CHAPTER 69 BASOPHILS AND MAST CELLS AND THEIR DISORDERS
CHAPTER 69 BASOPHILS AND MAST CELLS AND THEIR DISORDERS
STEPHEN J. GALLI
DEAN D. METCALFE
ANN M. DVORAK
Distinguishing Features of Basophils and Mast Cells
Morphology of Basophils and Mast Cells
Biochemistry and Role in Ige-Associated Immune Responses
Role in Acute Reactions
Role in Late-Phase and Chronic Allergic Reactions
Role in Late-Phase Reactions and the Mast Cell–Leukocyte Cytokine Cascade
Ige-Dependent Upregulation of Fce Ri Expression and Fce Ri-Dependent Function
Roles in T-Cell-Dependent Responses not Involving IGE
Biological Functions of Basophils and Mast Cells
Roles in Host Defense
Other Functions and Mast Cell Knock-In Mice
Blood Basophil Count
Disorders Affecting Mast Cells
Normal Mast Cell Levels
Secondary Changes in Mast Cell Numbers
Disorders of Mast Cell Hyperplasia/Neoplasia
Although basophils and mast cells share certain biochemical and functional characteristics, they are not identical. In humans, basophils are the least frequent of the three granulocytes, typically accounting for less than 0.5 percent of blood leukocytes. Basophils circulate as mature cells and can be recruited into tissues, particularly at sites of immunological or inflammatory responses, but they ordinarily do not reside in tissues. By contrast, mast cells typically are derived from blood precursors that lack many of the characteristic features of the mature cells and complete their maturation in the tissues. The mature mast cells can reside in tissues for long periods of time. Mast cells are particularly abundant near blood vessels and nerves and in connective tissues beneath surfaces that are exposed to the external environment, such as the skin, gastrointestinal, and urogenital tracts and the respiratory system. Tissue mast cell numbers can increase at sites of parasite infection, certain chronic allergic diseases, or other forms of pathology, by the recruitment and local maturation of blood precursors and the proliferation of resident mast cells.
Mast cells and basophils express the high-affinity receptor for IgE (FceRI) on their surface, and both types of cells can be triggered to release potent mediators in response to activation via the FceRI, e.g., when their cell-bound IgE recognizes bi- or multivalent allergens. Accordingly, mast cells and basophils have long been regarded as important effector cells in asthma, hay fever, and other allergic disorders. Indeed, it is thought that the cells’ cytoplasmic granule-associated preformed mediators, including histamine and certain proteases, their lipid mediators (such as prostaglandin D2 and leukotriene C4), which are generated upon activation of the cells, and their cytokines, contribute to many of the characteristic signs and symptoms of these diseases. However, several lines of evidence indicate that mast cells and basophils also contribute to protective host responses that are associated with IgE production, especially those directed against parasites, and for mast cells in innate immune responses to certain bacterial infections. Through cytokine production and other mechanisms, mast cells and basophils may also execute immunoregulatory functions.
While a variety of systemic disorders have been associated with changes in the numbers of blood basophils, and many pathological processes can be associated with changes in the numbers of tissue mast cells, patients with primary deficiencies in basophils appear to be exceedingly rare (if they exist at all), and there have been no reports of patients with a primary deficiency of tissue mast cells. By contrast, neoplastic processes can affect both of these lineages. Increased numbers of basophils may be present in association with myeloproliferative disorders and several forms of myelogenous or promyelocytic leukemias, and increased numbers of basophils, sometimes to levels of 20 to 90 percent of blood leukocytes, occur in virtually all patients with chronic myelogenous leukemia. It is thought that the basophils associated with cases of leukemia are themselves neoplastic. The management of patients with “basophilic leukemia” can be complicated by shock due to the massive release of histamine and other mediators in association with acute cytolysis.
Disorders of mast cell hyperplasia/neoplasia include solitary mastocytomas, the pathogenesis of which is uncertain, the spectrum of disorders encompassed in the term mastocytosis, in which significantly increased numbers of mast cells occur in the skin and/or other organs, and mast cell leukemia. The most common form of mastocytosis (category I or indolent mastocytosis), typically presents with urticaria pigmentosa involving the skin, although other organs may also be involved; patients with indolent mastocytosis have the best prognosis and can expect a normal life-span. The prognosis of category II disease (mastocytosis with an associated hematological disorder) depends on the course of the associated disease. Patients with category III disease (aggressive mastocytosis) have a guarded prognosis because of complications arising from rapid increases in tissue mast cell numbers. And patients with mast cell leukemia (category IV disease), who often present with large numbers of immature mast cells in the peripheral blood at the time of diagnosis, have a fulminant and rapidly fatal course. Many, if not all, adult patients with mastocytosis have gain-of-function mutations affecting c-kit, which encodes the receptor for the major mast cell growth factor, stem cell factor (also known as kit ligand and mast cell growth factor). Some pediatric patients with mastocytosis have been reported to have the same Asp816Val gain-of-function c-kit mutation that is observed in adult patients, others have a dominant inactiviating c-kit mutation, whereas others appear to lack c-kit mutations entirely.
Acronyms and abbreviations that appear in this chapter include: AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia; GGTP, gamma-glutamyltranspeptidase; H&E, hematoxylin and eosin; IL, interleukin; PUVA, psoralen ultraviolet A; SCF, stem cell factor; TNF-aa, tumor necrosis factor a; UP, urticaria pigmentosa.
DISTINGUISHING FEATURES OF BASOPHILS AND MAST CELLS
Despite certain striking similarities in biochemistry and function, mammalian basophils and mast cells are not identical, 1,2,3,4 and 5 a distinction appreciated by Paul Ehrlich, who described the histochemical staining characteristics of both of these cells in the late nineteenth century. Many lines of evidence indicate that basophils share a common precursor with other granulocytes and monocytes.1,2,3,4 and 5 Basophils have a short life-span6 and retain granulocytic features even after emigrating into tissues (Fig. 69-1).
FIGURE 69-1 Mast cell (M) and basophil (B) in the ileal submucosa of a patient with Crohn’s disease. The mast cell is a larger, mononuclear cell with a more complex plasma membrane surface and cytoplasmic granules that are smaller and more numerous than those of the basophil. In this section plane, the basophil exhibits two nuclear lobes. Several basophil cytoplasmic granules contain whorls of membranes (arrows). Osmium collidine uranyl en bloc processing. (Source: Dvorak and coworkers37 with permission.)
The human basophil is the least common blood granulocyte, with a prevalence of about 0.5 percent of total leukocytes and about 0.3 percent of nucleated marrow cells.7 Although the basophil’s prominent metachromatic cytoplasmic granules allow unmistakable identification in Wright-Giemsa–stained films of blood or marrow, accurate basophil determinations require absolute counting methods.8 Differential counts of blood films yield valid results only if the percentage of basophils is substantially elevated or if many thousands of leukocytes are counted.
