep sequencing of ALL genomes is rapidly filling in the remaining gaps. Early returns suggest that fewer than 10 mutations are sufficient to produce full-blown ALL; hence, compared to solid tumors, ALL is a genetically simple tumor

Answer 166

Changes in chromosome numbers are of uncertain pathogenic significance, but are important because they frequently correlate with immunophenotype and sometimes prognosis. For example, hyperdiploidy and hypodiploidy are seen only in B-ALL. In addition, B- and T-ALL are associated with completely different sets of translocations, indicating that they are pathogenetically distinct

Answer 167

In both B- and T-ALL, the tumor cells have scant basophilic cytoplasm and nuclei somewhat larger than those of small lymphocytes ( Fig. 13-6 A ). The nuclear chromatin is delicate and finely stippled, and nucleoli are usually small and often demarcated by a rim of condensed chromatin. In many cases the nuclear membrane is 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 in Fig. 13-15 ).

Answer 168

Compared with myeloblasts, lymphoblasts have more condensed chromatin, less conspicuous nucleoli, and smaller amounts of cytoplasm that usually lacks granules. However, these morphologic distinctions are not absolute and definitive diagnosis relies on stains performed with antibodies specific for B- and T-cell antigens ( Fig. 13-6 B and C ). Histochemical stains are also helpful, in that (in contrast to myeloblasts) lymphoblasts are myeloperoxidase-negative and often contain periodic acid-Schiff–positive cytoplasmic material

Answer 169

B-ALLs are arrested at various stages of pre–B-cell development. The lymphoblasts usually express the pan B-cell marker CD19 and the transcription factor PAX5, as well as CD10. In very immature B-ALLs, CD10 is negative. Alternatively, more mature “late pre-B” ALLs express CD10, CD19, CD20, and cytoplasmic IgM heavy chain (µ chain

Answer 170

within days to a few weeks of the first symptoms

Answer 171

including fatigue due to anemia; fever, reflecting infections secondary to neutropenia; and bleeding due to thrombocytopenia

Answer 172

including bone pain resulting from marrow expansion and infiltration of the subperiosteum; generalized lymphadenopathy, splenomegaly, and hepatomegaly; testicular enlargement; and in T-ALL, complications related to compression of large vessels and airways in the mediastinum

Answer 173

S uch as headache, vomiting, and nerve palsies resulting from meningeal spread, all of which are also more common in ALL

Answer 174

With aggressive chemotherapy about 95% of children with ALL obtain a complete remission, and 75% to 85% are cured. Despite these achievements, however, ALL remains the leading cause of cancer deaths in children, and only 35% to 40% of adults are cured. Several factors are associated with a worse prognosis: (1) age younger than 2 years, largely because of the strong association of infantile ALL with translocations involving the MLL gene; (2) presentation in adolescence or adulthood; and (3) peripheral blood blast counts greater than 100,000, which probably reflects a high tumor burden. Favorable prognostic markers include (1) age between 2 and 10 years, (2) a low white cell count, (3) hyperdiploidy, (4) trisomy of chromosomes 4, 7, and 10, and (5) the presence of a t(12;21). Notably, the molecular detection of residual disease after therapy is predictive of a worse outcome in both B- and T-ALL and is being used to guide new clinical tria

Answer 175

. In B-ALL, the BCR-ABL protein is usually 190 kDa in size and has stronger tyrosine kinase activity than the form of BCR-ABL that is found in chronic myelogenous leukemia, in which a BCR-ABL protein of 210 kDa in size is usually seen. Treatment of t(9;22)-positive ALLs with BCR-ABL kinase inhibitors in combination with conventional chemotherapy is highly effective and has greatly improved the outcome for this molecular subtype of B-ALL in children. The outlook for adults with ALL remains more guarded, in part because of differences in the molecular pathogenesis of adult and childhood ALL, but also because older adults cannot tolerate the very intensive chemotherapy regimens that are curative in children.

Answer 176

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) differ only in the degree of peripheral blood lymphocytosis. Most affected patients have sufficient lymphocytosis to fulfill the diagnostic requirement for CLL (absolute lymphocyte count > 5000 per mm 3 ). CLL is the most common leukemia of adults in the Western world. There are about 15,000 new cases of CLL each year in the United States. The median age at diagnosis is 60 years, and there is a 2 : 1 male predominance. In contrast, SLL constitutes only 4% of NHLs. CLL/SLL is much less common in Japan and other Asian countries than in the West

Answer 177

Molecular characterization of the region deleted on chromosome 13 has implicated two microRNAs, miR-15a and miR-16-1, as possible tumor suppressor genes. DNA sequencing has revealed that the Ig genes of some CLL/SLL are somatically hypermutated, whereas others are not, suggesting that the cell of origin may be either a postgerminal center memory B cell or a naive B cell. For unclear reasons, tumors with unmutated Ig segments (those putatively of naive B-cell origin) pursue a more aggressive course. Deep sequencing of CLL genomes has also revealed gain-of-function mutations involving the NOTCH1 receptor in 10% to 18% of tumors, as well as frequent mutations in genes that regulate RNA splicing.

Answer 178

Stromal cells in proliferation centers seem to express a variety of factors that stimulate the activity of the transcription factor NF-κB, which promotes cell growth and survival. In addition, experimental models of CLL suggest that tumor cells rely on signals generated by the B-cell receptor (membrane bound immunoglobulin) for growth and survival. These signals are transduced by a cascade of kinases that include the Bruton tyrosine kinase (BTK), which is defective in patients with congenital X-linked agammaglobulinemia ( Chapter 6 ). Of note, BTK inhibitors now being tested in clinical trials have produced sustained responses in a high fraction of CLL patients, indicating that human CLL cells are also dependent on this signaling pathway.

Answer 179

Admixed are variable numbers of larger activated lymphocytes that often gather in loose aggregates referred to as proliferation centers , which contain mitotically active cells. When present, proliferation centers are pathognomonic for CLL/SLL . The blood contains large numbers of small round lymphocytes with scant cytoplasm ( Fig. 13-8 ). Some of these cells are usually disrupted in the process of making smears, producing so-called smudge cells . The bone marrow is almost always involved by interstitial infiltrates or aggregates of tumor cells. Infiltrates are also virtually always seen in the splenic white and red pulp and the hepatic portal tracts ( Fig. 13-9 ).

Answer 180

CLL/SLL has a distinctive immunophenotype. The tumor cells express the pan B-cell markers CD19 and CD20, as well as CD23 and CD5, the latter a marker that is found on a small subset of normal B cells. Low-level expression of surface Ig (usually IgM or IgM and IgD) is also typical

Answer 181

Generalized lymphadenopathy and hepatosplenomegaly are present in 50% to 60% of symptomatic patients. The leukocyte count is highly variable; leukopenia can be seen in individuals with SLL and marrow involvement, while counts in excess of 200,000/mm 3 are sometimes seen in CLL patients with heavy tumor burdens. A small monoclonal Ig “spike” is present in the blood of some patients. At the other end of the spectrum are asymptomatic patients with monoclonal B cells in their peripheral blood but in numbers that are too few to merit the diagnosis of CLL. These abnormal B cells often have some of the same genetic aberrations that are seen in CLL, such as 13q deletions and trisomy 12, yet only about 1% of such patients progress to symptomatic CLL per year, presumably due to acquisition of additional genetic lesions

Answer 182

Hypogammaglobulinemia is common and contributes to an increased susceptibility to infections, particularly those caused by bacteria. Conversely, 10% to 15% of patients develop hemolytic anemia or thrombocytopenia due to autoantibodies made by nonneoplastic B cells

Answer 183

Other variables that correlate with a worse outcome include (1) the presence of deletions of 11q and 17p, (2) a lack of somatic hypermutation, (3) the expression of ZAP-70, a protein that augments signals produced by the Ig receptor, and (4) the presence of NOTCH1 mutations. Symptomatic patients are generally treated with “gentle” chemotherapy and immunotherapy with antibodies against proteins found on the surface of CLL/SLL cells, particularly CD20. Hematopoietic stem cell transplantation is being offered to the relatively young. The most promising new therapy is BTK inhibitors, described earli

Answer 184

Most commonly this takes the form of a transformation to diffuse large B-cell lymphoma, so-called Richter syndrome (approximately 5% to 10% of patients). Transformation to diffuse large B-cell lymphoma is often heralded by the development of a rapidly enlarging mass within a lymph node or the spleen. Transformation probably stems from the acquisition of additional, still mutations that increase growth. Large-cell transformation is an ominous event, with most patients surviving less than 1 year.

Answer 185

It usually presents in middle age and afflicts males and females equally. It is less common in Europe and rare in Asian populations.

Answer 186

Its hallmark is a (14;18) translocation that juxtaposes the IGH locus on chromosome 14 and the BCL2 locus on chromosome 18. The t(14;18) is seen in up to 90% of follicular lymphomas, and leads to overexpression of BCL2 (see Fig. 13-12 ). BCL2 antagonizes apoptosis ( Chapter 7 ) and promotes the survival of follicular lymphoma cells. Notably, while normal germinal centers contain numerous B cells undergoing apoptosis, follicular lymphoma is characteristically devoid of apoptotic cells. Deep sequencing of follicular lymphoma genomes have identified mutations in the MLL2 gene in about 90% of cases as well. MLL2 encodes a histone methyltransferase that regulates gene expression, suggesting that epigenetic abnormalities have an important role in this neoplasm; however, the functional significance of MLL2 mutations has yet to be deciphered

Answer 187

Expression profiling studies have shown that differences in the genes expressed by these reactive cells are predictive of outcome, implying that the response of follicular lymphoma cells to therapy is influenced by the surrounding microenvironment.

Answer 188

Two principal cell types are present in varying proportions: (1) small cells with irregular or cleaved nuclear contours and scant cytoplasm, referred to as centrocytes (small cleaved cells); and (2) larger cells with open nuclear chromatin, several nucleoli, and modest amounts of cytoplasm, referred to as centroblasts ( Fig. 13-10 B ). In most follicular lymphomas, small cleaved cells are in the majority. Peripheral blood involvement sufficient to produce lymphocytosis (usually less than 20,000 cells/mm 3 ) is seen in about 10% of cases. Bone marrow involvement occurs in 85% of cases and characteristically takes the form of paratrabecular lymphoid aggregates. The splenic white pulp ( Fig. 13-11 ) and hepatic portal triads are also frequently involved.

Answer 189

, Nodular aggregates of lymphoma cells are present throughout lymph node. B, At high magnification, small lymphoid cells with condensed chromatin and irregular or cleaved nuclear outlines (centrocytes) are mixed with a population of larger cells with nucleoli (centroblasts).

Answer 190

Prominent nodules represent white pulp follicles expanded by follicular lymphoma cells. Other indolent B-cell lymphomas (small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma) can produce an identical pattern of involvement

Answer 191

BCL2 is expressed in more than 90% of cases, in distinction to normal follicular center B cells, which are BCL2-negative ( Fig. 13-12 ).

Answer 192

BCL2 protein was detected by using an immunohistochemical technique that produces a brown stain. In reactive follicles (A), BCL2 is present in mantle zone cells but not follicular-center B cells, whereas follicular lymphoma cells (B) show strong BCL2 staining.

Answer 193

tends to present with painless, generalized lymphadenopathy. Involvement of extranodal sites, such as the gastrointestinal tract, central nervous system, or testis, is relatively uncommon. Although incurable, it usually follows an indolent waxing and waning course. Survival (median, 7 to 9 years) is not improved by aggressive therapy; hence, the usual approach is to palliate patients with low-dose chemotherapy or immunotherapy (e.g., anti-CD20 antibody) when they become symptomatic.

Answer 194

in 30% to 50% of follicular lymphomas, most commonly to diffuse large B-cell lymphoma. Less commonly, tumors resembling Burkitt lymphoma emerge that are associated with chromosomal translocations involving MYC . Like normal germinal center B cells, follicular lymphomas have ongoing somatic hypermutation, which may promote transformation by causing point mutations or chromosomal aberrations. The median survival is less than 1 year after transformation.

Answer 195

Each year in the United States there are about 25,000 new cases. There is a slight male predominance. The median patient age is about 60 years, but DLBCL also occurs in young adults and children

Answer 196

One frequent pathogenic event is dysregulation of BCL6, a DNA-binding zinc-finger transcriptional repressor that is required for the formation of normal germinal centers. About 30% of DLBCLs contain various translocations that have in common a breakpoint in BCL6 at chromosome 3q27. Acquired mutations in BCL6 promoter sequences that abrogate BCL6 autoregulation (an important negative-regulatory mechanism) are seen even more frequently. It is hypothesized that both types of lesions are inadvertent byproducts of somatic hypermutation that result in overexpression of BCL6 , which has several important consequences. BCL6 represses the expression of factors that normally serve to promote germinal center B-cell differentiation, growth arrest, and apoptosis, and each of these effects is believed to contribute to the development of DLBCL. Mutations similar to those found in BCL6 are also seen in multiple other oncogenes, including MYC , suggesting that somatic hypermutation in DLBCL cells is “mistargeted” to a wide variety of loci.

Answer 197

Tumors with BCL2 rearrangements usually lack BCL6 rearrangements, suggesting that these rearrangements define two distinct molecular classes of DLBCL. Some tumors with BCL2 rearrangements may arise from unrecognized underlying follicular lymphomas, which frequently transform to DLBCL. Roughly 5% of DLBCLs are associated with translocations involving MYC ; these tumors may have a distinctive biology and are discussed further under Burkitt Lymphoma (later). Finally, deep sequencing of DLBCL genomes has identified frequent mutations in genes encoding histone acetyltransferases such as p300 and CREBP, proteins that regulate gene expression by modifying histones and altering chromatin structure. This association has sparked interest in using drugs that target the epigenome as therapies for DLBCL.

