13 Heme Lymph Flashcards
Myeloid tissue
Bone marrow and cells derived from it
Lymphoid tissue
Thymus, lymph nodes, spleen
When do blood cell progenitors first pappear adnexal what are they derived from?
Cells derived from the yolk sac are the source of long-lived tissue macrophages, such as microglial cells in the brain and Kupffer cells in the liver ( Chapter 3 ), but the contribution of the yolk sac to blood formation, mainly in the form of embryonic red blood cells, is only transient
Definitive hematopoietic stem cells . When arise?
Definitive hematopoietic stem cells (HSCs) arise several weeks later in the mesoderm of the intraembryonic aorta/gonad/mesonephros region
3rd 4th month embryogenesis
During the third month of embryogenesis, HSCs migrate to the liver, which becomes the chief site of blood cell formation until shortly before birth. HSCs also take up residence in the fetal placenta; this pool of HSCs is of uncertain physiologic relevance, but has taken on substantial clinical importance, as HSCs harvested at birth from umbilical cord blood are being used increasingly in therapeutic hematopoietic stem cell transplantation. By the fourth month of development, HSCs shift in location yet again, taking up residence in the bone marrow
Birth
By birth, marrow throughout the skeleton is hematopoietically active and hepatic hematopoiesis dwindles to a trickle, persisting only in widely scattered foci that become inactive soon after birth
Until puberty
Until puberty, hematopoietically active marrow is found throughout the skeleton, but soon thereafter it becomes restricted to the axial skeleton. Thus, in normal adults, only about half of the marrow space is hematopoietically active
Formed elements of blood
red cells, granulocytes, monocytes, platelets, and lymphocytes—have a common origin from HSCs, pluripotent cells that sit at the apex of a hierarchy of bone marrow progenitors
Colony forming unity’s
they produce colonies composed of specific kinds of mature cells when grown in culture.
From the various committed progenitors are derived the morphologically recognizable precursors
myeloblasts, proerythroblasts, and megakaryoblasts, which are the immediate progenitors of mature granulocytes, red cells, and platelets
HSCs have two essential properties that are required for the maintenance of hematopoiesis
pluripotency and the capacity for self-renewal
Pluripotent
Pluripotency refers to the ability of a single HSC to generate all mature blood cells
When HSC divides
, at least one daughter cell must self-renew to avoid stem cell depletion
Self renewing divisions
Self-renewing divisions occur within a specialized marrow niche, in which stromal cells and secreted factors nurture and protect the HSCs
HSC sessile?
No
What happens to HSC when under stress, such as severe anemia or acute inflammation
, HSCs are mobilized from the bone marrow and appear in the peripheral blood
Where get HSC used in transplantation
n fact, HSCs used in transplantation are now mainly collected from the peripheral blood of donors treated with granulocyte colony stimulating factor (G-CSF), one of the factors that can mobilize a fraction of marrow HSCs from their stem cell niches.
Marrow response to short term physiologic needs regulated
The marrow response to short-term physiologic needs is regulated by hematopoietic growth factors through effects on the committed progenitors
Why must blood elements be constantly replenished
s. Because mature blood elements are terminally differentiated cells with finite life spans, their numbers must be constantly replenished
Multi potent progenitors
which are more proliferative than HSCs but have a lesser capacity for self-renewal ( Fig. 13-1 ). Division of multipotent progenitors gives rise to at least one daughter cell that leaves the stem cell pool and begins to differentiate. Once past this threshold, these newly committed cells lose the capacity for self-renewal and commence an inexorable journey down a road that leads to terminal differentiation and death. However, as these progenitors differentiate, they also begin to proliferate more rapidly in response to growth factors, expanding their numbers
Stem cell factor (KIT ligand) and FLT3 ligand
Some growth factors, such as stem cell factor (also called KIT ligand ) and FLT3-ligand, act through receptors that are expressed on very early committed progenitors
Epo, GM-CSF, G-CSF and thrombophlebitis
Others, such as erythropoietin, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and thrombopoietin, act through receptors that are only expressed on committed progenitors with more restricted differentiation potentials
White cell range
4.8-10.8 x10^3
Granulocytes range %
40-70
Neutrophils 10^3 range
1.4-6.5
Lymphocytes x10^3 range
1.2-3.4
Monocytes x1-^3/microL
.1-,6
Eosinophilsx10^3
0-.5
Basophils x10^3 range
0-.2
Red cells range x1-^3/microL
- 3-5 men
3. 5-5 women
Platelets x10^3 microL
150-450
Blood cells in response to disease
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
Tumors of hematopoietic origin are often associated with mutations that block progenitor cell maturation or abrogate their growth factor dependence
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 ).