Interleukin-3 (IL-3) promotes the production and survival of human basophils in vitro3,9 and can induce basophilia in vivo.10 Findings in IL-3 –/– mice indicate that IL-3 is not necessary for the development of normal numbers of bone marrow or blood basophils but is very important for the bone marrow and blood basophilia associated with certain Th2 cell-associated immunological responses.11,12 Basophils also express receptors for several other cytokines (Table 69-1). IL-3 and some of these other cytokines can modulate basophil function, e.g., by inducing mediator release directly and/or by augmenting the cells’ ability to release mediators in response to challenge with IgE and specific antigen.3,10,13,14
TABLE 69-1 NATURAL HISTORY, MAJOR MEDIATORS, AND SURFACE MEMBRANE STRUCTURES OF HUMAN MAST CELLS AND BASOPHILS
Mast cells normally reside in the connective tissue, particularly beneath epithelial surfaces and around blood vessels and, in some species, in serous cavities.1,2,4,5,15,16 and 17 Mast cells are derived from hemopoietic precursors,15,18 but, except for a numerically minor population of mast cells that resides in the marrow,7 this lineage completes its program of maturation in the tissues.1,2,4,15,16,17 and 18 Unlike basophils, mast cells are long-lived cells, and at least some mast cells can locally proliferate in the tissues during a variety of inflammatory or reparative processes.1,2,4,15,16 and 17
Studies in murine rodents, nonhuman primates, and humans indicate that many aspects of mast cell development are critically regulated by SCF, the ligand for the c-kit tyrosine growth factor receptor.11,16,17,18,19 and 20 SCF is produced in both membrane-associated and soluble forms, both of which are biologically active.17,21 In addition to promoting the migration, survival, proliferation, and maturation of cells in the mast cell lineage, SCF also can directly promote mast cell mediator release20,22,23,24,25 and 26 and, at even lower concentrations, can augment mast cell mediator release in response to stimulation by IgE and antigen.23,24 and 25 Abnormalities affecting the c-kit receptor are involved in the pathogenesis of certain examples of mastocytosis (see below). Moreover, it is likely that alterations in the production of SCF by fibroblasts and other cells can contribute to the changes in mast cell numbers that occur during many chronic inflammatory conditions and other pathological responses.16,17,19,27
MAST CELL AND BASOPHIL HETEROGENEITY
Variation in the morphologic, biochemical, and/or functional characteristics of mast cells from different anatomic locations or from the same organ or site has been reported in several mammalian species, including humans.1,2,5,15,17,28,29 and 30 This phenomenon, often referred to as mast cell heterogeneity, raises the possibility that mast cells of different phenotype may express different functions in health or disease and may also exhibit different sensitivities to pharmacologic manipulation. At least four mechanisms may account for phenotypic variation in mast cell populations: (1) factors promoting branching within the mast cell lineage; (2) factors influencing differentiation/maturation (within single pathways or, if they occur, within multiple pathways); (3) factors modulating mast cell function; and (4) factors influencing local concentrations of exogenous substances not derived from mast cells but taken up and stored in mast cell granules. Of these four mechanisms, experimental evidence has been obtained for all but the first.29 Basophils can also exhibit some variation in phenotypic characteristics, such as immunoreactivity for tryptase, chymase, and carboxypeptidase A.31
RELATIONSHIP BETWEEN BASOPHILS AND MAST CELLS
Mature basophils and mast cells differ in morphology, natural history, tissue distribution, mediator production, cell surface phenotype, growth factor requirements, and responses to drugs (see Fig. 69-1 and Table 69-1).1,2,3,4 and 5 Nevertheless, the two cells do exhibit a number of striking similarities. These similarities, taken together with evidence from murine rodents indicating that tissue mast cells are derived from circulating marrow-derived precursors,15,18 have suggested to some investigators that basophils might represent the circulating precursor of mast cells. Although this hypothesis has not formally been excluded, current evidence greatly favors the view that mature basophils represent terminally differentiated granulocytes and not circulating mast cell precursors. In addition to the morphologic evidence discussed below, the latter position is supported by the following observations: (1) no actual evidence has been presented, in any species, indicating that mature circulating basophils are capable either of mitosis or of differentiation into mast cells; (2) the rare reports of patients with hereditary or acquired abnormalities affecting basophil numbers or morphology indicate that eosinophils may also be affected in these disorders but not mast cells32,33 and 34; (3) morphologically identifiable human tissue mast cells can exhibit mitotic activity,35 indicating that this cell lineage is capable of replication independent of a stage resembling that of circulating basophils.
MORPHOLOGY OF BASOPHILS AND MAST CELLS
Routine methods of tissue fixation and processing are poorly suited for demonstration of basophils and mast cells (See Plate VII); optimal visualization is achieved in appropriately prepared 1-µm sections or with an ultrastructural approach.1,4 Ultrastructurally, human basophils are 5 to 7 µm in spherical diameter, exhibit a segmented or, in some cases, unsegmented nucleus with marked condensation of nuclear chromatin, and contain round or oval cytoplasmic granules; these granules are surrounded by a membrane and contain a substructure of dense particles, less dense matrix, and, in some granules, membrane whorls and Charcot-Leyden crystals1,4 (see Fig. 69-1). A second, minor population of small, uniform granules is characteristically located close to the nucleus.36 The cytoplasm of mature human basophils also contains glycogen particles, mitochondria, free ribosomes, and small membrane-bound vesicles; lipid bodies are rarely present. Other organelles are inconspicuous.
In tissue sections, mast cells typically appear as either round or elongated cells, usually with a nonsegmented nucleus with moderate condensation of nuclear chromatin, and contain prominent cytoplasmic granules; mast cell granules are smaller, more numerous, and generally more variable in appearance than in basophils and contain scroll-like structures, particles, and crystals, alone or in combination.1,4 In contrast to the irregularly spaced blunt surface projections of basophils, mast cells are covered by uniformly distributed thin surface processes. Mast cells also differ from basophils in that they have many more cytoplasmic filaments and lack cytoplasmic glycogen deposits. Human mast cells can also contain numerous cytoplasmic lipid bodies. Figure 69-1 is an electron micrograph showing a human basophil adjacent to a human mast cell in the same tissue, the ileal submucosa.