Answer 198

In other respects, substantial morphologic variation is seen. Most commonly, the tumor cells have a round or oval nucleus that appears vesicular due to margination of chromatin to the nuclear membrane, but large multilobated or cleaved nuclei are prominent in some cases. Nucleoli may be two to three in number and located adjacent to the nuclear membrane, or single and centrally placed. The cytoplasm is usually moderately abundant and may be pale or basophilic. More anaplastic tumors may even contain multinucleated cells with large inclusion-like nucleoli that resemble Reed-Sternberg cells (the malignant cell of Hodgkin lymphoma).

Answer 199

These mature B-cell tumors express CD19 and CD20 and show variable expression of germinal center B-cell markers such as CD10 and BCL6. Most have surface Ig

Answer 200

Immunodeficiency associated large B cell lymphoma Primary effusion lymphoma

Answer 201

occurs in the setting of severe T-cell immunodeficiency (e.g., advanced HIV infection and allogeneic bone marrow transplantation). The neoplastic B cells are usually infected with EBV, which plays a critical pathogenic role. Restoration of T-cell immunity may lead to regression of these proliferations

Answer 202

presents as a malignant pleural or ascitic effusion, mostly in patients with advanced HIV infection or older adults. The tumor cells are often anaplastic in appearance and typically fail to express surface B- or T-cell markers, but have clonal IgH gene rearrangements. In all cases the tumor cells are infected with KSHV/HHV-8 , which appears to have a causal role

Answer 203

DLBCL typically presents as a rapidly enlarging mass at a nodal or extranodal site. It can arise virtually anywhere in the body. Waldeyer ring, the oropharyngeal lymphoid tissue that includes the tonsils and adenoids, is involved commonly. Primary or secondary involvement of the liver and spleen may take the form of large destructive masses ( Fig. 13-14 ). Extranodal sites include the gastrointestinal tract, skin, bone, brain, and other tissues. Bone marrow involvement is relatively uncommon and usually occurs late in the course. Rarely, a leukemic picture emerges

Answer 204

DLBCLs are aggressive tumors that are rapidly fatal without treatment. With intensive combination chemotherapy, 60% to 80% of patients achieve a complete remission, and 40% to 50% are cured. Adjuvant therapy with anti-CD20 antibody improves both the initial response and the overall outcome. Individuals with limited disease fare better than those with widespread disease or bulky tumor masses. Expression profiling has identified distinct molecular subtypes with differing clinical outcomes and has provided the rationale for new therapies directed at inhibiting the NF-κB and B cell receptor signaling pathways. Of note, about 5% of DLBCLs have MYC translocations, and these cases of DLBCL may be difficult to distinguish from Burkitt lymphoma (described later) by conventional diagnostic tests. In fact, recent data suggest that DLBCLs with MYC translocations have a worse prognosis than those without and may be better treated with chemotherapy regimens that are now standard for Burkitt lymphoma

Answer 205

Within the category of Burkitt Lymphoma fall (1) African (endemic) Burkitt lymphoma, (2) sporadic (nonendemic) Burkitt lymphoma, and (3) a subset of aggressive lymphomas occurring in individuals infected with HIV. Burkitt lymphomas occurring in each of these settings are histologically identical but differ in some clinical, genotypic, and virologic characteristics

Answer 206

MYC is a master transcriptional regulator that increases the expression of genes that are required for aerobic glycolysis, the so-called Warburg effect ( Chapter 7 ). When nutrients such as glucose and glutamine are available, Warburg metabolism allow cells to biosynthesize all of the building blocks—nucleotides, lipids, proteins—that are needed for growth and cell division. Consequently, Burkitt lymphoma is believed to be the fastest growing human tumor. The translocation partner for MYC is usually the IgH locus [t(8;14)] but may also be the Ig κ [t(2;8)] or λ [t(8;22)] light chain loci. The breakpoints in the IgH locus in sporadic Burkitt lymphoma are usually found in the class switch regions, whereas the breakpoints in endemic Burkitt lymphoma tend to lie within more 5′ V(D)J sequences. The basis for this subtle molecular distinction is not known, but both types of translocations can be induced in germinal center B cells by AID, a specialized DNA-modifying enzyme required for both Ig class switching and somatic hypermutation (see earlier). The net effect of these translocations is similar; the MYC coding sequence is repositioned adjacent to strong Ig promoter and enhancer elements, which drive increased MYC expression. In addition, the translocated MYC allele often harbors point mutations that further increase its activity.

Answer 207

The configuration of the EBV DNA is identical in all tumor cells within individual cases, indicating that infection precedes transformation. Although this places EBV at the “scene of the crime,” its precise role in the genesis of Burkitt lymphoma remains poorly understood.

Answer 208

Involved tissues are effaced by a diffuse infiltrate of intermediate-sized lymphoid cells 10 to 25 µm in diameter with round or oval nuclei, coarse chromatin, several nucleoli, and a moderate amount of cytoplasm ( Fig. 13-15 ). The tumor exhibits a high mitotic index and contains numerous apoptotic cells , the nuclear remnants of which are phagocytosed by interspersed benign macrophages. These phagocytes have abundant clear cytoplasm, creating a characteristic “starry sky” pattern . When the bone marrow is involved, aspirates reveal tumor cells with slightly clumped nuclear chromatin, two to five distinct nucleoli, and royal blue cytoplasm containing clear cytoplasmic vacuoles

Answer 209

Burkitt lymphoma. A, At low power, numerous pale tingible body macrophages are evident, producing a “starry sky” appearance. B, At high power, tumor cells have multiple small nucleoli and high mitotic index. The lack of significant variation in nuclear shape and size lends a monotonous appearance.

Answer 210

These are tumors of mature B cells that express surface IgM, CD19, CD20, CD10, and BCL6, a phenotype consistent with a germinal center B-cell origin. Unlike other tumors of germinal center origin, Burkitt lymphoma almost always fails to express the antiapoptotic protein BCL2

Answer 211

Both endemic and sporadic Burkitt lymphomas are found mainly in children or young adults; overall, it accounts for about 30% of childhood NHLs in the United States. Most tumors manifest at extranodal sites . Endemic Burkitt lymphoma often presents as a mass involving the mandible and shows an unusual predilection for involvement of abdominal viscera, particularly the kidneys, ovaries, and adrenal glands. In contrast, sporadic Burkitt lymphoma most often appears as a mass involving the ileocecum and peritoneum. Involvement of the bone marrow and peripheral blood is uncommon, especially in endemic cases

Answer 212

Burkitt lymphoma is very aggressive but responds well to intensive chemotherapy. Most children and young adults can be cured. The outcome is more guarded in older adults

Answer 213

▪ Most common type of cancer in children, may be derived from either precursor B of T cells ▪ Highly aggressive tumors manifest with signs and symptoms of bone marrow failure, or as rapidly growing masses. ▪ Tumor cells contain genetic lesions that block differentiation, leading to the accumulation of immature, nonfunctional blasts

Answer 214

▪ Most common leukemia of adults ▪ Tumor of mature B cells that usually manifests with bone marrow and lymph node involvement ▪ Indolent course, commonly associated with immune abnormalities, including an increased susceptibility to infection and autoimmune disorders

Answer 215

Most common indolent lymphoma of adults ▪ Tumor cells recapitulate the growth pattern of normal germinal center B cells; most cases are associated with a (14;18) translocation that results in the overexpression of BCL2

Answer 216

Most common lymphoma of adults ▪ Heterogeneous group of mature B-cell tumors that shares a large cell morphology and aggressive clinical behavior ▪ Rearrangements or mutations of BCL6 gene are recognized associations; one third carry a (14;18) translocation involving BCL2 and may arise from follicular lymphomas

Answer 217

Very aggressive tumor of mature B cells that usually arises at extranodal sites. ▪ Strongly associated with translocations involving the MYC proto-oncogene ▪ Tumor cells often are latently infected by EBV

Answer 218

These B-cell proliferations contain neoplastic plasma cells that virtually always secrete a monoclonal Ig or Ig fragment, which serve as tumor markers and often have pathologic consequences. Collectively, the plasma cell neoplasms (often referred to as dyscrasias ) account for about 15% of the deaths caused by lymphoid neoplasms. The most common and deadly of these neoplasms is multiple myeloma, of which there are about 15,000 new cases per year in the United States.

Answer 219

Because complete M components have molecular weights of 160,000 or higher, they are restricted to the plasma and extracellular fluid and excluded from the urine in the absence of glomerular damage

Answer 220

Hence jones protein

Answer 221

• Multiple myeloma (plasma cell myeloma) , the most important plasma cell neoplasm, usually presents as tumorous masses scattered throughout the skeletal system

Answer 222

Solitary myeloma ( plasmacytoma ) is an infrequent variant that presents as a single mass in bone or soft tissue

Answer 223

S moldering myeloma refers to another uncommon variant defined by a lack of symptoms and a high plasma M component

Answer 224

is a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood. It occurs in older adults, most commonly in association with lymphoplasmacytic lymphoma (described later)

Answer 225

is a rare monoclonal gammopathy that is seen in association with a diverse group of disorders, including lymphoplasmacytic lymphoma and an unusual small bowel marginal zone lymphoma that occurs in malnourished populations (so-called Mediterranean lymphoma ). The common feature is the synthesis and secretion of free heavy-chain fragments.

Answer 226

sis results from a monoclonal proliferation of plasma cells secreting light chains (usually of λ isotype) that are deposited as amyloid. Some patients have overt multiple myeloma, but others have only a minor clonal population of plasma cells in the marrow

Answer 227

is applied to patients without signs or symptoms who have small to moderately large M components in their blood. MGUS is very common in older adults and has a low but constant rate of transformation to symptomatic monoclonal gammopathies, most often multiple myeloma

Answer 228

Multiple myeloma is a plasma cell neoplasm commonly associated with lytic bone lesions, hypercalcemia, renal failure, and acquired immune abnormalities. Although bony disease dominates, it can spread late in its course to lymph nodes and extranodal sites . Multiple myeloma causes 1% of all cancer deaths in Western countries. Its incidence is higher in men and people of African descent. It is chiefly a disease of older adults, with a peak age of incidence of 65 to 70 years.

Answer 229

Multiple myeloma is associated with frequent rearrangements involving the IgH locus and various proto-oncogenes. Included among the loci that are recurrently involved in translocations with the Ig heavy-chain gene on chromosome 14q32 are the cell cycle-regulatory genes cyclin D1 on chromosome 11q13 and cyclin D3 on chromosome 6p21. Deletions of chromosome 17p that involve the TP53 tumor suppressor locus also occur and are associated with a poor outcome. Late-stage, highly aggressive forms of the disease such as plasma cell leukemia are associated with acquisition of rearrangements involving MYC . More recent deep sequencing of myeloma genomes has identified frequent mutations involving components of the NF-κB pathway, which supports B-cell survival. Based on these studies, it is evident that myeloma molecularly heterogeneous

Answer 230

IL-6 is an important growth factor for plasma cells. It is produced by the tumor cells themselves and by resident marrow stromal cells. High serum levels of IL-6 are seen in patients with active disease and are associated with a poor prognosis. Myeloma cell growth and survival are also augmented by direct physical interactions with bone marrow stromal cells, which is a focus of new therapeutic approaches.

Answer 231

. Of particular importance, myeloma-derived MIP1α up-regulates the expression of the receptor activator of NF-κB ligand (RANKL) by bone marrow stromal cells, which in turn activates osteoclasts. Other factors released from tumor cells, such as modulators of the Wnt pathway, are potent inhibitors of osteoblast function. The net effect is a marked increase in bone resorption, which leads to hypercalcemia and pathologic fractures.

Answer 232

he bones most commonly affected (in descending order of frequency) are the vertebral column, ribs, skull, pelvis, femur, clavicle, and scapula. Lesions begin in the medullary cavity, erode cancellous bone, and progressively destroy the bony cortex, often leading to pathologic fractures; these are most common in the vertebral column, but may occur in any affected bo

Answer 233

, and consist of soft, gelatinous, red tumor masses. Less commonly, widespread myelomatous bone disease produces diffuse demineralization (osteopenia) rather than focal defects.

Answer 234

Multiple myeloma of the skull (radiograph, lateral view). The sharply punched-out bone lesions are most obvious in the calvarium

Answer 235

The plasma cells may infiltrate the interstitium or be present in sheets that completely replace normal elements. Like their benign counterparts, malignant plasma cells have a perinuclear clearing due to a prominent Golgi apparatus and an eccentrically placed nucleus ( Fig. 13-17 ). Relatively normal-appearing plasma cells, plasmablasts with vesicular nuclear chromatin and a prominent single nucleolus, or bizarre, multinucleated cells may predominate. Other cytologic variants stem from the dysregulated synthesis and secretion of Ig, which often leads to intracellular accumulation of intact or partially degraded protein. Such variants include flame cells with fiery red cytoplasm, Mott cells with multiple grapelike cytoplasmic droplets, and cells containing a variety of other inclusions, including fibrils, crystalline rods, and globules . The globular inclusions are referred to as Russell bodies (if cytoplasmic) or Dutcher bodies (if nuclear). In advanced disease, plasma cell infiltrates may be present in the spleen, liver, kidneys, lungs, lymph nodes, and other soft tissues.

Answer 236

Multiple myeloma (bone marrow aspirate). Normal marrow cells are largely replaced by plasma cells, including forms with multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing

Answer 237

Rouleaux formation is characteristic but not specific, as it may be seen in other conditions in which Ig levels are elevated, such as lupus erythematosus and early HIV infection. Rarely, tumor cells flood the peripheral blood, giving rise to plasma cell leukemia .