Bone marrow morphology
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.
Mega karyotype s
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
Leukoerythroblastosis
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
Best assessment of morphology of hematopoietic cells
Marrow aspirate
Immature precursors
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
Mature marrow
Morphology alone
In normal adults ratio fat ells to hematopoietic elements
1:1
Hypoplastic state
Fat decreased,
Hematopoietic tumors and diseases with compensatory hyperplasias (hemolyticanemias) and neoplastic proliferations such as Leukemias
Fat cells disappear
Marrow fibrosis-inaspirable and bes with biopsies
Metastatic cancer and granulomatous
Two categories of disorders of white blood cells
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.
Why proliferations of white cells
Reactive or neoplastic
Reactive proliferations white cells
Reactive proliferations in the setting of infections or inflammatory processes, when leukocytes are needed for an effective host response, are fairly common
Neoplastic disorders
Neoplastic disorders, though less frequent, are much more important clinically
Leukopenia
An abnormally low white cell count (leukopenia) ) usually results from reduced numbers of neutrophils (neutropenia, granulocytopenia) .
Lymphopenia
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.
Acute viral infections
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
Granulocytopenia
Granulocytopenia is more common and is often associated with diminished granulocyte function, and thus merits further discussion
Neutropenia
Neutropenia , a reduction in the number of neutrophils in the blood, occurs in a wide variety of circumstances
Agranulocytosis
Agranulocytosis , a clinically significant reduction in neutrophils, has the serious consequence of making individuals susceptible to bacterial and fungal infections
Causes of neutropenia
(1) inadequate or ineffective granulopoiesis, or (2) increased destruction or sequestration of neutrophils in the periphery
Suppression of hematopoietic stem cells
, 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
Suppression of committed granulocytic precursors
Exposure to certain drugs
Ineffective hematopoiesis
, such as megaloblastic anemias ( Chapter 14 ) and myelodysplastic syndromes, in which defective precursors die in the marrow
Congenital conditions (kostmann)
e.g., Kostmann syndrome) in which inherited defects in specific genes impair granulocytic differentiation
Accelerated destruction with
Immunologically mediated injury to neutrophils
Splenmegaly
Increased peripheral utilization
Immunologically mediated injury
• 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
Splenomegaly
• Splenomegaly , in which splenic enlargement leads to sequestration of neutrophils and modest neutropenia, sometimes associated with anemia and often with thrombocytopenia
Increased peripheral utilization
Increased peripheral utilization , which can occur in overwhelming bacterial, fungal, or rickettsial infections
Most common cause of agranulocytosis
Drug toxicity
Drugs agranulocytosis
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
Agranulocytosis can also occur as an idiosyncratic reaction to a large variety of agents.
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.
In contrast, agranulocytosis following administration of other drugs, such as sulfonamides, probably stems from antibody-mediated destruction of mature neutrophils through mechanisms similar to those involved in drug-induced immunohemolytic anemias
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In some patients with acquired idiopathic neutropenia, autoantibodies directed against neutrophil-specific antigens are detected
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.
Bone marrow With excessive destruction of neutrophils in the periphery
With excessive destruction of neutrophils in the periphery, the marrow is usually hypercellular due to a compensatory increase in granulocytic precursors.
Ineffective granulocytes s
Hypercellularity is also the rule with neutropenias caused by ineffective granulopoiesis, as occurs in megaloblastic anemias and myelodysplastic syndromes.