BIOCHEMISTRY AND ROLE IN IGE-ASSOCIATED IMMUNE RESPONSES
The cytoplasmic granules of basophils and mast cells contain proteoglycans, consisting of sulfated glycosaminoglycans covalently linked to a protein core.38,39 Under appropriate conditions, these substances stain metachromatically with basic dyes. In humans and murine species, individual mast cell populations can contain variable mixtures of heparin and chondroitin sulfate proteoglycans.15,29,38,39 Although the sulfated glycosaminoglycans of normal human blood basophils have not yet been characterized, two studies of the proteoglycans synthesized by blood leukocytes (containing 10 to 75 percent basophils) of 5 patients with myelogenous leukemia indicate that such cells may produce entirely chondroitin sulfates40 or a mixture of chondroitin sulfates (50 to 84 percent) and heparin (8 to 43 percent).41 Normal guinea pig basophils synthesize predominantly (85 percent) chondroitin sulfates, with the remainder characterized as heparan sulfate rather than heparin.42 While the biological functions of basophil and mast cell proteoglycans are not yet fully understood, in mice, heparin is required for normal packaging of certain neutral proteases in mast cell cytoplasmic granules.43,44 Both human mast cells and basophils synthesize and store histamine.1,31,38 Basophils represent the source of most (if not all) of the histamine present in normal human blood.45 Studies in mice indicate that mast cells represent the source of virtually all the histamine stored in normal tissues, with the notable exceptions of the glandular stomach and parts of the central nervous system.46
In addition to proteoglycans and histamine, basophils and mast cells generate many other mediators that can influence the course of inflammatory processes1,2 and 3,5,38,47 (see Table 69-1). These substances are either preformed and granule-associated (e.g., histamine, neutral proteases, proteoglycans) or produced during activation of the cell [e.g., prostaglandin D2, leukotrienes (“slow-reacting substances of anaphylaxis”) and other metabolites of arachidonic acid, and platelet-activating factor]. Appropriately, stimulated mouse or human mast cells can release the cytokine TNF-a,2,5,48,49 and 50 and mouse and perhaps human mast cells,2,5,50,51 and human basophils,5,52 can produce IL-4. Work with mouse and human mast cells indicates that mast cells may also represent a potential source of many additional cytokines with effects in inflammation, immunity, hematopoiesis, tissue remodeling, and many other biological processes.5,50,53,54,55 and 56 By contrast, the spectrum of basophil-derived cytokines appears to be more limited but includes IL-4 and IL-13.5,52,57
ROLE IN ACUTE REACTIONS
Basophils and mast cells have specific, high-affinity plasma membrane receptors for the Fc region of homocytotropic immunoglobulins; in humans this is largely IgE.58,59 and 60 When IgE antibodies bound to the basophil or mast cell surface are bridged by specific di- or multi-valent antigens, anaphylactic degranulation is triggered.1,2,5,38,39,58,59 and 60 The critical signal in this event is the bridging of IgE receptors (FceRI) on the plasma membrane, and antibodies to the receptors may substitute for IgE and antigen to initiate degranulation in vitro.58,59 and 60 Antigen binding is independent of divalent cations. However, later steps in degranulation require both calcium and physiologic temperatures.31,58,59 and 60 Morphologically, anaphylactic degranulation involves the fusion of plasma membranes with the membranes delimiting individual cytoplasmic granules or with groups of granules whose membranes have undergone fusion, leading to rapid noncytolytic release of granule contents, such as histamine and other preformed mediators.1,4 The complex sequence of biochemical events associated with anaphylactic degranulation and the rationale of their pharmacologic manipulation have been reviewed.31,38,59,60 and 61
The sudden, massive release of mediators from basophils and mast cells is thought to provoke many of the clinical manifestations of acute immediate hypersensitivity reactions in such disorders as certain forms of bronchial asthma; urticaria; allergic rhinitis; and anaphylaxis to foods, drugs, insect stings, and other antigens.1,2,31,38,61 Other diverse stimuli, including certain complement fragments (anaphylatoxins), neutrophil lysosomal proteins, a variety of basic peptides and peptide hormones, components of insect venoms, radiocontrast solutions, cold, calcium ionophores, and certain drugs such as narcotics and muscle relaxants, may also initiate rapid release of mediators from basophils and mast cells, independently of IgE.5,31,38,61 The clinical reactions provoked by these agents can closely mimic those of immediate hypersensitivity. Finally, certain agents, including protein Fv (pFv), a sialoprotein found in normal liver and released into the intestinal tract in patients with viral hepatitis, can interact with the VH3 domain of IgE and thereby induce histamine release from human basophils and mast cells and IL-4 release from human basophils.62 The extent to which this proposed “endogenous superallergen” function of pFv is important in host defense or in the pathogenesis of viral infections remains to be determined.62
ROLE IN LATE-PHASE AND CHRONIC ALLERGIC REACTIONS
ROLE IN LATE-PHASE REACTIONS AND THE MAST CELL–LEUKOCYTE CYTOKINE CASCADE
In addition to their roles in classic acute immediate hypersensitivity responses, such as anaphylaxis, mast cells and basophils also can contribute to late-phase reactions. Late-phase reactions occur when antigen challenge is followed, hours after initial IgE-dependent mast cell activation, by the recurrence of signs (e.g., cutaneous edema) and symptoms (e.g., bronchoconstriction).61,63 It is widely believed that much of the morbidity associated with chronic allergic conditions, such as allergic asthma, reflects the actions of leukocytes that are recruited to sites of late-phase reactions.61,63 Studies in mast cell knock-in mice (see below) indicate that mast cells are responsible for virtually all of the vascular permeability changes and leukocyte infiltration associated with cutaneous late-phase reactions and that TNF-a importantly contributes to these responses.64 It is likely that mast cell TNF-a production also helps to initiate late-phase reactions in humans2,5,49,50 and that basophils, eosinophils, and other leukocytes that are recruited to these reactions produce cytokines and other mediators that regulate the further development and, ultimately, the resolution of these reactions.2,5,50 This sequence of events in the pathogenesis of late-phase reactions is termed the mast cell–leukocyte cytokine cascade.2,5,50
IGE-DEPENDENT UPREGULATION OF FCeRI EXPRESSION AND FCeRI-DEPENDENT FUNCTION
Notably, as plasma levels of IgE increase (as typically occurs in subjects with allergic diseases or parasite infections), levels of FceRI expression on the surface of basophils and mast cells also increase.65,66 Compared with cells with low “baseline” levels of FceRI expression, such cells can bind more IgE, release mediators in response to lower concentrations of allergens, and produce significantly larger amounts of preformed and lipid mediators and cytokines.54,65,66,67 and 68 Thus, basophils and mast cells in subjects with high levels of IgE may be significantly enhanced in their ability to express IgE-dependent and/or immunoregulatory functions.61
ROLES IN T-CELL-DEPENDENT RESPONSES NOT INVOLVING IGE
Mast cell activation, and/or infiltration of affected tissues with circulating basophils, also can occur during a variety of T-cell-dependent immunological responses in both humans and experimental animals.1,69 However, genetically mast-cell-deficient mice can express certain apparently unimpaired T-cell-dependent responses.2,16,70 Accordingly, the specific roles of mast cells and basophils in such responses remain to be determined.