Answer 238

myeloma kidney . This important complication is discussed in detail in Chapter 2

Answer 239

Plasma cell tumors are positive for CD138, an adhesion molecule also known as syndecan-1, and often express CD56, a feature that can be helpful in identifying small populations of neoplastic cells

Answer 240

The clinical features of multiple myeloma stem from (1) the effects of plasma cell growth in tissues, particularly the bones; (2) the production of excessive Igs, which often have abnormal physicochemical properties; and (3) the suppression of normal humoral immunity

Answer 241

Bone resorption often leads to pathologic fractures and chronic pain . The attendant hypercalcemia can give rise to neurologic manifestations, such as confusion, weakness, lethargy, constipation, and polyuria, and contributes to renal dysfunction. Decreased production of normal Igs sets the stage for recurrent bacterial infections. Cellular immunity is relatively unaffected. Of great significance is renal insufficiency, which trails only infections as a cause of death. The pathogenesis of renal failure ( Chapter 20 ), which occurs in up to 50% of patients, is multifactorial. However, the single most important factor seems to be Bence-Jones proteinuria , as the excreted light chains are toxic to renal tubular epithelial cells. Certain light chains (particularly those of the λ6 and λ3 families) are prone to cause amyloidosis of the AL type ( Chapter 6 ), which can exacerbate renal dysfunction and deposit in other tissues as wells

Answer 242

In 99% of patients, laboratory analyses reveal increased levels of Igs in the blood and/or light chains (Bence-Jones proteins) in the urine. The monoclonal Igs are usually first detected as abnormal protein “spikes” in serum or urine electrophoresis and then further characterized by immunofixation ( Fig. 13-18 ). Most myelomas are associated with more than 3 gm/dL of serum Ig and/or more than 6 mg/dL of urine Bence-Jones protein. The most common monoclonal Ig (“M protein”) is IgG (approximately 55% of patients), followed by IgA (approximately 25% of cases). Myelomas expressing IgM, IgD, or IgE occur but are rare. Excessive production and aggregation of M proteins, usually of the IgA and or IgG 3 subtype, leads to symptoms related to hyperviscosity (described under lymphoplasmacytic lymphoma) in about 7% of patients. Both free light chains and a serum M protein are observed together in 60% to 70% of patients. However, in about 20% of patients only free light chains are present. Around 1% of myelomas are nonsecretory; hence, the absence of detectable M proteins does not completely exclude the diagnosis

Answer 243

Figure 13-18 M protein detection in multiple myeloma. Serum protein electrophoresis (SP) is used to screen for a monoclonal immunoglobulin (M protein). Polyclonal IgG in normal serum ( arrow ) appears as a broad band; in contrast, serum from a patient with multiple myeloma contains a single sharp protein band ( arrowhead ) in this region of the electropherogram. The suspected monoclonal Ig is confirmed and characterized by immunofixation. In this procedure, proteins separated by electrophoresis within a gel are reacted with specific antisera. After extensive washing, proteins that are cross-linked by antisera are retained and detected with a protein stain. Note the sharp band in the patient serum is cross-linked by antisera specific for IgG heavy chain (G) and kappa light chain (κ), indicating the presence of an IgGκ M protein. Levels of polyclonal IgG, IgA (A), and lambda light chain (λ) are also decreased in the patient serum relative to normal, a finding typical of multiple myeloma.

Answer 244

The clinicopathologic diagnosis of multiple myeloma rests on radiographic and laboratory findings. It can be strongly suspected when the distinctive radiographic changes are present, but definitive diagnosis requires a bone marrow examination. Marrow involvement often gives rise to a normocytic normochromic anemia, sometimes accompanied by moderate leukopenia and thrombocytopenia

Answer 245

The prognosis is variable, but has improved in recent years with new therapeutic approaches. The median survival is 4 to 7 years, and cures have yet to be achieved. Patients with multiple bony lesions, if untreated, rarely survive for more than 6 to 12 months, whereas patients with “smoldering myeloma” may be asymptomatic for many years. Translocations involving cyclin D1 are associated with a good outcome, whereas deletions of 13q, deletions of 17p, and the t(4;14) all portend a more aggressive course

Answer 246

New therapies are bringing hope. Myeloma cells are sensitive to inhibitors of the proteasome, a cellular organelle that degrades unwanted and misfolded proteins. As discussed in Chapter 2 , misfolded proteins activate apoptotic pathways. Myeloma cells are prone to the accumulation of misfolded, unpaired Ig chains. Proteasome inhibitors may induce cell death by exacerbating this inherent tendency, and also seem to retard bone resorption through effects on stromal cells. Thalidomide and related compounds such as lenalidomide also have activity against myeloma. Interestingly, this may also involve changes in protein degradation, as lenalidamide appears to activate ubiquitin ligases, thereby targeting proteins for proteolysis that are required for myeloma growth. Biphosphonates, drugs that inhibit bone resorption, reduce pathologic fractures and limit the hypercalcemia. Hematopoietic stem cell transplantation prolongs life but has not yet proven to be curative

Answer 247

About 3% to 5% of plasma cell neoplasms present as a solitary lesion of bone or soft tissue. The bone lesions tend to occur in the same locations as in multiple myeloma. Extraosseous lesions are often located in the lungs, oronasopharynx, or nasal sinuses. Modest elevations of M proteins in the blood or urine may be found in some patients. Solitary osseous plasmacytoma almost inevitably progresses to multiple myeloma, but this can take 10 to 20 years or longer. In contrast, extraosseous plasmacytomas, particularly those involving the upper respiratory tract, are frequently cured by local resection

Answer 248

This entity defines a middle ground between multiple myeloma and monoclonal gammopathy of uncertain significance. Plasma cells make up 10% to 30% of the marrow cellularity, and the serum M protein level is greater than 3 gm/dL, but patients are asymptomatic. About 75% of patients progress to multiple myeloma over a 15-year period

Answer 249

MGUS is the most common plasma cell dyscrasia, occurring in about 3% of persons older than 50 years of age and in about 5% of individuals older than 70 years of age. By definition, patients are asymptomatic and the serum M protein level is less than 3 gm/dL. Approximately 1% of patients with MGUS develop a symptomatic plasma cell neoplasm, usually multiple myeloma, per year , a rate of conversion that remains roughly constant over time. The clonal plasma cells in MGUS contain many of the same chromosomal translocations and deletions that are found in full-blown multiple myeloma, indicating that MGUS is an early stage of myeloma development. As in patients with smoldering myeloma, progression to multiple myeloma is unpredictable; hence, periodic assessment of serum M component levels and Bence Jones proteinuria is warranted

Answer 250

L ymphoplasmacytic lymphoma is a B-cell neoplasm of older adults that usually presents in the sixth or seventh decade of life. Although bearing a superficial resemblance to CLL/SLL, it differs in that a substantial fraction of the tumor cells undergo terminal differentiation to plasma cells. Most commonly, the plasma cell component secretes monoclonal IgM, often in amounts sufficient to cause a hyperviscosity syndrome known as Waldenström macroglobulinemia . Unlike multiple myeloma, complications stemming from the secretion of free light chains (e.g., renal failure and amyloidosis) are relatively rare and bone destruction does not occur.

Answer 251

Recent deep sequencing studies have shown that virtually all cases of lymphoplasmacytic lymphoma are associated with acquired mutations in MYD88 . The MYD88 gene encodes an adaptor protein that participates in signaling events that activate NF-κB and also augment signals downstream of the B-cell receptor (Ig) complex, both of which may promote the growth and survival of the tumor cells

Answer 252

Typically, the marrow contains an infiltrate of lymphocytes, plasma cells, and plasmacytoid lymphocytes in varying proportions, often accompanied by mast cell hyperplasia ( Fig. 13-19 ). Some tumors also contain a population of larger lymphoid cells with more vesicular nuclear chromatin and prominent nucleoli. Periodic acid-Schiff-positive inclusions containing Ig are frequently seen in the cytoplasm ( Russell bodies ) or the nucleus ( Dutcher bodies ) of some of the plasma cells. At diagnosis the tumor has usually disseminated to the lymph nodes, spleen, and liver. Infiltration of the nerve roots, meninges, and more rarely the brain can also occur with disease progression

Answer 253

The lymphoid component expresses B-cell markers such as CD20 and surface Ig, whereas the plasma cell component secretes the same Ig that is expressed on the surface of the lymphoid cells. This is usually IgM but can also be IgG or IgA

Answer 254

The dominant presenting complaints are nonspecific and include weakness, fatigue, and weight loss. Approximately half the patients have lymphadenopathy, hepatomegaly, and splenomegaly. Anemia caused by marrow infiltration is common. About 10% of patients have autoimmune hemolysis caused by cold agglutinins , IgM antibodies that bind to red cells at temperatures of less than 37

Answer 255

Because of its large size, at high concentrations IgM greatly increases the viscosity of the blood, giving rise to a hyperviscosity syndrome characterized by the following:

Answer 256

ssociated with venous congestion, which is reflected by striking tortuosity and distention of retinal veins; retinal hemorrhages and exudates can also contribute to the visual problems

Answer 257

• Neurologic problems such as headaches, dizziness, deafness, and stupor, all stemming from sluggish blood flow and sludging

Answer 258

• Bleeding related to the formation of complexes between macroglobulins and clotting factors as well as interference with platelet functions

Answer 259

• Cryoglobulinemia resulting from the precipitation of macroglobulins at low temperatures, which produces symptoms such as Raynaud phenomenon and cold urticaria

Answer 260

Because most IgM is intravascular, symptoms caused by the high IgM levels (e.g., hyperviscosity and hemolysis) can be alleviated by plasmapheresis. Tumor growth can be controlled for a time with low doses of chemotherapeutic drugs and immunotherapy with anti-CD20 antibody. Transformation to large-cell lymphoma occurs but is uncommon. Median survival is about 4 years.

Answer 261

Plasma cell tumor that manifests with multiple lytic bone lesions associated with pathologic fractures and hypercalcemia ▪ Neoplastic plasma cells suppress normal humoral immunity and secrete partial immunoglobulins that are nephrotoxic ▪ Associated with diverse translocations involving the IgH locus; frequent dysregulation and overexpression of D cyclins ▪ May be associated with AL amyloidosis (as may other neoplasms later

Answer 262

▪ MGUS (monoclonal gammopathy of unknown significance): common in older adults, progresses to myeloma at a rate of 1% per year

Answer 263

▪ Smoldering myeloma: disseminated disease that pursues an unusually indolent course

Answer 264

▪ Solitary osseous plasmacytoma: solitary bone lesion identical to disseminated myeloma; most progress to myeloma within 7 to 10 years

Answer 265

solitary mass, usually in the upper aerodigestive tract; rarely progresses to systemic disease

Answer 266

▪ Lymphoplasmacytic lymphoma: B cell lymphoma that exhibits plasmacytic differentiation; clinical symptoms dominated by hyperviscosity related to high levels of tumor-derived IgM; highly associated with mutations in the MYD88 gene

Answer 267

Mantle cell lymphoma is an uncommon lymphoid neoplasm that makes up about 2.5% of NHL in the United States and 7% to 9% of NHL in Europe. It usually presents in the fifth to sixth decades of life and shows a male predominance. As the name implies, the tumor cells closely resemble the normal mantle zone B cells that surround germinal centers.

Answer 268

Virtually all mantle cell lymphomas have an (11;14) translocation involving the IgH locus on chromosome 14 and the cyclin D1 locus on chromosome 11 that leads to overexpression of cyclin D1. This translocation is detected in about 70% of cases by standard karyotyping and in virtually all tumors by fluorescence in situ hybridization. The resulting up-regulation of cyclin D1 promotes G1- to S-phase progression during the cell cycle, as was described

Answer 269

At diagnosis the majority of patients have generalized lymphadenopathy, and 20% to 40% have peripheral blood involvement. Frequent sites of extranodal involvement include the bone marrow, spleen, liver, and gut. Occasionally, mucosal involvement of the small bowel or colon produces polyp-like lesions (lymphomatoid polyposis); of all forms of NHL, mantle cell lymphoma is most likely to spread in this fashion

Answer 270

Nodal tumor cells may surround reactive germinal centers to produce a nodular appearance at low power, or diffusely efface the node. Typically, the proliferation consists of a homogeneous population of small lymphocytes with irregular to occasionally deeply clefted (cleaved) nuclear contours ( Fig. 13-20 ). Large cells resembling centroblasts and proliferation centers are absent, distinguishing mantle cell lymphoma from follicular lymphoma and CLL/SLL, respectively. In most cases the nuclear chromatin is condensed, nucleoli are inconspicuous, and the cytoplasm is scant. Occasionally, tumors composed of intermediate-sized cells with more open chromatin and a brisk mitotic rate are observed; immunophenotyping is necessary to distinguish these “blastoid” variants from ALL

Answer 271

Mantle cell lymphoma. A, At low power, neoplastic lymphoid cells surround a small, atrophic germinal center, producing a mantle zone pattern of growth. B, High-power view shows a homogeneous population of small lymphoid cells with somewhat irregular nuclear outlines, condensed chromatin, and scant cytoplasm. Large cells resembling prolymphocytes (seen in chronic lymphocytic leukemia) and centroblasts (seen in follicular lymphoma) are absent

Answer 272

Mantle cell lymphomas express high levels of cyclin D1. Most tumors are also express CD19, CD20, and moderately high levels of surface Ig (usually IgM and IgD with κ or λ light chain). It is usually CD5+ and CD23−, which help to distinguish it from CLL/SLL. The IgH genes lack somatic hypermutation, supporting an origin from a naive B cell

Answer 273

The most common presentation is painless lymphadenopathy. Symptoms related to involvement of the spleen (present in ~50% of cases) and gut are also common. The prognosis is poor; the median survival is only 3 to 4 years. This lymphoma is not curable with conventional chemotherapy, and most patients eventually succumb to organ dysfunction caused by tumor infiltration. The blastoid variant and a “proliferative” expression profiling signature are associated with even shorter survivals. Hematopoietic stem cell transplantation and proteasome inhibitors are newer therapeutic approaches that show some promise

Answer 274

The category of marginal zone lymphoma encompasses a heterogeneous group of B-cell tumors that arise within lymph nodes, spleen, or extranodal tissues. The extranodal tumors were initially recognized at mucosal sites and are often referred to as mucosa-associated lymphoid tumors (or “MALTomas”). In most cases, the tumor cells show evidence of somatic hypermutation and are considered to be of memory B-cell origin

Answer 275

* They often arise within tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology; examples include the salivary gland in Sjögren disease, the thyroid gland in Hashimoto thyroiditis, and the stomach in Helicobacter gastritis. * They remain localized for prolonged periods, spreading systemically only late in their course. * They may regress if the inciting agent (e.g., Helicobacter pylori) is eradicated.