Agranulocytosis
Agranulocytosis caused by agents that suppress or destroy granulocytic precursors is understandably associated with marrow hypocellularity
Infections
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.
Symptoms neutropenia
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.
Serious neutropenia
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.
Leukocytosis
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
What influences peripheral blood leukocyte count
- 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
How is leukocyte hemostasis maintained
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
Most important mechanism of neutrophilic leukocytosis and its causes
Infection
Acute infection
. 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
Increased production in marrow
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)
Increased release from marrow stores
Endotoxemia
Infection
Hypoxia
Decreased margination
Exercise
Catecholamines
Decreased extravasation into tissues
Glucocorticoids
Some growth factors preferentially stimulate the production of a single type of leukocyte
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
Neutrophilic leukocytosis
Acute bacterial infections, especially those caused by pyogenic organisms; sterile inflammation caused by, for example, tissue necrosis (myocardial infarction, burns
Eosinophilic leukocytosis
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
Basophils leukocytosis
Rare, often indicative of a myeloproliferative disease (e.g., chronic myelogenous leukemia
Monocytos
Chronic infections (e.g., tuberculosis), bacterial endocarditis, rickettsiosis, and malaria; autoimmune disorders (e.g., systemic lupus erythematosus); inflammatory bowel diseases (e.g., ulcerative colitis
Lymphotisis
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
Sepsis of severe inflammatory disorders(Kawasaki)
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
In most instances it is not difficult to distinguish reactive and neoplastic leukocytoses, but uncertainties may arise in two settings
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
CD34
CD34: Antigen/marker of HSC cells
Cd45
leukocyte common antigen – found on all white cells
Following their initial development from precursors in the central (also called primary) lymphoid organs—the bone marrow for B cells and the thymus for T cells—lymphocytes
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
Activation of resident immune cells leads to
morphologic changes in lymph nodes
Within several days of antigenic stimulation, the primary follicles enlarge and develop pale-staining germinal centers
, 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.
The degree and pattern of the morphologic changes are dependent on the inciting stimulus and the intensity of the response
Trivial injuries and infections induce subtle changes, while more significant infections inevitably produce nodal enlargement and sometimes leave residual scarring.
For this reason, lymph nodes in adults are almost never “normal” or “resting,” and it is often necessary to distinguish morphologic changes secondary to past experience from those related to present disease
Infections and inflammatory stimuli often elicit regional or systemic immune reactions within lymph nodes. Some that produce distinctive morphologic patterns are described in other chapters. Most, however, cause stereotypical patterns of lymph node reaction designated acute and chronic nonspecific lymphadenitis.
Acute nonspecific lymphadenitis
Acute lymphadenitis in the cervical region is most often due to drainage of microbes or microbial products from infections of the teeth or tonsils, while in the axillary or inguinal regions it is most often caused by infections in the extremities. Acute lymphadenitis also occurs in mesenteric 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
Morphology acute nonspecific lymphadenitis
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
Nodes in acute lymphadenitis
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
Chronic nonspecific lymphadenitis
Chronic immunologic stimuli produce several different patterns of lymph node reaction, as described later
Follicular hyperplasia
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
Follicular hyperplasia
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
Causes of ollicular hyperplasia
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
Paracortical hyperplasia
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
Sinus histoocytosis
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
Lymph nodes in chronic reactions
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.
Furthermore, chronic immune reactions can promote the appearance of organized collections of immune cells in nonlymphoid tissues
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.
Hemophagocytic lymphohistocytosis
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
The common feature of all forms of HLH is systemic activation of macrophages and CD8+ cytotoxic T cells
. 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 ).
Familial forms of HLH are associated with several different mutations, all of which impact the ability of cytotoxic T cells and NK cells to properly form or deploy cytotoxic granules
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).