BIOLOGICAL FUNCTIONS OF BASOPHILS AND MAST CELLS
ROLES IN HOST DEFENSE
It is likely that basophils and mast cells have critical roles in the expression of host resistance to certain parasites. Whether the basophil or the mast cell represents the major effector cell type in these responses appears to vary according to such factors as species of parasite, species of host, and site of infection. Thus, in the guinea pig, basophils appear to be required for the expression of immune resistance to infestation of the skin by larval ixodid Amblyomma americanum ticks,69,71,72 whereas expression of IgE-dependent immune resistance to the cutaneous infestation of larval Haemaphysalis longicornis ticks in mice is dependent on mast cells.72 Findings such as these support the notion that basophils and mast cells may express similar or complementary functions in host defense against parasites and other agents.
Studies in “mast cell knock-in mice” (see below) have shown that mast cells can also contribute to “innate immunity” to host defense against some bacterial infections.73 This role of the mast cell in “natural immunity” is due in part to complement-dependent activation of mast cells and in part to TNF-a production by mast cells.73
OTHER FUNCTIONS AND MAST CELL KNOCK-IN MICE
Factors capable of inducing basophil infiltration, mast cell proliferation, and/or basophil or mast cell degranulation are generated during a wide variety of immunological or pathological processes, in addition to immune responses to parasites.1,11,29,31,61,69 As a result, there has been considerable speculation that basophils and mast cells may express critical roles in diverse biological responses. On the other hand, the precise functions of basophils and mast cells in most of the biological responses in which the cells have been implicated are obscure.16,46 In the mouse, mutant animals virtually devoid of mast cells and the congenic normal mice may be used to define and quantify the contributions of mast cells to many different biological responses.2,15,16,46,73,74 A particularly useful approach is to transfer cultured mast cells derived from the bone marrow of normal (WBB6F1-+/+) mice (or mast cells derived from precursors with spontaneous or targeted mutations that affect mast cell development or function) into the skin or other tissues of WBB6F1-W/W v mice, which lack mast cells because of mutations at the W/c-kit locus.16,17,73,74 After sufficient time has been allowed to permit the transferred mast cells to acquire phenotypic characteristics appropriate for their anatomical location, biological responses can be elicited at the sites where the mast cell deficiency has been locally and selectively repaired and at paired (“control”) mast-cell–deficient sites.
Studies employing such mast cell knock-in mice have shown that mast cells are essential for certain IgE-dependent acute- or late-phase reactions in the skin,2,65 gastrointestinal tract,75 or respiratory system,76 that they significantly augment innate immunity to certain bacterial infections,73 and that they contribute to certain other immunologically nonspecific acute inflammatory reactions.2,16 However, no human patients devoid of mast cells have yet been identified. Nor is it easy to interpret the clinical findings in those rare patients who have been found to express a deficiency of basophils. Thus, one human patient with a profound basopenia experienced persistent and severe infestation with scabies,32 a finding that might be viewed as consistent with the role of basophils in resisting ectoparasites in humans. But that patient also had eosinopenia, IgA deficiency, and multiple other clinical problems.32 A second basophil-deficient patient had a history of recurrent bacterial and viral infections.34 However, this patient also had a deficiency of eosinophils, hypogammaglobulinemia, abnormal suppressor T-cell function in vitro, and a thymoma.34
BLOOD BASOPHIL COUNT
The normal blood basophil count is difficult to define precisely, but two studies place the normal range between 20 and 80/µl (0.020 and 0.080 × 109/liter).7,8,47,77 The blood basophil count has been reported to vary by age,78 gender,78 and season.79
Because numbers of blood basophils can be very low even in apparently normal individuals,7,8,47,77 it can be difficult to determine whether examples of basophilopenia reflect pathological processes as opposed to normal variation. Nevertheless, reduced numbers of circulating basophils have been reported in several disorders (Table 69-2). Basophilopenia has been recorded in association with urticaria and anaphylaxis,80,81 but the extent to which this finding represents a loss of metachromatic staining of circulating degranulated cells rather than a true decrease in the number of cells is undetermined. Basophilopenia occurs in conditions that are also associated with eosinophilopenia; these conditions are often associated with increased secretion of adrenal glucocorticoids.47,77,82,83 Basophil counts may diminish, sometimes markedly, during leukocytosis accompanying infection, inflammatory states, immunological reactions, neoplasia, or hemorrhage.82 Also, basophil counts are diminished in thyrotoxicosis or after pharmacologic administration of thyroid hormones, and, conversely, basophil counts may be increased in myxedema or after ablation of thyroid function.47,82 A rapid and significant drop of up to 50 percent in blood basophil levels has been documented at ovulation.84 A few patients with an apparent total lack of basophils have been reported.32,34
TABLE 69-2 CONDITIONS ASSOCIATED WITH ALTERATIONS IN NUMBERS OF BLOOD BASOPHILS47,77,82
A morphologic abnormality expressed in the majority of eosinophils and basophils but not in other leukocytes or mast cells, has been described as an autosomal dominant condition affecting four members of a family.33 Cytoplasmic inclusions and crystals in basophils resembling the May-Hegglin anomaly have occurred in healthy individuals.
Conditions associated with increased numbers of blood basophils (basophilia) are presented in Table 69-2.
An increase in the number of basophils is commonly associated with hypersensitivity disorders of the IgE-associated “immediate” type. This is often accompanied by increased levels of IgE. While serum IgE levels and basophil numbers are not directly related,85 increased levels of IgE are associated with increased expression of FceRI on the surfaces of both basophils and mast cells.66,67,86 Moreover, basophils can be recruited into tissues at sites of IgE-associated and other immunological responses.1,5,31,61,69 Basophil levels may be elevated in ulcerative colitis87 and juvenile rheumatoid arthritis,88 whereas many inflammatory conditions that cause a leukocytosis are associated with basophilopenia. Basophilia can also occur in subjects exposed to ionizing radiation.89
HEMATOPOIETIC STEM CELL DISEASES
Chronic Myeloproliferative Diseases The concentration of blood basophils is slightly increased in many patients with polycythemia vera (see Chap. 61), idiopathic myelofibrosis (see Chap. 95), and thrombocythemia (see Chap. 118), and a slight increase in the absolute basophil count may be a useful early sign of a myeloproliferative disease. An increase in absolute basophil count occurs in virtually all patients with CML,90,91 and 92 and, in some, basophils can represent 20 to 90 percent of blood leukocytes (see Chap. 94). Exaggerated basophilia of this type is a poor prognostic sign and may herald transformation to the accelerated phase of CML.93 The basophil in myeloproliferative diseases is generally thought to be derived from the malignant clone, and in CML can contain the Ph chromosome94 and presumably also the breakpoint cluster gene rearrangement on chromosome 22. The basophils in CML exhibit a variety of ultrastructural and biochemical abnormalities,95,96 in some cases obscuring some of the typical distinctions between basophils and mast cells.97,98,99 and 100 Release of basophil-associated histamine can lead to episodes of flushing, pruritus, and hypotension in occasional patients with basophilic CML,101,102 and severe peptic ulcer of the stomach and duodenum can occur in association with hypersecretion of gastric acid and pepsin.103,104 Ph chromosome–positive acute basophilic leukemia may be a presenting manifestation of CML.105
Basophilic Leukemias The literature includes many reports of basophilic leukemias. However, the basis for designating some cases as basophilic leukemias as opposed to examples of myelogenous leukemia with an associated pronounced basophilia is not always clear. Accordingly, we have referred to these conditions herein as leukemias associated with basophilia. The leukemias associated with basophilia are listed in Table 69-3. In addition to extreme basophilia in chronic phase CML, or as a manifestation of the accelerated phase of CML, acute basophilic leukemia apparently can rarely occur de novo.106,107,108,109,110 and 111 A form of acute myelogenous leukemia (AML) in which the blast cells contain a translocation between chromosomes 6 and 9, t(6;9), is associated with marrow basophilia (see Chap. 93),112,113 although basophilia can also occur in cases of AML with other translocations or inversions.114,115 Finally, basophilic maturation of leukemic cells may be observed in cases of acute promyelocytic leukemia.116,117 and 118
TABLE 69-3 LEUKEMIAS ASSOCIATED WITH BASOPHILIA
While the clinical and pathological features of acute basophilic leukemia are largely similar to those of myelogenous leukemia, affected patients occasionally exhibit symptoms that result from release of mediators (especially histamine) derived from degranulating or dying basophils.47,101,102,111,119 Remission induction therapy is similar to that used for other types of AML (see Chap. 93), but management can be complicated by shock due to massive release of histamine and other mediators associated with acute cytolysis.