Answer 276

The disease begins as a polyclonal immune reaction. With the acquisition of still-unknown initiating mutations, a B-cell clone emerges that still depends on antigen-stimulated T-helper cells for signals that drive growth and survival. At this stage, withdrawal of the responsible antigen causes tumor involution. A clinically relevant example is found in gastric “MALToma,” in which antibiotic therapy directed against H. pylori often leads to tumor regression ( Chapter 17 ). With time, however, tumors may acquire additional mutations that render their growth and survival antigen-independent, such as the (11;18), (14;18), or (1;14) chromosomal translocations, which are relatively specific for extranodal marginal zone lymphomas. All of these translocations up-regulate the expression and function of BCL10 or MALT1, protein components of a signaling complex that activates NF-κB and promotes the growth and survival of B cells. With further clonal evolution, spread to distant sites and transformation to diffuse large B-cell lymphoma may occur. This theme of polyclonal to monoclonal transition during lymphomagenesis is also applicable to the pathogenesis of EBV-induced lymphoma and is discussed more fully in Chapter 7 .

Answer 277

This rare but distinctive B-cell neoplasm constitutes about 2% of all leukemias. It is predominantly a disease of middle-aged white males, with a median age of 55 and a male-to-female ratio of 5 : 1

Answer 278

Hairy cell leukemias are associated in more than 90% of cases with activating point mutations in the serine/threonine kinase BRAF, which is positioned immediately downstream of RAS in the MAPK signaling cascade ( Chapter 7 ). The specific mutation, a valine to glutamate substitution at residue 600, is also found in diverse other neoplasms, including many melanomas and Langerhans cell histiocytosis (discussed later)

Answer 279

Hairy cell leukemia derives its picturesque name from the appearance of the leukemic cells, which have fine hairlike projections that are best recognized under the phase-contrast microscope ( Fig. 13-21 ). On routine peripheral blood smears, hairy cells have round, oblong, or reniform nuclei and moderate amounts of pale blue cytoplasm with threadlike or bleblike extensions. The number of circulating cells is highly variable. The marrow is involved by a diffuse interstitial infiltrate of cells with oblong or reniform nuclei, condensed chromatin, and pale cytoplasm. Because these cells are enmeshed in an extracellular matrix composed of reticulin fibrils, they usually cannot be aspirated (a clinical difficulty referred to as a “dry tap”) and are only seen in marrow biopsies. The splenic red pulp is usually heavily infiltrated, leading to obliteration of white pulp and a beefy red gross appearance. Hepatic portal triads are also involved frequently

Answer 280

Hairy cell leukemia (peripheral blood smear). A, Phase-contrast microscopy shows tumor cells with fine hairlike cytoplasmic projections. B, In stained smears, these cells have round or folded nuclei and modest amounts of pale blue, agranular cytoplasm

Answer 281

Hairy cell leukemias typically express the pan-B-cell markers CD19 and CD20, surface Ig (usually IgG), and certain relatively distinctive markers, such as CD11c, CD25, CD103, and annexin A1

Answer 282

Clinical manifestations result largely from infiltration of the bone marrow, liver, and spleen. Splenomegaly , often massive, is the most common and sometimes the only abnormal physical finding. Hepatomegaly is less common and not as marked; lymphadenopathy is rare. Pancytopenia resulting from marrow involvement and splenic sequestration is seen in more than half the cases. About one third of those affected present with infections. There is an increased incidence of atypical mycobacterial infections, possibly related to frequent unexplained monocytopenia

Answer 283

Hairy cell leukemia follows an indolent course. For unclear reasons, this tumor is exceptionally sensitive to “gentle” chemotherapeutic regimens, which produce long-lasting remissions. Tumors often relapse after 5 or more years, yet generally respond well when retreated with the same agents, a feature that is highly unusual among human cancers. BRAF inhibitors appear to produce excellent responses in tumors that have failed conventional chemotherapy. The overall prognosis is excellent

Answer 284

These categories include a heterogeneous group of neoplasms having phenotypes resembling mature T cells or NK cells. Peripheral T-cell tumors make up about 5% to 10% of NHLs in the United States and Europe, while NK cell tumors are rare. By contrast, for unknown reasons both T cell and NK cell tumors are relatively more common in the Far East. Only the most common diagnoses and those of particular pathogenetic interest will be discussed

Answer 285

Although the WHO classification includes a number of distinct peripheral T-cell neoplasms, many of these lymphomas are not easily categorized and are lumped into a “wastebasket” diagnosis, peripheral T-cell lymphoma, unspecified . As might be expected, no morphologic feature is pathognomonic, but certain findings are characteristic. These tumors efface lymph nodes diffusely and are typically composed of a pleomorphic mixture of variably sized malignant T cells ( Fig. 13-22 ). There is often a prominent infiltrate of reactive cells, such as eosinophils and macrophages, probably attracted by tumor-derived cytokines. Brisk neoangiogenesis may also be seen

Answer 286

Figure 13-22 Peripheral T-cell lymphoma, unspecified (lymph node). A spectrum of small, intermediate, and large lymphoid cells, many with irregular nuclear contours, is visible

Answer 287

. They usually express CD2, CD3, CD5, and either αβ or γδ T-cell receptors. Some also express CD4 or CD8; such tumors are taken to be of helper or cytotoxic T-cell origin, respectively. However, many tumors have phenotypes that do not resemble any known normal T cell. In difficult cases where the differential diagnosis lies between lymphoma and a florid reactive process, DNA analysis is used to confirm the presence of clonal T-cell receptor rearrangements

Answer 288

Most patients present with generalized lymphadenopathy, sometimes accompanied by eosinophilia, pruritus, fever, and weight loss. Although cures of peripheral T-cell lymphoma have been reported, these tumors have a significantly worse prognosis than comparably aggressive mature B-cell neoplasms (e.g., diffuse large B-cell lymphoma

Answer 289

This uncommon entity is defined by the presence of rearrangements in the ALK gene on chromosome 2p23. These rearrangements break the ALK locus and lead to the formation of chimeric genes encoding ALK fusion proteins, constitutively active tyrosine kinases that trigger the RAS and JAK/STAT signaling pathways

Answer 290

The tumor cells often cluster about venules and infiltrate lymphoid sinuses, mimicking the appearance of metastatic carcinoma. ALK is not expressed in normal lymphocytes; thus, the detection of ALK protein in tumor cells ( Fig. 13-23 B ) is a reliable indicator of an ALK gene rearrangem

Answer 291

Several “hallmark” cells with horseshoe-like or “embryoid” nuclei and abundant cytoplasm lie near the center of the field. B, Immunohistochemical stain demonstrating the presence of ALK fusion protein.

Answer 292

T-cell lymphomas with ALK rearrangements tend to occur in children or young adults, frequently involve soft tissues, and carry a very good prognosis (unlike other aggressive peripheral T-cell neoplasms

Answer 293

The cure rate with chemotherapy is 75% to 80%. Inhibitors of ALK have been developed and are being evaluated as a form of selective, targeted therapy. Morphologically similar tumors lacking ALK rearrangements occur in older adults and have a substantially worse prognosis. Both the ALK+ and ALK- tumors usually express CD30, a member of the TNF receptor family; of note, recombinant antibodies that bind and kill CD30-expressing cells have produced promising responses in patients with anaplastic large cell lymphoma and Hodgkin lymphoma, another CD30+ tumor (described later).

Answer 294

This neoplasm of CD4+ T cells is only observed in adults infected by human T-cell leukemia retrovirus type 1 (HTLV-1) , which was discussed in Chapter 7 . It occurs mainly in regions where HTLV-1 is endemic, namely southern Japan, West Africa, and the Caribbean basin. Common findings include skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, and hypercalcemia. The appearance of the tumor cells varies, but cells with multilobated nuclei (“cloverleaf” or “flower” cells) are frequently observed. The tumor cells contain clonal HTLV-1 provirus, which is believed to play a critical pathogenic role. Notably, HTLV-1 encodes a protein called Tax that is a potent activator of NF-κB, which, as previously discussed, enhances lymphocyte growth and survival

Answer 295

Most patients present with rapidly progressive disease that is fatal within months to 1 year despite aggressive chemotherapy. Less commonly, the tumor involves only the skin and follows a much more indolent course, like that of mycosis fungoides (described below). It should be noted that in addition to adult T-cell leukemia/lymphoma, HTLV-1 infection sometimes gives rise to a progressive demyelinating disease of the central nervous system and spinal cord ( Chapter 28 ).

Answer 296

Mycosis fungoides and Sézary syndrome are different manifestations of a tumor of CD4+ helper T cells that home to the skin. Clinically, the cutaneous lesions of mycosis fungoides typically progress through three somewhat distinct stages, an inflammatory premycotic phase , a plaque phase , and a tumor phase ( Chapter 25 ). Histologically, the epidermis and upper dermis are infiltrated by neoplastic T cells, which often have a cerebriform appearance due to marked infolding of the nuclear membrane. Late disease progression is characterized by extracutaneous spread, most commonly to lymph nodes and bone marrow

Answer 297

the skin lesions rarely proceed to tumefaction, and there is an associated leukemia of “Sézary” cells with characteristic cerebriform nuclei.

Answer 298

The tumor cells express the adhesion molecule cutaneous leukocyte antigen (CLA) and the chemokine receptors CCR4 and CCR10, all of which contribute to the homing of normal CD4+ T cells to the skin. Although cutaneous disease dominates the clinical picture, sensitive molecular analyses have shown that the tumor cells circulate through the blood, marrow, and lymph nodes even early in the course. Nevertheless, these are indolent tumors, with a median survival of 8 to 9 years. Transformation to aggressive T-cell lymphoma occurs occasionally as a terminal event

Answer 299

T-cell and NK-cell variants of this rare neoplasm are recognized , both of which occur mainly in adults. Individuals with T-cell disease usually present with mild to moderate lymphocytosis and splenomegaly. Lymphadenopathy and hepatomegaly are usually absent. NK-cell disease often presents in an even more subtle fashion, with little or no lymphocytosis or splenomegaly

Answer 300

Recent work has shown that 30% to 40% of large granular lymphocytic leukemias have acquired mutations in the transcription factor STAT3, which functions downstream of cytokine receptors. These mutations occur in both T-cell and NK-cell forms of the disease and appear to result in cytokine-independent activation of STAT3, which is now postulated to have a major role in the pathogenesis of these heretofore mysterious proliferations.

Answer 301

The tumor cells are large lymphocytes with abundant blue cytoplasm and a few coarse azurophilic granules, best seen in peripheral blood smears. The marrow usually contains sparse interstitial lymphocytic infiltrates, which can be difficult to appreciate without immunohistochemical stains. Infiltrates are also usually present in the spleen and liver. As might be expected, T-cell variants are CD3+, whereas NK-cell large granular lymphocytic leukemias are CD3−, CD56

Answer 302

Neutropenia is often accompanied by a striking decrease in late myeloid forms in the marrow. Rarely, pure red cell aplasia is seen. There is also an increased incidence of rheumatologic disorders . Some patients with Felty syndrome , a triad of rheumatoid arthritis, splenomegaly, and neutropenia, have this disorder as an underlying cause. The basis for these varied clinical abnormalities is unknown, but autoimmunity, provoked in some way by the tumor, seems likely.

Answer 303

The course is variable, being largely dependent on the severity of the cytopenias and their responsiveness to low-dose chemotherapy or steroids. In general, tumors of T-cell origin pursue an indolent course, whereas NK-cell tumors behave more aggressively

Answer 304

This neoplasm is rare in the United States and Europe, but constitutes as many as 3% of NHLs in Asia. It presents most commonly as a destructive nasopharyngeal mass; less common sites of presentation include the testis and the skin. The tumor cell infiltrate typically surrounds and invades small vessels, leading to extensive ischemic necrosis. In touch preparations, large azurophilic granules are seen in the cytoplasm of the tumor cells that resemble those found in normal NK cells.

Answer 305

. Within individual patients, all of the tumor cells contain identical EBV episomes, indicating that the tumor originates from a single EBV-infected cell. How EBV gains entry is uncertain, since the tumor cells do not express CD21, the surface protein that serves as the B-cell EBV receptor. Most tumors are CD3− and lack T-cell receptor rearrangements and express NK-cell markers, supporting an NK-cell origin. No consistent chromosome aberration has been described.