Clincial
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
Treatment
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
Malignancies white cells
Malignancies are clinically the most important disorders of white cells. These diseases fall into several broad categories
Lymphoid neoplasma
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
Myeloid neoplasma
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;
Myelodysplasia syndromes
myelodysplastic syndromes , which are associated with ineffective hematopoiesis and resultant peripheral blood cytopenias
Chronic myeloproliferative disorders
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
Histiocytosis
• 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
Nonrandom chromosomal abnormalities, most commonly translocations, are present in the majority of white cell neoplasms
. Many specific rearrangements are associated with particular neoplasms, suggesting a critical role in their genesis ( Chapter 7 ).
• The genes that are mutated or otherwise altered often play crucial roles in the development, growth, or survival of the normal counterpart of the malignant cell
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).
• Oncoproteins created by genomic aberrations often block normal maturation, turn on pro-growth signaling pathways, or protect cells from apoptotic cell death
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.
• Many oncoproteins cause an arrest in differentiation, often at a stage when cells are proliferating rapidly
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.
• Other mutations in transcriptional regulators seem to directly enhance the self-renewal of tumors cells, giving such cells stem-cell–like properties
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.
• Finally, mutations that inhibit apoptosis are prevalent in certain hematologic malignancies
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Pathogenesis of white cell malignancies
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
• Proto-oncogenes are often activated in lymphoid cells by errors that occur during antigen receptor gene rearrangement and diversification
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
Protooncogene
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
Inherited disorders
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
Three lymphotropic viruses
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
Chronic inflammation
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
Iatrogenic factors
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
Smoking
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
Leukemia
is used for neoplasms that present with widespread involvement of the bone marrow and (usually, but not always) the peripheral blood
Lymphoma
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
Hodgkin lymphoma
Hodgkin lymphoma has distinctive pathologic features and is treated in a unique fashion.
Plasma cell neoplasma
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
T aken together, the diverse lymphoid neoplasms constitute a complex, clinically important group of cancers, with about 100,000 new cases being diagnosed each year in the United States.
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Clincial presentation of various neoplasma
is most often determined by the anatomic distribution of disease
Two thirds of NHLs and virtually all Hodgkin lymphomas present as enlarged nontender lymph nodes (often > 2 cm). The remaining one third of NHLs present with symptoms related to the involvement of extranodal sites (e.g., skin, stomach, or brain)
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
Most common plasma cell neoplasm
multiple myeloma, causes bony destruction of the skeleton and often presents with pain due to pathologic fractures.
Symptoms lymphoid tumros
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
Specific examples include the plasma cell tumors, in which much of the pathophysiology is related to the secretion of whole antibodies or Ig fragments;
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
Precursor B cell neoplasms
Neoplasms of immature B cells
Peripheral B cell neoplasms
Neoplasms of mature B cells
Precursor T cell neoplasms
Neoplasms of immature T cells
Peripheral T cell and nk cell neoplasms
Neoplasms of mature T cells and NK cells
Hodgkin lymphoma
Neoplasms of reed stern berg cells and variants
Precursor B cell neoplasms
B-cell acute lymphoblastic leukemia/lymphoma (B-ALL
Peripheral B cell neoplasms
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
Precursor T cell neoplasms
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL
Peripheral T cell and nk cel neoplasms
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
Hodgkin lymphoma
Classical subtypes Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depletion Lymphocyte predominance
Antigen receptor gene rearrangement generally precedes transformation of lymphoid cells; hence, all daughter cells derived from the malignant progenitor share the same antigen receptor gene configuration and sequence, and synthesize identical antigen receptor proteins (either Igs or T-cell receptors
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
• Most lymphoid neoplasms resemble some recognizable stage of B- or T-cell differentiation
( 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
Origin of lymphoid neoplasms
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.