DISORDERS AFFECTING MAST CELLS
NORMAL MAST CELL LEVELS
Mast cells cannot be identified in the blood of healthy individuals by standard techniques. However, mast cells can be observed in the blood of monkeys that have been treated chronically with large amounts of the c-kit ligand, stem cell factor,19 and in the blood of some patients with systemic mastocytosis.120 Increases in tissue mast cells can occur by a combination of enhanced progenitor influx and proliferation of resident mast cells in tissues.5,15,121 Human mast cells have been classified according to their content of neutral proteases: MCT, so designated because its granules contain tryptase but not detectable chymase, and MCTC, whose secretory granules contain both enzymes.30 The former mast cell type ordinarily predominates in lung and gastrointestinal mucosal tissues and the latter type in dermis and submucosal tissues.122,123 and 124 Mast cells that express chymase but little or no tryptase (MCC) also have been described.125
SECONDARY CHANGES IN MAST CELL NUMBERS
Although long-term treatment with glucocorticoids (particularly topical treatment of the skin) can result in diminished mast cell numbers,126 there has been no report of a clinical disorder whose primary feature is a reduction in levels of tissue mast cells. Studies of small numbers of patients indicate that certain mast cell populations, namely the MCT mast cells in the gastrointestinal mucosa, can be strikingly reduced in numbers in subjects with genetically determined or acquired (HIV-induced) immunodeficiency.127
A number of disorders are associated with small to up to several-fold increases in mast cell numbers in or near the tissues affected by the disorder (Table 69-4). Tissues at sites of recurrent allergic reactions often exhibit increases in mast cell numbers, to levels as high as approximately fourfold normal.122,128 Small increases in mast cell numbers have been observed at sites of pathology in rheumatoid arthritis, psoriatic arthritis, scleroderma, and systemic lupus erythematosus.129,130 Mast cells have been reported to be increased in osteoporosis,131 but it is unclear to what extent this may reflect decreases in other cell types and/or a decrease in bone matrix. Numbers of marrow mast cells can be increased in patients with chronic liver or renal diseases.132 Increases in mast cells have also been documented in infectious diseases, particularly at sites of infection with parasites such as Strongyloides, in which a greater than fourfold increase in mast cell numbers can occur.133 In such settings, mast cell numbers can return toward normal upon resolution of the infection. Finally, mast cell numbers can be increased several-fold in lymph nodes draining areas of tumor growth,132,134 and in subjects with stem cell diseases and lymphoproliferative diseases, including lymphoma in the bone marrow, as well as in association with chronic myelogenous leukemia.132,135,136 and 137
TABLE 69-4 CONDITIONS ASSOCIATED WITH SECONDARY CHANGES IN MAST CELL NUMBERS
DISORDERS OF MAST CELL HYPERPLASIA/NEOPLASIA
DEFINITION AND HISTORY
A group of systemic disorders associated with significant increases in mast cell numbers in the skin and internal organs have been brought together under the term mastocytosis. The first report138 of a primary mast cell disorder was probably that of Unna in 1887, who found that the skin lesions of UP139,140 contained numerous mast cells. But it was not until 1949 that Ellis141 recognized the systemic nature of this disorder. In addition to the systemic disorders classified as mastocytosis, apparently localized cutaneous aggregates of mast cells, ranging from mast cells nevuses and mastocytomas in infants and children to multiple nodules in older children have also been reported.142,143 Solitary mastocytomas generally present before 6 months of age and usually involute spontaneously, although in rare cases they have been followed by urticaria pigmentosa.143 The pathogenesis of such lesions has not yet been elucidated. Accordingly, the remainder of this section will focus on mastocytosis.
It should be emphasized that the clinical patterns of disease in mastocytosis, and their prognosis, can vary substantially from one patient to the next (see “Course and Prognosis,” below). To address this issue, and to provide guidelines regarding prognosis and treatment, a consensus classification for mastocytosis was developed144 that is now widely used (Table 69-5). Patients in Category I (indolent mastocytosis), comprising the great majority of subjects with mastocytosis, can expect a normal life-span. Patients with Category II disease have a prognosis determined by the associated hematologic disorder, and patients with Category III disease (aggressive mastocytosis) generally have a 3- to 5-year survival. Mastocytic leukemia (Category IV disease, see “Mast Cell Leukemia,” below) is usually rapidly fatal.