Answer 306

Most extranodal NK/T-cell lymphomas are highly aggressive neoplasms that respond well to radiation therapy but are resistant to chemotherapy. Thus, the prognosis is poor in patients with advanced disease

Answer 307

Mantle cell lymphoma : Tumor of naive B cells that pursues a moderately aggressive course and is highly associated with translocations involving the cyclin D1 gene

Answer 308

Marginal zone lymphoma : Indolent tumors of antigen-primed B cells that arise at sites of chronic immune stimulation and often remain localized for long periods of time

Answer 309

Hairy cell leukemia : Morphologically distinct, very indolent tumor of mature B cells that is highly associated with mutations in the BRAF serine/threonine kinase

Answer 310

▪ Anaplastic large cell lymphoma: Aggressive T cell tumor, associated in a subset with activating mutations in the ALK tyrosine kinase ▪ Adult T cell leukemia/lymphoma: Aggressive tumor of CD4+ T cells that is uniformly associated with HTLV-1 infection ▪ Large granular lymphocytic leukemia: Indolent tumor of cytotoxic T cells or NK cells that is associated with mutations in the transcription factor STAT3 and with autoimmune phenomena and cytopenias ▪ Extranodal NK/T cell lymphoma: Aggressive tumor, usually derived from NK cells, that is strongly associated with EBV infection

Answer 311

Aggressive T cell tumor, associated in a subset with activating mutations in the ALK tyrosine kinase

Answer 312

A ggressive tumor of CD4+ T cells that is uniformly associated with HTLV-1 infection

Answer 313

ndolent tumor of cytotoxic T cells or NK cells that is associated with mutations in the transcription factor STAT3 and with autoimmune phenomena and cytopenias

Answer 314

Aggressive tumor, usually derived from NK cells, that is strongly associated with EBV infection

Answer 315

Hodgkin lymphoma (HL) encompasses a group of lymphoid neoplasms that differ from NHL in several respects ( Table 13-7 ). While NHLs frequently occur at extranodal sites and spread in an unpredictable fashion, HL arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues. HL also has distinctive morphologic features. It is characterized by the presence of neoplastic giant cells called Reed-Sternberg cells . These cells release factors that induce the accumulation of reactive lymphocytes, macrophages, and granulocytes, which typically make up greater than 90% of the tumor cellularity. In the vast majority of HLs, the neoplastic Reed-Sternberg cells are derived from germinal center or postgerminal center B cells

Answer 316

Hodgkin Lymphoma Non-Hodgkin Lymphoma More often localized to a single axial group of nodes (cervical, mediastinal, para-aortic) More frequent involvement of multiple peripheral nodes Orderly spread by contiguity Noncontiguous spread Mesenteric nodes and Waldeyer ring rarely involved Waldeyer ring and mesenteric nodes commonly involved Extranodal presentation rare

Answer 317

More frequent involvement of multiple peripheral nodes Noncontiguous spreas Walleyed ring and mesenteric nodes commonly involved Extranodal presentation common

Answer 318

Hodgkin lymphoma accounts for 0.7% of all new cancers in the United States; there are about 8000 new cases each year. The average age at diagnosis is 32 years. It is one of the most common cancers of young adults and adolescents, but also occurs in the aged. It was the first human cancer to be successfully treated with radiation therapy and chemotherapy, and is curable in most cases

Answer 319

1. Nodular sclerosis 2. Mixed cellularity 3. Lymphocyte-rich 4. Lymphocyte depletion 5. Lymphocyte predominance

Answer 320

The origin of the neoplastic Reed-Sternberg cells of classical HL has been explained through elegant studies relying on molecular analysis of single isolated Reed-Sternberg cells and variants. In the vast majority of cases, the Ig genes of Reed-Sternberg cells have undergone both V(D)J recombination and somatic hypermutation, establishing an origin from a germinal center or postgerminal center B cell. Despite having the genetic signature of a B cell, the Reed-Sternberg cells of classical HL fail to express most B-cell–specific genes, including the Ig genes. The cause of this wholesale reprogramming of gene expression has yet to be fully explained, but presumably is the result of widespread epigenetic changes of uncertain etiology

Answer 321

* NF-κB may be activated either by EBV infection or by some other mechanism and turns on genes that promote lymphocyte survival and proliferation. * EBV + tumor cells express latent membrane protein-1 (LMP-1), a protein encoded by the EBV genome that transmits signals that up-regulate NF-κB. * Activation of NF-κB may occur in EBV-tumors as a result of acquired loss-of-function mutations in IκB or A20 (also known as TNF alpha-induced protein 3, or TNFAIP3 ), which are both negative regulators of NF-κB. * It is hypothesized that activation of NF-κB by EBV or other mechanisms rescues “crippled” germinal center B cells that cannot express Igs from apoptosis, setting the stage for the acquisition of other unknown mutations that collaborate to produce Reed-Sternberg cells

Answer 322

Reed-Sternberg cells are aneuploid and possess diverse clonal chromosomal aberrations. Copy number gains in the REL proto-oncogene on chromosome 2p are particularly common and may also contribute to increases in NF-κB activity

Answer 323

Diagnostic Reed-Sternberg cells are large cells (45 µ m in diameter) with multiple nuclei or a single nucleus with multiple nuclear lobes, each with a large inclusion-like nucleolus about the size of a small lymphocyte (5 to 7 µ m in diameter) ( Fig. 13-24 A ). The cytoplasm is abundant. Several Reed-Sternberg cell variants are also recognized. Mononuclear variants contain a single nucleus with a large inclusion-like nucleolus ( Fig. 13-24 B ). Lacunar cells (seen in the nodular sclerosis subtype) have more delicate, folded, or multilobate nuclei and abundant pale cytoplasm that is often disrupted during the cutting of sections, leaving the nucleus sitting in an empty hole (a lacuna) ( Fig. 13-24 C ). In classical forms of HL, Reed-Sternberg cells undergo a peculiar form of cell death in which the cells shrink and become pyknotic, a process described as “mummification.” Lymphohistiocytic variants (L&H cells) with polypoid nuclei, inconspicuous nucleoli, and moderately abundant cytoplasm are characteristic of the lymphocyte predominance subtype

Answer 324

Reed-Sternberg cells and variants. A, Diagnostic Reed-Sternberg cell, with two nuclear lobes, large inclusion-like nucleoli, and abundant cytoplasm, surrounded by lymphocytes, macrophages, and an eosinophil. B, Reed-Sternberg cell, mononuclear variant. C, Reed-Sternberg cell, lacunar variant. This variant has a folded or multilobated nucleus and lies within a open space, which is an artifact created by disruption of the cytoplasm during tissue sectioning. D, Reed-Sternberg cell, lymphohistiocytic variant. Several such variants with multiply infolded nuclear membranes, small nucleoli, fine chromatin, and abundant pale cytoplasm are present

Answer 325

cells can be seen, such as infectious mononucleosis, solid tissue cancers, and large-cell NHLs. The diagnosis of HL depends on the identification of Reed-Sternberg cells in a background of non-neoplastic inflammatory cells. The Reed-Sternberg cells of HL also have a characteristic immunohistochemical profile.

Answer 326

Frequent lacunar cells and occasional diagnostic RS cells; background infiltrate composed of T lymphocytes, eosinophils, macrophages, and plasma cells; fibrous bands dividing cellular areas into nodules. RS cells CD15+, CD30+; usually EBV Most common subtype; usually stage I or II disease; frequent mediastinal involvement; equal occurrence in males and females (F = M), most patients young adults

Answer 327

Frequent mononuclear and diagnostic RS cells; background infiltrate rich in T lymphocytes, eosinophils, macrophages, plasma cells; RS cells CD15+, CD30+; 70% EBV More than 50% present as stage III or IV disease; M greater than F; biphasic incidence, peaking in young adults and again in adults older than 55

Answer 328

Frequent mononuclear and diagnostic RS cells; background infiltrate rich in T lymphocytes; RS cells CD15+, CD30+; 40% EBV Uncommon; M greater than F; tends to be seen in older adults

Answer 329

Reticular variant: Frequent diagnostic RS cells and variants and a paucity of background reactive cells; RS cells CD15+, CD30+; most EBV+ Uncommon; more common in older males, HIV-infected individuals, and in developing countries; often presents with advanced disease

Answer 330

Frequent L&H (popcorn cell) variants in a background of follicular dendritic cells and reactive B cells; RS cells CD20+, CD15−, C30−; EB- Uncommon; young males with cervical or axillary lymphadenopathy; mediastinal

Answer 331

This is the most common form of HL, constituting 65% to 70% of cases. It is characterized by the presence of lacunar variant Reed-Sternberg cells and the deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules ( Fig. 13-25 ). The fibrosis may be scant or abundant. The Reed-Sternberg cells are found in a polymorphous background of T cells, eosinophils, plasma cells, and macrophages. Diagnostic Reed-Sternberg cells are often uncommon. The Reed-Sternberg cells in this and other “classical” HL subtypes have a characteristic immunophenotype; they are positive for PAX5 (a B-cell transcription factor), CD15, and CD30, and negative for other B-cell markers, T-cell markers, and CD45 (leukocyte common antigen). As in other forms of HL, involvement of the spleen, liver, bone marrow, and other organs and tissues can appear in due course in the form of irregular tumor nodules resembling those seen in lymph nodes. This subtype is uncommonly associated with EBV

Answer 332

Hodgkin lymphoma, nodular sclerosis type. A low-power view shows well-defined bands of pink, acellular collagen that subdivide the tumor into nodules

Answer 333

The nodular sclerosis type occurs with equal frequency in males and females. It has a propensity to involve the lower cervical, supraclavicular, and mediastinal lymph nodes of adolescents or young adults.

Answer 334

This form of HL constitutes about 20% to 25% of cases. Involved lymph nodes are diffusely effaced by a heterogeneous cellular infiltrate, which includes T cells, eosinophils, plasma cells, and benign macrophages admixed with Reed-Sternberg cells ( Fig. 13-26 ). Diagnostic Reed-Sternberg cells and mononuclear variants are usually plentiful. The Reed-Sternberg cells are infected with EBV in about 70% of cases. The immunophenotype is identical to that observed in the nodular sclerosis type

Answer 335

Mixed-cellularity HL is more common in males. Compared with the lymphocyte predominance and nodular sclerosis subtypes, it is more likely to be associated with older age, systemic symptoms such as night sweats and weight loss, and advanced tumor stage

Answer 336

V ery good

Answer 337

. This is an uncommon form of classical HL in which reactive lymphocytes make up the vast majority of the cellular infiltrate . In most cases, involved lymph nodes are diffusely effaced, but vague nodularity due to the presence of residual B-cell follicles is sometimes seen. This entity is distinguished from the lymphocyte predominance type by the presence of frequent mononuclear variants and diagnostic Reed-Sternberg cells with a “classical” immunophenotypic profile. It is associated with EBV in about 40% of cases and has a very good to excellent prognosis

Answer 338

This is the least common form of HL, amounting to less than 5% of cases. It is characterized by a paucity of lymphocytes and a relative abundance of Reed-Sternberg cells or their pleomorphic variants. The immunophenotype of the Reed-Sternberg cells is identical to that seen in other classical types of HL. Immunophenotyping is essential, since most tumors suspected of being lymphocyte depletion HL actually prove to be large-cell NHLs. The Reed-Sternberg cells are infected with EBV in over 90% of cases

Answer 339

Lymphocyte depletion HL occurs predominantly in older adults, in HIV+ individuals of any age, and in nonindustrialized countries. Advanced stage and systemic symptoms are frequent,

Answer 340

d the overall outcome is somewhat less favorable than in the other subtypes.

Answer 341

This uncommon “nonclassical” variant of HL accounts for about 5% of cases. Involved nodes are effaced by a nodular infiltrate of small lymphocytes admixed with variable numbers of macrophages ( Fig. 13-27 ). “Classical” Reed-Sternberg cells are usually difficult to find. Instead, this tumor contains so-called L&H (lymphocytic and histiocytic) variants, which have a multilobed nucleus resembling a popcorn kernel (“popcorn cell”). Eosinophils and plasma cells are usually scant or absent

Answer 342

A majority of patients are males, usually younger than 35 years of age, who typically present with cervical or axillary lymphadenopathy. Mediastinal and bone marrow involvement is rare. In some series, this form of HL is more likely to recur than the classical subtypes, but the prognosis is excellent

Answer 343

HL most commonly present as painless lymphadenopathy. Patients with the nodular sclerosis or lymphocyte predominance types tend to have stage I-II disease and are usually free of systemic manifestations. Patients with disseminated disease (stages III-IV) or the mixed-cellularity or lymphocyte depletion subtypes are more likely to have constitutional symptoms, such as fever, night sweats, and weight loss. Cutaneous immune unresponsiveness (also called anergy) resulting from depressed cell-mediated immunity is seen in most cases. The mix of factors released from Reed-Sternberg cells ( Fig. 13-28 ) suppress T H 1 immune responses and may contribute to immune dysregulation.

Answer 344

The spread of HL is remarkably stereotyped: nodal disease first, then splenic disease, hepatic disease, and finally involvement of the marrow and other tissues. Staging involves physical examination, radiologic imaging of the abdomen, pelvis, and chest, and biopsy of the bone marrow ( Table 13-9 ). With current treatment protocols, tumor stage rather than histologic type is the most important prognostic variable. The cure rate of patients with stages I and IIA is close to 90%. Even with advanced disease (stages IVA and IVB), disease-free survival at 5 years is 60% to 70%

Answer 345

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

Answer 346

nvolvement of two or more lymph node regions on the same side of the diaphragm alone (II) or localized involvement of an extralymphatic organ or site (IIE)

Answer 347

Involvement of lymph node regions on both sides of the diaphragm without (III) or with (IIIE) localized involvement of an extralymphatic organ or site

Answer 348

Diffuse involvement of one or more extralymphatic organs or sites with or without lymphatic involvement

Answer 349

All stages are further divided on the basis of the absence (A) or presence (B) of the following symptoms: unexplained fever, drenching night sweats, and/or unexplained weight loss of greater than 10% of normal body weight.