CD1
Thymocytes and Langerhans cells
Cd3
Thymocytes, mature T cells
Cd4
Helper T cells, subset of thymocytes
Cd5
T cells and a small subset of B cells
Cd8
Cytotoxic T cells, subset of thymocytes, and some NK cells
Cd10
Pre-B cells and germinal-center B cells
Cd19
Pre-B cells and mature B cells but not plasma cells
Cd20
Pre-B cells after CD19 and mature B cells but not plasma cells
Cd21
EBV receptor; mature B cells and follicular dendritic cells
Cd23
Activated mature B cells
Cd79a
Marrow pre-B cells and mature B cells
Cd11c
Granulocytes, monocytes, and macrophages; also expressed by hairy cell leukemias
Cd13
Immature and mature monocytes and granulocytes
Cd14
Monocytes
Cd15
Granulocytes; Reed-Sternberg cells and variants
Cd33
Myeloid progenitors and monocytes
Cd64
Mature myeloid cells
Cd16
NK cells and granulocytes
Cd56
NK cells and a subset of T cells
Cd34
Pluripotent hematopoietic stem cells and progenitor cells of many lineages
Cd30
Activated B cells, T cells, and monocytes; Reed-Sternberg cells and variants
Cd45
All leukocytes; also known as leukocyte common antigen (LCA)
Lymphoid neoplasms are often associated with immune abnormalities
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
• Neoplastic B and T cells tend to recapitulate the behavior of their normal counterparts
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
• Hodgkin lymphoma spreads in an orderly fashion, whereas most forms of NHL spread widely early in their course in a less predictable fashion
Hence, while lymphoma staging provides generally useful prognostic information, it is of most utility in guiding therapy in Hodgkin lymphoma
We now turn to the specific entities of the WHO classification. We will begin with neoplasms of immature lymphoid cells, and then discuss the more common Non-Hodgkin lymphomas and plasma cell neoplasms, followed by a selection of rarer lymphoid neoplams that are pathogenically informative or of particular clinical importance. Some of the salient molecular and clinical features of these neoplasms are summarized in Table 13-6 . We will finish by discussing the Hodgkin lymphomas
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B cell acute lymphoblastic leukemia/lymphoma
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
T cell acute lymphocblastic leukemia/lymphoma
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
Burkitt lymphoma
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
Diffuse large B cell lymphoma
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
Extranodal marginal zone lymphoma
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
Follicular lymphoma
Germinal-center B cell t(14;18) creating BCL2-IgH fusion gene Older adults with generalized lymphadenopathy and marrow involvement; indolent
Hairy cell leukemia
Memory B cell Activating BRAF mutations Older males with pancytopenia and splenomegaly; indolent
Mantle
Naive B cell t(11;14) creating CyclinD1 - IgH fusion gene Older males with disseminated disease; moderately aggressive
MULTIPLE MYELOMA/SOLITARY PLASMACYTOMA
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
Small lymphocytic lymphoma/chronic lymphocytic leukemia
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
Adult T cell leukemia/lymphoma
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
Peripheral T cell lymphoma, unspecified
Helper or cytotoxic T cell No specific chromosomal abnormality Mainly older adults; usually presents with lymphadenopathy; aggressive
Anaplastic large cell lymphoma
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
Extranodal nk/t cell lymphoma
NK-cell (common) or cytotoxic T cell (rare) EBV-associated; no specific chromosomal abnormality Adults with destructive extranodal masses, most commonly sinonasal; aggressive
My oasis fungoides/sezary syndrome
Helper T cell No specific chromosomal abnormality Adult patients with cutaneous patches, plaques, nodules, or generalized erythema; indolent
Large granular lymphocytic leukemia
Two types: cytotoxic T cell and NK cell Point mutations in STAT3 Adult patients with splenomegaly, neutropenia, and anemia, sometimes, accompanied by autoimmune disease
Acute lymphoblastic leukemia/lymphomas (ALLs) are neoplasms composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts
. 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
ALL is the most common cancer of children
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
Many of the chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors required for normal B- and T-cell development
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
n keeping with the multistep origin of cancer ( Chapter 7 ), single mutations are not sufficient to produce ALL
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
Approximately 90% of ALLs have numerical or structural chromosomal changes. Most common is hyperploidy (>50 chromosomes), but hypoploidy and a variety of balanced chromosomal translocations are also seen
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
In leukemic presentations, the marrow is hypercellular and packed with lymphoblasts, which replace the normal marrow elements. Mediastinal thymic masses occur in 50% to 70% of T-ALLs, which are also more likely to be associated with lymphadenopathy and splenomegaly.
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 ).