TABLE 69-5 MASTOCYTOSIS CLASSIFICATION*
ETIOLOGY AND PATHOGENESIS
Activating mutations in c-KIT, which encodes the receptor for stem cell factor, recently have been identified in patients with mastocytosis, and several lines of evidence indicate that such mutations can be involved in the pathogenesis of this disease. The most common of these mutations (Asp816Val), which results in ligand-independent activation of the c-KIT receptor, was first identified in a long-term cell line derived from a patient with mast cell leukemia.145 It was then detected in mononuclear cells in the peripheral blood of patients with mastocytosis who had an associated hematologic disorder,146 as a somatic mutation in lesional tissue obtained from one patient with an aggressive form of mastocytosis and from a second patient with an indolent form of urticaria pigmentosa,147 and in the skin, but not the bone marrow and peripheral blood, of an 11-month-old child with mastocytosis.148
Taken together, these findings suggest that the mutation may occur initially in a mast cell progenitor and that, as the clone expands, it first becomes detectable in mastocytosis skin lesions. In patients with more severe disease, and thus with a larger clonal expansion, it can also be identified in circulating cells. The Asp816Val mutation, or similar 816 activating mutations that result in the substitution of valine or tyrosine for aspartate, are now believed to occur in all adult patients with mastocytosis, in whom the mutation can be readily identified in the skin lesions of urticaria pigmentosa.149 Mutations at codon 816 (valine, tyrosine, or phenylalanine for aspartate) have also been identified in a small subset of pediatric patients, whereas other pediatric patients exhibit a dominant inactivating c-KIT mutation, in which lysine is substituted for glutamic acid in position 839, the site of a potential salt bridge.149
The extent to which the presence of various c-kit mutations, and the anatomical distribution of the affected cells, can be used to predict prognosis or disease severity in patients with mastocytosis largely remains to be determined. Notably, some pediatric patients with mastocytosis appear to lack any c-KIT mutations.149 Perhaps additional “gain-of-function” mutations of c-KIT in human subjects with mastocytosis remain to be characterized. In dogs, a species in which up to 20 percent of all neoplasms are mast cell tumors, 5 of 11 analyzed mast cell tumors exhibited tandem duplications involving exons 11 and 12 of c-KIT.150 Analysis of a dog mastocytoma cell line indicates that such mutations, which affect the juxtamembrane portion of the cytoplasmic domain of the c-KIT receptor, result in ligand-independent activation of the receptor.150 Gain-of-function mutations of c-KIT have also been reported in gastrointestinal stromal tumors,151 in one pedigree as a germ line mutation.152 However, in these subjects, it is not yet clear whether mast cell numbers are increased.
The organs that are most frequently involved in systemic mastocytosis are the skin, lymph nodes, liver, spleen, marrow, and gastrointestinal tract.
The Skin The usual presenting lesion of cutaneous mast cell disease is UP. UP lesions appear as small yellowish-tan to reddish-brown macules or slightly raised papules (Fig. 69-2), which can exhibit the Darier sign, that is, urticaria after mild friction of the skin.120,153 The palms, soles, face, and scalp generally remain free of lesions. In many cases, UP can develop before the age of 2 and can subside by puberty; in adults with UP, extracutaneous involvement by mastocytosis is common.120,153,154 and 155 However, some patients, particularly those with mastocytosis and an associated hematologic disorder, may entirely lack cutaneous lesions. In such cases, other organs must be biopsied to make the diagnosis (see below). Diffuse cutaneous mastocytosis is an unusual manifestation of mastocytosis143,155 The skin appears yellowish-brown and is thickened. Young children with cutaneous disease may have bullous eruptions with hemorrhage.143 Some adult patients develop prominent vascularity in association with the skin lesions, a condition termed telangiectasia macularis eruptiva perstans.143
FIGURE 69-2 Urticaria pigmentosa in an adult man with indolent systemic mastocytosis. Multiple pigmented macules are present, and if local pressure were to be applied to the skin, individual lesions would show urtication and become raised, pruritic, and erythematous.
Lymph Nodes In one series, peripheral lymphadenopathy occurred in 26 percent and central lymphadenopathy in 19 percent of patients at diagnosis.156 Lymphadenopathy tends to be most prominent in patients with Category II or III disease. Mast cell infiltrates are observed in the paracortex, follicles, medullary cords, and sinuses. Additional findings can include prominent infiltrates of eosinophils (accounting for the alternative term for aggressive mastocytosis: lymphadenopathic mastocytosis with eosinophilia), blood vessel proliferation in association with mast cells in the paracortical areas, and extramedullary hematopoiesis. In routine H&E, stained sections, mast cell infiltrates in the lymph nodes may resemble T-cell lymphomas in their pericortical distribution, in the clear cytoplasm that is sometimes exhibited by the mast cells, and in the associated vascular proliferation and eosinophilia.156 Alternatively, when mast cells replace lymphoid follicles, the pattern may resemble follicular hyperplasia or follicular lymphoma.156
Liver Patients with mastocytosis frequently exhibit infiltration of the liver with mast cells. While many of these individuals have some associated liver pathology, severe liver disease is uncommon. When it does occur, it typically affects those with mastocytosis (Category II or III disease) and an associated hematologic disorder or aggressive mastocytosis. In one series of 41 patients, 61 percent had some liver disease.157 Elevated alkaline phosphatase aminotransamidases, 5′ nucleotidase, or GGTP was detected in the serum of approximately half of the patients. Hepatomegaly, prominent infiltration of the liver with mast cells, and hepatic fibrosis are positively correlated with elevated levels of alkaline phosphatase and were observed more frequently in patients with aggressive disease, and ascites or portal hypertension occurred in some of these individuals. Portal fibrosis was observed in 68 percent and was positively correlated with hepatic inflammation and mast cells infiltrates. Venopathy and associated veno-occlusive disease was observed in four patients, all of whom had an associated hematologic disorder.
Spleen Splenic involvement at diagnosis has been reported in approximately half of the patients with systemic disease.156,158 Mast cells most commonly occurred in a paratrabecular distribution, followed by perifollicular, follicular, and diffuse infiltrates. Trabecular and capsular fibrosis and eosinophilic infiltration were also observed, and extramedullary hematopoiesis was documented in the majority of biopsies. On H&E sections, the infiltrates of mast cells produced lesions that resembled those of T-cell lymphoma, follicular hyperplasia, follicular lymphoma, Kaposi sarcoma, myeloproliferative disorder, hairy cell leukemia, or a granulomatous process. Splenomegaly was also noted to occur in the absence of infiltration of the spleen by mast cells.159 Increased splenic weights of greater than 700 g generally occurred in patients within unfavorable categories of mastocytosis.
Marrow More than 90 percent of adults with systemic mast cell disease have focal mast cell lesions in the marrow,158,160,161,162 and 163 which typically appear as foci of spindle-shaped mast cells in a fibrotic background (Fig. 69-3), sometimes with associated eosinophils and lymphocytes. These collections of cells can occur in perivascular, paratrabeuclar, and intertrabecular locations. There may be an increase in reticulin staining, and Masson trichome staining may reveal collagen deposition. In specimens that are extensively involved by mast cell lesions, the bony trabeculae may be moderately to markedly thickened.
FIGURE 69-3 Bone marrow biopsy from an adult with indolent systemic mastocytosis showing characteristic collections of mast cells, some of which appear spindle-shaped; different areas of the specimen were stained by H&E; (A) or with an antibody to human mast cell tryptase (B) (X100). Areas that contain many mast cells are depicted with arrows in A and B.