Answer 350

d a high incidence of secondary tumors, particularly acute myeloid leukemia. These sobering results spurred the development of current treatment regimens, which minimize the use of radiotherapy and employ less genotoxic chemotherapeutic agents; as a result, the incidence of secondary tumors appears to have been reduced markedly, without any loss of therapeutic efficacy. Anti-CD30 antibodies have produced excellent responses in patients with disease that has failed conventional treatments and represent a promising targeted therap

Answer 351

odgkin Lymphoma * Unusual tumor consisting mostly of reactive lymphocytes, macrophages, eosinophils, plasma cells and stromal cells mixed with rare tumor giant cells called Reed-Sternberg cells and variants * Two broad types, classical (which has several subtypes) and lymphocyte predominant, which are distinguished based on morphologic and immunophenotypic grounds * Reed-Sternberg cells of classical types make multiple cytokines and chemokines that influence the host response, and the host response in turn makes factors that support the growth of the tumor cells * Classical forms are frequently associated with acquired mutations that activate the transcription factor NF-κB and with EBV infection * Lymphocyte predominance type expresses B cell markers and is not associated with EBV

Answer 352

The common feature of this heterogeneous group of neoplasms is an origin from hematopoietic progenitor cells. These diseases primarily involve the marrow and to a lesser degree the secondary hematopoietic organs (the spleen, liver, and lymph nodes), and usually present with symptoms related to altered hematopoiesis. Three broad categories of myeloid neoplasia exist:

Answer 353

• Acute myeloid leukemias , in which an accumulation of immature myeloid forms (blasts) in the bone marrow suppresses normal hematopoiesis

Answer 354

• Myelodysplastic syndromes , in which defective maturation of myeloid progenitors gives rise to ineffective hematopoiesis, leading to cytopenias

Answer 355

• Myeloproliferative disorders , in which there is usually increased production of one or more types of blood cells

Answer 356

The pathogenesis of myeloid neoplasms is best understood in the context of normal hematopoiesis, which involves a hierarchy of hematopoietic stem cells, committed progenitors, and more differentiated elements ( Fig. 13-1 ). Normal hematopoiesis is finely tuned by homeostatic feedback mechanisms involving cytokines and growth factors that modulate the production of red cells, white cells, and platelets in the marro

Answer 357

* The position of the transformed cell within the hierarchy of progenitors (i.e., a pluripotent hematopoietic stem cell versus a more committed progenitor) * The effect of the transforming events on differentiation , which may be inhibited, skewed, or deranged by particular oncogenic mutations

Answer 358

Myeloid neoplasms, like other malignancies, tend to evolve over time to more aggressive forms of disease. In particular, both myelodysplastic syndromes and myeloproliferative disorders often “transform” to AML. In one of the most important myeloproliferative disorders, chronic myelogenous leukemia (CML), transformation to acute lymphoblastic leukemia is also seen, indicating that it originates from a transformed pluripotent hematopoietic stem

Answer 359

Acute myeloid leukemia (AML) is a tumor of hematopoietic progenitors caused by acquired oncogenic mutations that impede differentiation, leading to the accumulation of immature myeloid blasts in the marrow. The replacement of the marrow with blasts produces marrow failure and complications related to anemia, thrombocytopenia, and neutropenia. AML occurs at all ages, but the incidence rises throughout life, peaking after 60 years of age. There are about 13,000 new cases each year in the United States

Answer 360

AML is quite heterogeneous, reflecting the complexities of myeloid cell differentiation. The current WHO classification subdivides AML into four categories ( Table 13-10 ). The first includes forms of AML that are associated with particular genetic aberrations, which are important because they correlate with prognosis and guide therapy. Also included are categories of AML arising after a myelodysplastic disorder (MDS) or with MDS-like features, and therapy-related AML. AMLs in these two categories have distinct genetic features and respond poorly to therapy. A fourth “wastebasket” category includes AMLs lacking any of these features. These are classified based on the degree of differentiation and the lineage of the leukemic blasts. Given the increasing role of cytogenetic and molecular features in directing therapy, a further shift toward genetic classification of AML is both inevitable and desirable

Answer 361

Favorable Full range of myelocytic maturation; Auer rods easily found; abnormal cytoplasmic granules

Answer 362

Favorable. Myelocytic and monocytic differentiation; abnormal eosinophilic precursors with abnormal basophilic granules

Answer 363

Favorable Numerous Auer rods, often in bundles within individual progranulocytes; primary granules usually very prominent, but inconspicuous in microgranular variant; high incidence of DIC

Answer 364

Poor Usually some degree of monocytic differentiation

Answer 365

Favorable Detected by immunohistochemical staining for NPM

Answer 366

Poor | Diagnosis based on clinical history

Answer 367

Poor Maturing cells with dysplastic feature typical of mds

Answer 368

Poor Associated with 5q-, 7q-, 20q-aberrations

Answer 369

Very poor f following alkylator therapy or radiation therapy, 2- to 8-year latency period, MDS-like cytogenetic aberrations (e.g., 5q-, 7q-); if following topoisomerase II inhibitor (e.g., etoposide) therapy, 1- to 3-year latency, translocations involving MLL (11q23

Answer 370

Intermediate egative for myeloperoxidase; myeloid antigens detected on blasts by flow cytometry

Answer 371

Intermediate >3% of blasts positive for myeloperoxidase

Answer 372

Intermediate Full range of myelocytic maturation

Answer 373

Intermediate Myelocytic and monocytes differentiation

Answer 374

Intermediate Nonspecific esterase-positive monoblasts and pro-monocytes predominate in marrow; may see monoblasts or mature monocytes in the blood

Answer 375

Intermediate Erythroid/myeloid subtype defined by >50% dysplastic maturing erythroid precursors and >20% myeloblasts; pure erythroid subtype defined by >80% erythroid precursors without myeloblasts

Answer 376

Intermediate Blasts of megakaryocytic lineage predominate; detected with antibodies against megakaryocyte-specific markers (GPIIb/IIIa or vWF); often associated with marrow fibrosis; most common AML in Down syndrome

Answer 377

For example, the two most common chromosomal rearrangements, t(8;21) and inv(16), disrupt the RUNX1 and CBFB genes, respectively. These two genes encode polypeptides that bind one another to form a RUNX1/CBF1β transcription factor that is required for normal hematopoiesis. The t(8;21) and the inv(16) create chimeric genes encoding fusion proteins that interfere with the function of RUNX1/CBF1β and block the maturation of myeloid cells. However, experiments in mouse models indicate that genetic lesions that merely block the maturation of myeloid progenitors are not sufficient to cause AML. Thus other genetic changes (discussed next) are also essential

Answer 378

One example is found in AML with the t(15;17), acute promyelocytic leukemia. The t(15;17) creates yet another fusion gene encoding a chimeric protein consisting of the retinoic acid receptor-α (RARα) fused to a portion of a protein called PML (after the tumor). As discussed in Chapter 7 , this fusion protein interferes with the terminal differentiation of granulocytes, an effect that can be overcome by treatment with either all-trans retinoic acid or arsenic trioxide. However, expression of the PML-RARa fusion protein in the bone marrow cells of mice produces disease only in aged mice, suggesting that PML-RARα is not sufficient. Indeed, AMLs with the t(15;17) (a subtype referred to as acute promyelocytic leukemia) also have frequent activating mutations in FLT3, a receptor tyrosine kinase that transmits signals that mimic normal growth factor signaling, thereby increasing cellular proliferation and survival. As might be predicted, the combination of PML-RARα and activated FLT3 is a potent inducer of AML in mice. Other similar observations in human AML and in mouse models indicate that aberrant activation of growth factor signaling pathways is a common feature of AML.

Answer 379

Gene expression is regulated by two types of epigenetic modifications, DNA methylation and posttranslational modifications of histones (e.g., acetylation, methylation, phosphorylation). Some of the most commonly mutated genes in AML encode factors that influence DNA methylation or histone modifications. Another 15% of tumors have mutations involving genes encoding components of the cohesin complex, proteins that regulate the three-dimensional structure of chromatin. The precise mechanism by which these mutations contribute to the development of AML remains to be determined and is a “hot” area of current research

Answer 380

Several types of myeloid blasts are recognized, and individual tumors may have more than one type of blast or blasts with hybrid features

Answer 381

have delicate nuclear chromatin, two to four nucleoli, and more voluminous cytoplasm than lymphoblasts ( Fig. 13-29A ). The cytoplasm often contains fine, peroxidase-positive azurophilic granules

Answer 382

distinctive needle-like azurophilic granules, are present in many cases; they are particularly numerous in AML with the t(15;17) (acute promyelocytic leukemia

Answer 383

Monoblasts ( Fig. 13-30 B ) have folded or lobulated nuclei, lack Auer rods, and are nonspecific esterase-positive. In some AMLs, blasts show megakaryocytic differentiation, which is often accompanied by marrow fibrosis caused by the release of fibrogenic cytokines. Rarely, the blasts of AML show erythroid differentiation.

Answer 384

Because it can be difficult to distinguish myeloblasts and lymphoblasts morphologically, the diagnosis of AML is confirmed by performing stains for myeloid-specific antigens

Answer 385

Cytogenetic analysis has a central role in the classification of AML . Karyotypic aberrations are detected in 50% to 70% of cases with standard techniques and in approximately 90% of cases using special high-resolution banding. Particular chromosomal abnormalities correlate with certain clinical features. AMLs arising de novo in younger adults are commonly associated with balanced chromosomal translocations, particularly t(8;21), inv(16), and t(15;17). In contrast, AMLs following myelodysplastic syndromes or exposure to DNA-damaging agents (such as chemotherapy or radiation therapy) often have deletions or monosomies involving chromosomes 5 and 7 and usually lack chromosomal translocations. The exception to this rule is AML occurring after treatment with topoisomerase II inhibitors, which is strongly associated with translocations involving the MLL gene on chromosome 11q23. AML in older adults is also more likely to be associated with “bad” aberrations, such as deletions of chromosomes 5q and 7q.

Answer 386

Most patients present within weeks or a few months of the onset of symptoms with complaints related to anemia, neutropenia, and thrombocytopenia, most notably fatigue, fever, and spontaneous mucosal and cutaneous bleeding. You will remember that these findings are very similar to those produced by ALL. Thrombocytopenia results in a bleeding diathesis, which is often prominent. Cutaneous petechiae and ecchymoses, serosal hemorrhages into the linings of the body cavities and viscera, and mucosal hemorrhages into the gingivae and urinary tract are common. Procoagulants and fibrinolytic factors released by leukemic cells, especially in AML with the t(15;17), exacerbate the bleeding tendency. Infections are frequent, particularly in the oral cavity, skin, lungs, kidneys, urinary bladder, and colon, and are often caused by opportunists such as fungi, Pseudomonas , and commensals

Answer 387

Signs and symptoms related to involvement of tissues other than the marrow are usually less striking in AML than in ALL, but tumors with monocytic differentiation often infiltrate the skin (leukemia cutis) and the gingiva; this probably reflects the normal tendency of monocytes to extravasate into tissues. Central nervous system spread is less common than in ALL. AML occasionally presents as a localized soft-tissue mass known variously as a myeloblastoma, granulocytic sarcoma, or chloroma. Without systemic treatment, such tumors inevitably progress to full-blown AML over time

Answer 388

AML is generally a difficult disease to treat; about 60% of patients achieve complete remission with chemotherapy, but only 15% to 30% remain free of disease for 5 years. However, the outcome varies markedly among different molecular subtypes. With targeted therapy using all-trans retinoic acid and arsenic salts (described in Chapter 7 ), AMLs with the t(15;17) now have the best prognosis of any type, being curable in more than 80% of patients. AMLs with t(8;21) or inv(16) have a relatively good prognosis with conventional chemotherapy, particularly in the absence of KIT mutations. In contrast, the prognosis is dismal for AMLs that follow MDS or genotoxic therapy, or that occur in older adults, possibly because in these contexts the disease arises out of a background of hematopoietic stem cell damage or depletion. These “high-risk” forms of AML (as well as relapsed AML of all types) are treated with hematopoietic stem cell transplantation when possible

Answer 389

Sequencing of AML genomes has recently revealed new molecular predictors of outcome. It is certain that insights gained from DNA sequencing will have an increasingly important role in selecting therapy and stratifying patients in clinical trials of new therapeutics, such as drugs that target the tumor epigenome

Answer 390

The term “myelodysplastic syndrome” (MDS) refers to a group of clonal stem cell disorders characterized by maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML. In MDS the bone marrow is partly or wholly replaced by the clonal progeny of a neoplastic multipotent stem cell that retains the capacity to differentiate but does so in an ineffective and disordered fashion. These abnormal cells stay within the bone marrow and hence the patients have peripheral blood cytopenias

Answer 391

MDS may be either primary (idiopathic) or secondary to previous genotoxic drug or radiation therapy (t-MDS). t-MDS usually appears from 2 to 8 years after the genotoxic exposure. All forms of MDS can transform to AML, but transformation occurs with highest frequency and most rapidly in t-MDS. Although characteristic morphologic changes are typically seen in the marrow and the peripheral blood, the diagnosis frequently requires correlation with other laboratory tests. Cytogenetic analysis is particularly helpful, since certain chromosomal aberrations (discussed later) are often observed

Answer 392

The pathogenesis of MDS is poorly understood, but important new insights have come from recent deep sequencing of MDS genomes, which has identified a number of recurrently mutated genes. These genes can be lumped into three major functional categories, as follows

Answer 393

Frequent mutations are seen involving many of the same epigenetic factors that are mutated in AML, including factors that regulate DNA methylation and histone modifications; thus, like AML, dysregulation of the epigenome appears to be important in the genesis of MDS

Answer 394

A subset of tumors has mutations involving components of the 3' end of the RNA splicing machinery. The impact of these mutations on RNA splicing and other nuclear functions is not yet known

Answer 395

These mutations affect transcription factors that are are required for normal myelopoiesis and may contribute to the deranged differentiation that characterizes MDS

Answer 396

Both primary MDS and t-MDS are associated with similar recurrent chromosomal abnormalities, including monosomies 5 and 7, deletions of 5q, 7q, and 20q, and trisomy 8.

Answer 397

otably, the MYC gene is located on chromosome 8, and trisomy 8 is one of the most common forms of aneuploidy in a wide range of myeloid tumors. Similarly, the region that is commonly lost on chromosome 5q contains a gene encoding the ribosomal protein RPS14. In experimental systems, loss of one copy of RPS14 produces ineffective erythropoiesis, one of the hallmarks of MDS.