In H&E stained sections, the mast cells typically exhibit a spindle-shaped or oval nucleus, and fine eosinophilic granules are apparent in the cytoplasm at high-power magnification (Fig. 69-3A). Mast cells with bilobed nuclei also may be seen in these lesions; and this finding is associated with a poor prognosis.158 Wright-Giemsa and toluidine blue stains can be employed, especially with nondecalcified, plastic-embedded specimens, for a more definitive visualization of mast cells. Unfortunately, these stains are less effective on EDTA-decalcified, paraffin-embedded material. Mast cells also stain positively for chloracetate esterase and aminocaproate esterase, and, in suitably processed specimens, for mast cell tryptase by immunohistochemistry (Fig. 69-3B). Aspirate films or clot sections alone cannot be used to diagnose mast cell disease in the marrow. While increased numbers of mast cells may be present in bone marrow aspirate films of patients with systemic mast cell diseases, similar findings have been reported in patients without mast cell disorders or when there is a reactive increase in marrow mast cells.
Marrow involvement appears to be much less common in children. In a study163 of 17 children with cutaneous or disseminated mast cell disease, small focal mast cell lesions were observed in marrow biopsies in 10 individuals, and increased mast cells in bone marrow aspirate smears were noted in 5. Moreover, the focal lesions found in children were uniformly small and perivascular.
The progression of marrow involvement in systemic mast cell disease is variable. Many adults with indolent disease appear to have stable, or even decreasing, marrow involvement over time.158 In contrast, a progressive increase in focal mast cell lesions is more commonly observed in patients with more aggressive patterns of disease.
Even though they may differ in the specific pathogenesis of their disease, all patients within a given category of mastocytosis generally exhibit similar clinical features. Manifestations of the disease largely reflect the local and systemic consequences of mediator release from tissue mast cells. There also may be effects due to the disruption of normal structures by local collections of mast cells.
At presentation, patients with mastocytosis may complain of vague and nonspecific constitutional symptoms such as fatigue, weakness, flushing, and musculoskeletal pain; some experience fever and/or weight loss.120,155 A subset may present with recurrent episodes of unexplained anaphylaxis.164 However, most patients with indolent mastocytosis and a hematologic disorder are usually diagnosed on the basis of bone marrow biopsy findings, during the investigation of their hematologic disease.155,158 Those with aggressive disease often present with unexplained lymphadenopathy and splenomegaly and/or hepatomegaly.
Gastrointestinal disease and associated symptoms are also commonly associated with systemic mastocytosis, either at presentation or as the disease progresses.155,165 Findings include nausea, vomiting, abdominal pain, and diarrhea. Peptic ulcer disease, which is thought to reflect, at least in part, the promotion of gastric acid secretion by elevated histamine levels, occurs in up to 50 percent of those with systemic disease.165 With progressive disease, patients may develop mild malabsorption.165
If systemic involvement is already advanced at the time of diagnosis, patients may also exhibit lymphadenopathy, hepatomegaly, and splenomegaly during the initial evaluation.120,155 Because osteoporosis may accompany systemic disease, rare patients present with pathological fractures.166
When mastocytosis is suspected following the history and physical examination, a routine workup in adults should consist of a gross and microscopic examination of the skin, a bone marrow biopsy, and aspirate120,144,155; and serum for alpha and beta tryptase levels (Table 69-6)26 (two forms of tryptase, a protease that is produced abundantly by most if not all human mast cells, but which also may be found in at least some human basophils).31,167 Additional studies, as suggested by the need to assess the extent of disease or to evaluate pain, may include a bone scan and a skeletal survey. A gastrointestinal evaluation, involving radiographic studies of the upper gastrointestinal tract and small intestines, a computed tomography scan of the abdomen, and endoscopy may also be justified. The requirements for the diagnosis of mastocytosis remain the presence of substantial increases in mast cell numbers in one or more tissues. Slight increases (e.g., up to fourfold) in mast cell numbers in target tissues, such as the skin, gastrointestinal tract, or bone marrow, are not diagnostic because they may only reflect normal variation or inflammatory or reactive processes. In skin biopsies of sites that lack other causes of increased numbers of mast cells, such as chronic inflammatory processes, a tenfold increase in mast cells numbers is generally considered diagnostic of mastocytosis.20,128,143,155 Mast cell aggregates or the presence of confluent infiltrates of mast cells are required for the diagnosis of bone marrow involvement. In patients with advanced Category II or III disease, mast cells may be detectable in the peripheral blood, and rare patients can progress to mast cell leukemia (see below).155,158,168,169,170 and 171
TABLE 69-6 DIAGNOSTIC EVALUATION OF MASTOCYTOSIS
Plasma or urinary histamine levels are frequently increased in systemic mastocytosis.172 However, the isolated findings of increased levels of histamine or histamine metabolites may reflect any of a number of other situations, including anaphylaxis. Further, the accuracy of laboratory measurement of histamine depends on the assay used. Urine histamine levels may be falsely elevated as result of bacterial contamination, pharmacologic agents and their metabolites excreted in the urine, or diets rich in histamine or histamine precursors. Similarly, serum beta tryptase may be elevated after anaphylaxis. Alpha tryptase is more specific for mastocytosis but may sometimes be normal, even in patients with a diagnostic bone marrow biopsy.167 Thus, no single laboratory test is diagnostic of mastocytosis. Rather, the demonstration of mast cell mediators in blood or urine should prompt the clinician to investigate further for the presence of mastocytosis.
The differential diagnosis of systemic mastocytosis includes several disorders which may produce a similar clinical presentation, such as allergic diseases, the hyper-IgE syndrome, hereditary or acquired angioneurotic edema, idiopathic flushing or anaphylaxis, carcinoid tumor, and idiopathic capillary leak syndrome. When episodic hypertension is a major finding, pheochromocytoma must be considered. Significant unexplained gastroduodenal ulcer disease requires that a Zollinger-Ellison gastrinoma syndrome be ruled out. Helicobacter pylori infection should be considered in all patients with ulcer disease, even those diagnosed with mastocytosis.