Answer 398

Although the marrow is usually hypercellular at diagnosis, it is sometimes normocellular or, less commonly, hypocellular. The most characteristic finding is disordered (dysplastic) differentiation affecting the erythroid, granulocytic, monocytic, and megakaryocytic lineages to varying degrees

Answer 399

Within the erythroid series, common abnormalities include ring sideroblasts , erythroblasts with iron-laden mitochondria visible as perinuclear granules in Prussian blue-stained aspirates or biopsies

Answer 400

megaloblastoid maturation , resembling that seen in vitamin B 12 and folate deficiency

Answer 401

and nuclear budding abnormalities , recognized as nuclei with misshapen, often polyploid, outlines

Answer 402

Neutrophils frequently contain decreased numbers of secondary granules, toxic granulations, and/or Döhle bodies.

Answer 403

Pseudo-Pelger-Hüet cells , neutrophils with only two nuclear lobes, are commonly observed, and neutrophils are seen occasionally that completely lack nuclear segmentation

Answer 404

Megakaryocytes with single nuclear lobes or multiple separate nuclei ( pawn ball megakaryocytes ) are also characteristic

Answer 405

Myeloid blasts may be increased but make up less than 20% of the overall marrow cellularity. The blood often contains pseudo-Pelger-Hüet cells, giant platelets, macrocytes, and poikilocytes, accompanied by a relative or absolute monocytosis. Myeloid blasts usually make up less than 10% of the leukocytes in the blood.

Answer 406

ia. Characteristic forms of dysplasia are shown. A, Nucleated red cell progenitors with multilobated or multiple nuclei. B, Ringed sideroblasts, erythroid progenitors with iron-laden mitochondria seen as blue perinuclear granules (Prussian blue stain). C, Pseudo-Pelger-Hüet cells, neutrophils with only two nuclear lobes instead of the normal three to four, are observed at the top and bottom of this field. D, Megakaryocytes with multiple nuclei instead of the normal single multilobated nucleus. ( A, B, D, Marrow aspirates; C, peripheral blood smear.)

Answer 407

Primary MDS is predominantly a disease of older adults; the mean age of onset is 70 years. In up to half of the cases, it is discovered incidentally on routine blood testing. When symptomatic, it presents with weakness, infections, and hemorrhages, all due to pancytopenia

Answer 408

Primary MDS is divided into eight categories based on morphologic and cytogenetic features in the WHO classification, details of which are beyond our scope. A prognostic scoring system has been developed that groups patients into 5 major prognostic groups. In brief, worse outcomes are (understandably) predicted by higher blast counts and more severe cytopenias, as well as the presence of multiple clonal chromosomal abnormalities

Answer 409

The median survival in primary MDS varies from 9 to 29 months, but some individuals in good prognostic groups may live for 5 years or more. Overall, progression to AML occurs in 10% to 40% of individuals and is usually accompanied by the appearance of additional cytogenetic abnormalities. Patients often succumb to the complications of thrombocytopenia (bleeding) and neutropenia (infection). The outlook is even grimmer in t-MDS, which has a median survival of only 4 to 8 months. In t-MDS, cytopenias tend to be more severe and progression to AML is often rapid

Answer 410

Treatment options are fairly limited. In younger patients, allogeneic hematopoietic stem cell transplantation offers hope for reconstitution of normal hematopoiesis and possible cure. Older patients with MDS are treated supportively with antibiotics and blood product transfusions. Thalidomide-like drugs (see prior discussion in myeloma) and DNA methylation inhibitors improve the effectiveness of hematopoiesis and the peripheral blood counts in a subset of patients. The presence of isolated 5q- is correlated with a hematologic response to thalidomide-like drugs, but as yet response to DNA methylation inhibitors is unpredictable

Answer 411

The common pathogenic feature of the myeloproliferative disorders is the presence of mutated, constitutively activated tyrosine kinases or other acquired aberrations in signaling pathways that lead to growth factor independence. Hematopoietic growth factors act on normal progenitors by binding to surface receptors and activating tyrosine kinases, which turn on pathways that promote growth and survival ( Chapter 7 ). The mutated tyrosine kinases found in the myeloproliferative disorders circumvent normal controls and lead to the growth factor-independent proliferation and survival of marrow progenitors. Because the tyrosine kinase mutations underlying the various myeloproliferative disorders do not impair differentiation, the most common consequence is an increase in the production of one or more mature blood elements. Most myeloproliferative disorders originate in multipotent myeloid progenitors, whereas others arise in pluripotent stem cells that give rise to both lymphoid and myeloid cells

Answer 412

* Increased proliferative drive in the bone marrow * Homing of the neoplastic stem cells to secondary hematopoietic organs, producing extramedullary hematopoiesis * Variable transformation to a spent phase characterized by marrow fibrosis and peripheral blood cytopenias * Variable transformation to acute leukemia

Answer 413

. This insight and the availability of kinase inhibitors have increased the importance of molecular tests for tyrosine kinase mutations, both for purposes of diagnosis and the selection of therapy. This discussion is confined to the more common myeloproliferative disorders, which are classified based on clinical, laboratory, and molecular criteria. Systemic mastocytosis, a distinctive myeloproliferative disorder that is associated with mutations in the KIT tyrosine kinase, is discussed under disorders of the skin ( Chapter 25 ). The association of various myeloproliferative disorders with specific tyrosine kinase mutations (including rare disorders not discussed here) is summarized

Answer 414

BCR-ABL fusion gene 100% Constitutive ABO kinase activation

Answer 415

Jak2 >95% Constitutive jak2 kinase activation

Answer 416

Jak2 50-60%. Constitutive jak2 kinase activation Mpl point mutations 5-10% constitutive mpl kinase activation

Answer 417

Jak2 50-60%. Constitutive jak2 activation Mpl 5-10% constitutive mpl kinase activation

Answer 418

KIT point mutations >90% Constitutive kit kinase activation

Answer 419

FIP1L1-PDGFRA fusion gene Common Constitutive PDGFRa kinase activation PDE4DOP-PDGFRB fusion gene Rare Constitutive PDGFRB kinase activation

Answer 420

Various fgfr1 fusion genes 100% Constitutive FGFR1 kinase activity

Answer 421

Chronic myelogenous leukemia (CML) is distinguished from other myeloproliferative disorders by the presence of a chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9. BCR-ABL directs the synthesis of a constitutively active BCR-ABL tyrosine kinase ( Fig. 13-32 ), which in CML is usually 210 kDa in size. In more than 90% of cases, BCR-ABL is created by a reciprocal (9;22)(q34;q11) translocation (the so-called Philadelphia chromosome [Ph]). In the remaining cases the BCR-ABL fusion gene is formed by cytogenetically complex or cryptic rearrangements and must be detected by other methods, such as fluorescence in situ hybridization or polymerase chain reaction (PCR)-based tests. The cell of origin is a pluripotent hematopoietic stem cell.

Answer 422

Tyrosine kinases are normally regulated by ligand-mediated dimerization and autophosphorylation, which creates an activated kinase capable of phosphorylating other protein substrates ( Chapters 3 and 7 ). The BCR moiety of BCR-ABL contains a dimerization domain that self-associates, leading to the activation of the ABL tyrosine kinase moiety. The ABL kinase in turn phosphorylates proteins that induce signaling through the same pro-growth and pro-survival pathways that are turned on by hematopoietic growth factors, including the RAS and JAK/STAT pathways. For unknown reasons, BCR-ABL preferentially drives the proliferation of granulocytic and megakaryocytic progenitors, and also causes the abnormal release of immature granulocytic forms from the marrow into the blood.

Answer 423

The marrow is markedly hypercellular because of massively increased numbers of maturing granulocytic precursors, which usually include an elevated proportion of eosinophils and basophils. Megakaryocytes are also increased and usually include small, dysplastic forms. Erythroid progenitors are present in normal or mildly decreased numbers. A characteristic finding is the presence of scattered macrophages with abundant wrinkled, green-blue cytoplasm so-called sea-blue histiocytes. Increased deposition of reticulin is typical, but overt marrow fibrosis is rare early in the course. The blood reveals a leukocytosis, often exceeding 100,000 cells/mm 3 ( Fig. 13-33 ), which consists predominantly of neutrophils, band forms, metamyelocytes, myelocytes, eosinophils, and basophils. Blasts usually make up less than 10% of the circulating cells. Platelets are also usually increased, sometimes markedly. The spleen is often greatly enlarged as a result of extensive extramedullary hematopoiesis ( Fig. 13-34 ) and often contains infarcts of varying age. Extramedullary hematopoiesis can also produce mild hepatomegaly and lymphadenopathy

Answer 424

CML is primarily a disease of adults but also occurs in children and adolescents. The peak incidence is in the fifth to sixth decades of life. There are about 4500 new cases per year in the United States

Answer 425

The onset is insidious. Mild-to-moderate anemia and hypermetabolism due to increased cell turnover lead to fatigability, weakness, weight loss, and anorexia. Sometimes the first symptom is a dragging sensation in the abdomen caused by splenomegaly, or the acute onset of left upper quadrant pain due to splenic infarction. CML is best differentiated from other myeloproliferative disorders by detection of the BCR-ABL fusion gene through either chromosomal analysis or PCR-based tests

Answer 426

The natural history is one of slow progression; even without treatment, the median survival is about 3 years. After a variable period averaging 3 years, about 50% of patients enter an “accelerated phase” marked by increasing anemia and thrombocytopenia, sometimes accompanied by a rise in the number of basophils in the blood. Additional clonal cytogenetic abnormalities, such as trisomy 8, isochromosome 17q, or duplication of the Ph chromosome, often appear. Within 6 to 12 months, the accelerated phase terminates in a picture resembling acute leukemia ( blast crisis ). In the other 50% of patients, blast crises occur abruptly without an accelerated phase. In 70% of crises, the blasts are of myeloid origin (myeloid blast crisis), whereas in most of the remainder the blasts are of pre–B cell origin (lymphoid blast crisis). This is taken as evidence that CML originates from a pluripotent stem cell with both myeloid and lymphoid potential.

Answer 427

Given that we have seen that acute leukemias often stem from complementary mutations involving a transcription factor and a tyosine kinase, it might be predicted that blast crisis would be caused by an acquired mutation in a key transcriptional regulator. This prediction has been realized in lymphoid blast crisis, in which 85% of cases are associated with mutations that interfere with the activity of Ikaros, a transcription factor that regulates the differentiation of hematopoietic progenitors. The same types of Ikaros mutations are also seen in BCR-ABL-positive B-ALL, suggesting that these two varieties of aggressive leukemia have a similar pathogenic basis

Answer 428

The other major threat to the patient is the emergence of resistance to first generation BCR-ABL inhibitors, which in about 50% of cases stems from mutations in BCR-ABL and in the remaining cases mutations in other kinases. This problem has been overcome in part by development of second and third generation kinase inhibitors that are active against mutated forms of BCR-ABL. For relatively young patients, hematopoietic stem cell transplantation performed in the stable phase is curative in about 75% of cases. The outlook is less favorable once the accelerated phase or blast crisis supervenes, as transplantation and treatment with BCR-ABL inhibitors are both less effective in these settings

Answer 429

Polycythemia vera is strongly associated with activating point mutations in the tyrosine kinase JAK2 . Polycythemia vera (PCV) is characterized by increased marrow production of red cells, granulocytes, and platelets (panmyelosis), but it is the increase in red cells (polycythemia) that is responsible for most of the clinical symptoms. PCV must be differentiated from relative polycythemia resulting from hemoconcentration and other causes of absolute polycythemia

Answer 430

JAK2 participates in the JAK/ STAT pathway, which lies downstream of multiple hematopoietic growth factor receptors, including the erythropoietin receptor. In PCV the transformed progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic growth factors due to constitutive JAK2 signaling. Accordingly, serum erythropoietin levels in PCV are low, whereas secondary forms of polycythemia have high erythropoietin levels. The elevated hematocrit leads to increased blood viscosity and sludging. These hemodynamic factors, together with thrombocytosis and abnormal platelet function, make patients with PCV prone to both thrombosis and bleeding.

Answer 431

More than 97% of cases are associated with a mutation in JAK2 that results in a valine-to-phenylalanine substitution at residue 617; other JAK2 mutations are found in most (and perhaps all) of the remaining cases. The mutated forms of JAK2 found in PCV render hematopoietic cell lines growth factor-independent, and when expressed in murine bone marrow progenitors cause a PCV-like syndrome that is associated with marrow fibrosis. In 25% to 30% of cases the tumor cells contain two mutated copies of JAK2 , a genotype that is associated with higher white cell counts, more significant splenomegaly, symptomatic pruritus, and a greater rate of progression to the spent phase

Answer 432

The proliferative drive in PCV (and other myeloproliferative disorders associated with JAK2 mutations) is less than in CML, which is associated with more pronounced marrow hypercellularity, leukocytosis, and splenomegaly. Presumably, JAK2 signals are quantitatively weaker or qualitatively different from those produced by BCR-ABL ( Fig. 13-32 ).

Answer 433

The marrow is hypercellular, but some residual fat is usually present. The increase in red cell progenitors is subtle and usually accompanied by an increase in granulocytic precursors and megakaryocytes as well. At diagnosis, a moderate to marked increase in reticulin fibers is seen in about 10% of marrows. Mild organomegaly is common, being caused early in the course largely by congestion; at this stage extramedullary hematopoiesis is minimal. The peripheral blood often contains increased numbers of basophils and abnormally large platelets. Late in the course, PCV often progresses to a spent phase characterized by extensive marrow fibrosis that displaces hematopoietic cells. This is accompanied by increased extramedullary hematopoiesis in the spleen and liver, often leading to prominent organomegaly ( Fig. 13-35 ). Transformation to AML, with its typical features, occurs in about 1% of patients

Answer 434

PCV is uncommon, having an incidence of 1 to 3 per 100,000 per year. It appears insidiously, usually in adults of late middle age. Most symptoms are related to the increased red cell mass and hematocrit. Usually, there is also an increased total blood volume. Together, these factors cause abnormal blood flow, particularly on the low-pressure venous side of the circulation, which becomes greatly distended. Patients are plethoric and cyanotic due to stagnation and deoxygenation of blood in peripheral vessels. Headache, dizziness, hypertension, and gastrointestinal symptoms are common. Intense pruritus and peptic ulceration may occur, both possibly resulting from the release of histamine from basophils. High cell turnover gives rise to hyperuricemia; symptomatic gout is seen in 5% to 10% of cases

Answer 435

More ominously, the abnormal blood flow and platelet function lead to an increased risk of both major bleeding and thrombotic episodes. About 25% of patients first come to attention due to deep venous thrombosis, myocardial infarction, or stroke. Thromboses sometimes also occur in the hepatic veins (producing Budd-Chiari syndrome) and the portal and mesenteric veins (leading to bowel infarction). It should be remembered that thrombotic complications sometimes precede the appearance of the typical hematologic findings. Minor hemorrhages (epistaxis, bleeding gums) are common, and life-threatening hemorrhages occur in 5% to 10% of cases.

Answer 436

The hemoglobin concentration ranges from 14 to 28 gm/dL, and the hematocrit is usually 60% or more. Sometimes chronic bleeding leads to iron deficiency, which can suppress erythropoiesis sufficiently to lower the hematocrit into the normal range, an example of two defects counteracting one another to “correct” a laboratory abnormality. The white cell count ranges from 12,000 to 50,000 cells/mm 3 , and the platelet count is often greater than 500,000 platelets/mm 3 . The platelets usually exhibit morphologic abnormalities such as giant forms and are often defective in functional aggregation studies

Answer 437

Without treatment, death from bleeding or thrombosis occurs within months of diagnosis. However, simply maintaining the red cell mass at nearly normal levels by phlebotomy extends the median survival to about 10 years. JAK2 inhibitors are in preclinical development and represent a promising form of targeted therapy

Answer 438

Extended survival with treatment has revealed that PCV tends to evolve to a “spent phase,” during which clinical and anatomic features of primary myelofibrosis develop. The disease undergoes this transition in about 15% to 20% of patients after an average period of 10 years. It is marked by the appearance of obliterative fibrosis in the bone marrow (myelofibrosis) and extensive extramedullary hematopoiesis, principally in the spleen, which enlarges greatly. The mechanisms underlying the progression to the spent phase are not known.

Answer 439

Essential thrombocytosis (ET) is often associated with activating point mutations in JAK2 (50% of cases) or MPL (5% to 10% of cases), a receptor tyrosine kinase that is normally activated by thrombopoietin. In addition, recent DNA sequencing studies have revealed that most of the remaining cases have mutations in calreticulin, a protein with several described functions in the endoplasmic reticulum and the cytoplasm. Since JAK2 and calreticulin mutations are mutually exclusive, it is hypothesized that the calreticulin mutations also increase JAK-STAT signaling through currently unknown mechanisms

Answer 440

ET manifests clinically with elevated platelet counts and is separated from PCV and primary myelofibrosis based on the absence of polycythemia and marrow fibrosis, respectively. In those cases without tyrosine kinase mutations, causes of reactive thrombocytosis, such as inflammatory disorders and iron deficiency, must be excluded before the diagnosis can be established

Answer 441

Constitutive JAK2 or MPL signaling renders the progenitors thrombopoietin-independent and leads to hyperproliferation. The JAK2 mutation is the same as that found in almost all cases of PCV. Why some patients with JAK2 mutations present with PCV and others with ET is not understood. Some cases of “ET” may in fact be PCV disguised by iron deficiency (which is more common in individuals diagnosed with ET), but this is probably true of only a small fraction of patients. As mentioned, most cases without JAK2 or MPL mutations have calreticulin mutations instead

Answer 442

Bone marrow cellularity is usually only mildly increased, but megakaryocytes are often markedly increased in number and include abnormally large forms. Delicate reticulin fibrils are often seen, but the overt fibrosis of primary myelofibrosis (see later) is absent. Peripheral smears usually reveal abnormally large platelets ( Fig. 13-36 ), often accompanied by mild leukocytosis. Modest degrees of extramedullary hematopoiesis may occur, producing mild organomegaly in about 50% of patients. Uncommonly, a spent phase of marrow fibrosis or transformation to AML supervenes

Answer 443

The incidence of ET is 1 to 3 per 100,000 per year. It usually occurs past the age of 60 but may also be seen in young adults. Dysfunctions of platelets derived from the neoplastic clone can lead to thrombosis and hemorrhage, the major clinical manifestations. Platelets are not only increased in numbers but also frequently demonstrate qualitative abnormalities in functional tests. The types of thrombotic events resemble those observed in PCV; they include deep venous thrombosis, portal and hepatic vein thrombosis, and myocardial infarction. One characteristic symptom is erythromelalgia , a throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates, which may also be seen in PCV

Answer 444

ET is an indolent disorder with long asymptomatic periods punctuated by occasional thrombotic or hemorrhagic crises. Median survival times are 12 to 15 years. Thrombotic complications are most likely in patients with very high platelet counts and homozygous JAK2 mutations. Therapy consists of “gentle” chemotherapeutic agents that suppress thrombopoiesis

Answer 445

The hallmark of primary myelofibrosis is the development of obliterative marrow fibrosis. The replacement of the marrow by fibrous tissue reduces bone marrow hematopoiesis, leading to cytopenias and extensive extramedullary hematopoiesis. Histologically, the appearance is identical to the spent phase that occurs occasionally late in the course of other myeloproliferative disorders. This similarity also extends to the underlying pathogenesis

Answer 446

As with ET, most of the remaining cases have been recently observed to have mutations in calreticulin that are hypothesized to give rise to increased JAK-STAT signaling.

Answer 447

. The fibrosis inexorably displaces hematopoietic elements, including stem cells, from the marrow and eventually leads to marrow failure. It is probably caused by the inappropriate release of fibrogenic factors from neoplastic megakaryocytes. Two factors synthesized by megakaryocytes have been implicated: platelet-derived growth factor and TGF-β . As you recall, platelet-derived growth factor and TGF-β are fibroblast mitogens. In addition, TGF-β promotes collagen deposition and causes angiogenesis, both of which are observed in myelofibrosis

Answer 448

arly in the course, the marrow is often hypercellular due to increases in maturing cells of all lineages, a feature reminiscent of PCV. Morphologically, the erythroid and granulocytic precursors appear normal, but megakaryocytes are large, dysplastic, and abnormally clustered. At this stage fibrosis is minimal, and the blood may show leukocytosis and thrombocytosis. With progression, the marrow becomes more hypocellular and diffusely fibrotic. Clusters of atypical megakaryocytes with unusual nuclear shapes (described as “cloud-like”) are seen, and hematopoietic elements are often found within dilated sinusoids, which is a manifestation of severe architectural distortion cause by the fibrosis. Very late in the course, the fibrotic marrow space may be converted into bone, a change called “osteosclerosis.” These features are identical to those seen in the spent phase of other myeloproliferative disorders

Answer 449

which is usually markedly enlarged, sometimes up to 4000 gm. Grossly, such spleens are firm and diffusely red to gray. As in CML, subcapsular infarcts are common (see Fig. 13-40 ). Initially, extramedullary hematopoiesis is confined to the sinusoids, but later it expands into the cords. The liver may be enlarged moderately by sinusoidal foci of extramedullary hematopoiesis. Hematopoiesis can also appear within lymph nodes, but significant lymphadenopathy is uncommon.

Answer 450

Primary myelofibrosis is less common than PCV and ET and usually occurs in individuals older than 60 years of age. Except when preceded by another myeloproliferative disorder, it comes to attention because of progressive anemia and splenomegaly, which produces a sensation of fullness in the left upper quadrant. Nonspecific symptoms such as fatigue, weight loss, and night sweats result from an increase in metabolism associated with the expanding mass of hematopoietic cells. Hyperuricemia and secondary gout due to a high rate of cell turnover can complicate the picture

Answer 451

Laboratory studies typically show a moderate to severe normochromic normocytic anemia accompanied by leukoerythroblastosis. The white cell count is usually normal or mildly reduced, but can be markedly elevated (80,000 to 100,000 cells/mm 3 ) early in the course. The platelet count is usually normal or elevated at the time of diagnosis, but thrombocytopenia may supervene as the disease progresses. These blood findings are not specific; bone marrow biopsy is essential for diagnosis

Answer 452

Threats to life include intercurrent infections, thrombotic episodes, bleeding related to platelet abnormalities, and transformation to AML, which occurs in 5% to 20% of cases. When myelofibrosis is extensive, AML sometimes arises at extramedullary sites, including lymph nodes and soft tissues. JAK2 inhibitors have recently been approved to treat this disease and are effective at decreasing the splenomegaly and constitutional symptoms. Hematopoietic stem cell transplantation offers some hope for cure in those young and fit enough to withstand the procedure.

Answer 453

Aggressive tumors comprised of immature myeloid lineage blasts, which replace the marrow and suppress normal hematopoiesis ▪ Associated with diverse acquired mutations that lead to expression of abnormal transcription factors, which interfere with myeloid differentiation ▪ Often also associated with mutations in genes encoding growth factor receptor signaling pathway components or regulators of the epigenome

Answer 454

▪ Myeloid tumors in which production of formed myeloid elements is initially increased, leading to high blood counts and extramedullary hematopoiesis ▪ Commonly associated with acquired mutations that lead to constitutive activation of tyrosine kinases, which mimic signals from normal growth factors. The most common pathogenic kinases are BCR-ABL (associated with CML) and mutated JAK2 (associated with polycythemia vera and primary myelofibrosis). ▪ All can transform to acute leukemia and to a spent phase of marrow fibrosis associated with anemia, thrombocytopenia, and splenomegaly

Answer 455

▪ Poorly understood myeloid tumors characterized by disordered and ineffective hematopoiesis and dysmaturation ▪ Recently shown to frequently harbor mutations in splicing factors and epigenetic regulators ▪ Manifest with one or more cytopenias and progress in 10% to 40% of cases to AML

Answer 456

The term histiocytosis is an “umbrella” designation for a variety of proliferative disorders of dendritic cells or macrophages. Some, such as rare “histiocytic” lymphomas, are clearly malignant, whereas others, such as reactive proliferations of macrophages in lymph nodes, are clearly benign. Lying between these two extremes are the Langerhans cell histiocytoses, a spectrum of proliferations of a special type of immature dendritic cell called the Langerhans cell

Answer 457

Regardless of the clinical picture, the proliferating Langerhans cells have abundant, often vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds ( Fig. 13-38 A ). The presence of Birbeck granules in the cytoplasm is characteristic. Birbeck granules are pentalaminar tubules, often with a dilated terminal end producing a tennis racket-like appearance ( Fig. 13-38 B ), which contain the protein langerin. In addition, the tumor cells also typically express HLA-DR, S-100, and CD1a.

Answer 458

• Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease) occurs most frequently before 2 years of age but occasionally affects adults. A dominant clinical feature is the development of cutaneous lesions resembling a seborrheic eruption, which is caused by infiltrates of Langerhans cells over the front and back of the trunk and on the scalp. Most of those affected have concurrent hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and (eventually) destructive osteolytic bone lesions. Extensive infiltration of the marrow often leads to anemia, thrombocytopenia, and a predisposition to recurrent infections, such as otitis media and mastoiditis. In some instances the tumor cells are quite anaplastic; such tumors are sometimes referred to as Langerhans cell sarcoma. The course of untreated disease is rapidly fatal. With intensive chemotherapy, 50% of patients survive 5 years

Answer 459

• Unifocal and multifocal unisystem Langerhans cell histiocytosis (eosinophilic granuloma) is characterized by proliferations of Langerhans cells admixed with variable numbers of eosinophils, lymphocytes, plasma cells, and neutrophils. Eosinophils are usually, but not always, a prominent component of the infiltrate. It typically arises within the medullary cavities of bones, most commonly the calvarium, ribs, and femur. Less commonly, unisystem lesions of identical histology arise in the skin, lungs, or stomach.

Answer 460

. Unifocal lesions most commonly affect the skeletal system in older children or adults. Bone lesions can be asymptomatic or cause pain, tenderness, and, in some instances, pathologic fractures. Unifocal disease is indolent and may heal spontaneously or be cured by local excision or irradiation

Answer 461

Multifocal unisystem disease usually affects young children, who present with multiple erosive bony masses that sometimes expand into adjacent soft tissue. Involvement of the posterior pituitary stalk of the hypothalamus leads to diabetes insipidus in about 50% of patients

Answer 462

The combination of calvarial bone defects, diabetes insipidus, and exophthalmos is referred to as the Hand-Schüller-Christian triad. Many patients experience spontaneous regression; others can be treated successfully with chemotherapy.

Answer 463

• Pulmonary Langerhans cell histiocytosis represents a special category of disease, most often seen in adult smokers, which may regress spontaneously upon cessation of smoking. These lesions have been described as reactive proliferations of Langerhans cells, but fully 40% are associated with BRAF mutations, suggesting that in many instances, they too are neoplastic in origin

Answer 464

. For example, while normal epidermal Langerhans cells express CCR6, their neoplastic counterparts express both CCR6 and CCR7. This allows the neoplastic cells to migrate into tissues that express the relevant chemokines — CCL20 (a ligand for CCR6) in skin and bone, and CCL19 and 21 (ligands for CCR7) in lymphoid organs

Answer 465

Spleen The spleen is an ingeniously designed filter for the blood and a site of immune responses to blood-borne antigens. Normally in the adult it weighs about 150 gm and is enclosed within a thin, glistening, slate-gray connective tissue capsule. Its cut surface reveals extensive red pulp dotted with gray specks, which are the white pulp follicles. These consist of an artery with an eccentric collar of T lymphocytes, the so-called periarteriolar lymphatic sheath. At intervals this sheath expands to form lymphoid nodules composed mainly of B lymphocytes, which are capable of developing into germinal centers identical to those seen in lymph nodes in response to antigenic stimulation