THERAPY, COURSE, AND PROGNOSIS
There currently is no cure for mastocytosis.173 There also is no evidence that symptomatic therapy significantly alters the course of the underlying disease.173 Management of mastocytosis includes instruction on the avoidance of factors that may trigger symptoms (presumably by the direct or indirect activation of mast cell mediator production); these can include temperature extremes, physical exertion, or, in some unusual cases, the ingestion of ethanol, nonsteroidal anti-inflammatory drugs, or opiate analgesics.155,173 Anaphylaxis may sometimes follow insect stings, even in the absence of evidence of allergic sensitivity. For these reasons, consideration should be given to providing epinephrine-filled syringes to all patients. Patients with mast cell disease and a history of anaphylaxis clearly should be advised to carry epinephrine-filled syringes and taught to self-medicate. These patients may also benefit from the concurrent use of H1 and H2 antihistamines prophylactically. Patients may experience severe reactions to iodinated contrast materials. Thus, consideration should also be given to pre-medicating mastocytosis patients with H1 and H2 antihistamines and prednisone. Nonsedative H1 antihistamines decrease the irritability of the skin and pruritus.155,173,174 and 175 More potent H1 blockers, such as hydroxyzine and doxepin,176 may be useful in more severe cases. Pruritis may also be relieved by approaches that maintain the hydration of the skin. H2 antihistamines, including ranitidine and famotidine, are used to treat the gastritis and peptic ulcer disease associated with mastocytosis.155,173,177 H2 antihistamines may be titrated on the basis of symptom control or to a particular level of gastric secretion. Proton pump inhibitors (omeprazole) are also useful in the management of gastric hypersecretion.155,173
The oral administration of disodium cromoglycate has been reported to be useful in the treatment of gastrointestinal cramping and diarrhea.178,179 This agent has also been reported to be of benefit in cutaneous mast cell disease in children and infants.180 Other symptoms, including headache, have also been reported to improve somewhat with the administration of cromolyn sodium.
Ketotifen has been widely used outside of the United States. It has been reported to be effective in the relief of pruritus and wheal formation in cutaneous mastocytosis181 and even to improve osteoporosis.182 By contrast, one pediatric study found ketotifen to be no more effective than hydroxyzine.183 Similarly, in another study, azelastine offered only minimal benefit over chlorpheniramine.184 Diphosphonates have been reported to be useful in the treatment of the osteopenia associated with mastocytosis.185
Cutaneous lesions have been treated with either corticosteroids186 or 8-methoxypsoralen plus ultraviolet A (PUVA),187,188 largely to reduce pruritus or for cosmetic improvement. There is no evidence that such approaches alter the progression of systemic disease, and relapses 3 to 6 months after cessation of PUVA therapy are common. Patients may also experience a decrease in the intensity of lesions after exposure to natural sunlight. Repeated or extensive application of corticosteroids may result in cutaneous atrophy or adrenocortical suppression.186
Nonsteroidal anti-inflammatory agents have been useful in some patients whose primary manifestations are recurrent episodes of flushing or syncope, or both.173 However, these agents may also exacerbate ulcer disease. Patients with a history of aspirin sensitivity should not be placed on this therapy, unless they first undergo desensitization.
Systemic corticosteroids are employed to decrease significant malabsorption and ascites189 in patients with advanced disease. In adults, oral prednisone (40–60 mg/day) usually results in a decrease in symptoms over a 2- to 3-week period. After initial improvement, steroids usually may be tapered to an alternate-day regimen. However, with time, the ascites frequently recurs. It has been reported that such patients can benefit from a portacaval shunt.189
Patients with mastocytosis and an associated hematologic disorder are managed as dictated by the specific hematologic abnormality. Interferon-alfa-2b may have contributed to a decrease in mast cell infiltration in one patient with mastocytosis and an associated hematologic disorder,190 but a subsequent study reported that interferon-alfa-2b was of no benefit in three patients,191 and there is a report of an anaphylactic-like syndrome after treatment with interferon.192
A small number of patients with mastocytosis may have a syndrome resembling non-Hodgkin’s lymphoma, an aggressive myeloproliferative disease, or rarely an overt nonlymphocytic leukemia.193 Two patients have been reported with systemic mast cell disease associated with primary mediastinal germ cell tumor.194,195 In such patients, traditional chemotherapy directed toward the neoplastic process may be appropriate. Chemotherapy with cyclophosphamide, vincristine, and prednisone has been used in some mastocytosis patients whose clinical picture is that of a non-Hodgkin’s lymphoma, although the response to chemotherapy was variable.193 Radiotherapy has been used in a limited number of patients to control local disease.196 One patient with a myelodysplastic syndrome of recent onset, a leukemic spread of immature mast cells, and hyperfibrinolysis, possibly related to mast-cell–derived tissue plasminogen activator, responded well to remission-induction polychemotherapy followed by two cycles of consolidation with intermediate-dose ARA-C.197
Splenectomy has been performed on patients with severe aggressive mastocytosis, in an attempt to improve their limiting cytopenias.198 Based on comparisons to historical controls, splenectomy increased survival by an average of 12 months. Patients who had undergone splenectomy also appeared to be better able to tolerate chemotherapy. Splenectomy is of no value in the management of indolent mast cell disease.198
Course and Prognosis The prognosis of adult patients with mast cell disorders is related to the disease category. The vast majority of patients who present with UP and are found to have indolent (Category I) disease have a chronic protracted course that responds to symptomatic medical management. A normal life-span is the expectation, and few of these cases progress to more severe forms of the disease; some patients may even experience a diminution in the severity of skin lesions in later years.155,158,199 However, elevated serum lactate dehydrogenase levels, a late age of onset, and, in Category II patients, presence of a significant hematologic abnormality (such as a myeloproliferative or myelodysplastic disorder or, more rarely, overt leukemia) are indicators of a poor prognosis and shortened survival.158 Indeed, the prognosis for patients in Category II (mastocytosis with an associated hematologic disorder) depends on the course of the associated hematologic disorder.158 Patients with Category III disease (aggressive mastocytosis) have a guarded prognosis due to complications arising from rapid and profound increases in mast cell numbers; these patients usually have a 3- to 5-year survival.158 Patients with mast cell leukemia (Category IV disease) typically die within approximately 6 months of diagnosis.169
Mast Cell Leukemia This rapidly fatal disorder develops in a small minority of patients with Category II or III disease168,169,170 and 171 but can also represent the initial clinical presentation of the mast cell disorder.169,200,201 Patients with mast cell leukemia may have fever, anorexia, and weight loss, fatigue, severe abdominal cramping, nausea, vomiting, diarrhea, flushing, hypotension, pruritus, or bone pain. Peptic ulcer and gastrointestinal bleeding are frequent findings, as are hepatomegaly, splenomegaly, and lymph node enlargement. Anemia is a constant feature, and thrombocytopenia is nearly always present.169,200,201 The total leukocyte count varies from 10,000 to 150,000 µl (10 to 150 × 109/liter), and mast cells make up 10 to 90 percent of the leukocytes. Marrow biopsy invariably shows a striking increase in mast cells, sometimes up to 90 percent of marrow cells, although the leukemic mast cells are often hypogranular or agranular. Leukemic mast cells are stained with Sudan black and alcian blue; they are positive for chloracetate esterase and acid phosphatase and are negative in the peroxidase and a-naphthylesterase reactions.169,200 Electron microscopy may show the characteristic scroll-like ultrastructural features of the mast cell granule.
Mast Cell Sarcoma This apparently is a exceedingly rare tumor, characterized by nodules at various cutaneous and mucosal sites.132 Subsequently, almost every organ becomes involved by extensive mast cell infiltration. Terminally, the blood cells are nearly all immature mast cells with monocytoid appearance.
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