Chapter 63: Basophils, Mast Cells, and Related Disorders

BASOPHILS

Despite certain similarities in biochemistry and function, mammalian basophils and mast cells are not identical (Fig. 63–1).^1,2,3,4,5 The distinction was appreciated by Paul Ehrlich, who described the histochemical staining characteristics of these cells in the late 19th century. Much evidence indicates that basophils share a common precursor with other granulocytes and monocytes.^1,2,3,4,5 Basophils have a short life span^5,6 and retain granulocytic features even after emigrating into tissues (Fig. 63–1C).⁷

The basophil is the least-common granulocyte in human blood, with a prevalence of approximately 0.5 to 0.6 percent of total leukocytes and approximately 0.3 percent of nucleated marrow cells.^8,9 The basophil’s prominent metachromatic cytoplasmic granules allow unmistakable identification in Wright-Giemsa–stained films of blood (see Fig. 63–1B) or marrow, but accurate enumeration requires absolute counting methods.^9,10 Differential counts of blood films yield valid results only if the percentage of basophils is substantially elevated or many thousands of leukocytes are counted.

Interleukin (IL)-3 promotes the production and survival of human basophils in vitro^3,11 and induces basophilia in vivo.¹² Findings in IL-3 –/– mice indicate IL-3 is not necessary for the development of normal numbers of marrow or blood basophils, but is important for the marrow and blood basophilia associated with certain T-helper (Th) 2 cell-associated immunologic responses.^13,14 Basophils also express receptors for several other cytokines (Table 63–1).^5,15 IL-3 and many of these other cytokines, including IL-33, can modulate basophil function, for example, by inducing mediator release directly and/or by augmenting the cells’ ability to release mediators in response to immunoglobulin (Ig) E-dependent challenge.^3,5,12

MAST CELLS

Mast cells normally reside in the connective tissue, particularly beneath epithelial surfaces and around blood vessels, and, in some species, in serous cavities.^1,4,16,17 Mast cells are derived from hematopoietic precursors.^{16,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21} Except for a numerically minor population of mast cells residing in the marrow (see Fig. 63–1A),⁸ this lineage completes its program of maturation in other tissues.^{16,17,18,19,20,21} Unlike basophils, mast cells can be long-lived. At least some mast cells can proliferate in the tissues during a variety of inflammatory or reparative processes.^1,16,17 Studies in mice, rats, nonhuman primates, and humans indicate many aspects of mast cell development are critically regulated by stem cell factor (SCF), the ligand for the KIT receptor tyrosine kinase.^17,22,23,24 SCF is produced in membrane-associated and soluble forms, both of which are biologically active (Chap. 18).^17,24 Beside promoting the migration, survival, proliferation, and maturation of cells in the mast cell lineage, SCF can directly promote mast cell mediator release^23,25,26,27 and, at even lower concentrations, can augment mast cell mediator release in response to stimulation by IgE and antigen.^25,26 Abnormalities affecting KIT are involved in the pathogenesis of certain types of mastocytosis (see “Disorders Affecting Mast Cells” below). Alterations in the production of SCF by fibroblasts and other cells may contribute to the changes in mast cell numbers that occur during many chronic inflammatory conditions and other pathologic responses.^17,22,28

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.^{16,17,21,29,30} This phenomenon, often referred to as mast cell heterogeneity, raises the possibility that mast cells of different phenotype express different functions in health or disease and may 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 and maturation (within a single pathway 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.^21,30 Basophils can exhibit some variation in phenotypic characteristics also, such as immunoreactivity for tryptase, chymase, and carboxypeptidase A,¹⁵ or levels of expression of surface structures, including human leukocyte antigen (HLA)-DR, CD32 (FcγRII), and receptors for cytokines.^5,31 Such variation in basophil mediator content and/or cell surface phenotype may reflect individual differences among different subjects and/or the effects of disease processes¹⁵ or the consequences of immunotherapy.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. 63–1 and Table 63–1).^1,2,3,4,5 Nevertheless, certain similarities of the two cells, taken together with evidence indicating that tissue mast cells are derived from circulating marrow-derived precursors,^16,18 had suggested to some investigators that basophils might be circulating precursors of mast cells. However, the following evidence strongly favors the view that mature basophils represent terminally differentiated granulocytes and not circulating mast cell precursors: (1) no evidence has been presented, in any species, indicating that mature circulating basophils are capable of either mitosis or differentiation into mast cells; (2) rare reports of patients with hereditary or acquired abnormalities affecting basophil numbers or morphology indicate that eosinophils also may be affected in these disorders but not mast cells^32,33,34; (3) morphologically identifiable human tissue mast cells can exhibit mitotic activity,³⁵ indicating that mast cells can replicate independently of a stage resembling that of basophils, and (4) in mice, evidence indicates that a mast cell–committed progenitor (MCP) present in the marrow is developmentally distinct during hematopoiesis from a Sca-1^lo granulocyte-macrophage progenitor.^19,20 Evidence for a committed bipotential precursor of mast cells and basophils during hematopoiesis in the mouse has been reported by some studies^36,37 but not others.^19,20,38

MORPHOLOGY OF BASOPHILS AND MAST CELLS

Routine histologic methods are poorly suited for demonstrating basophils and mast cells. Optimal visualization is achieved in appropriately prepared 1 μm sections or by electron microscopy.^1,2 By ultrastructure, human basophils are 5 to 7 μm in spherical diameter, exhibit a segmented or unsegmented nucleus with marked condensation of nuclear chromatin, and contain round or oval cytoplasmic granules surrounded by a membrane and containing a substructure of dense particles, less-dense matrix, and, in some granules, membrane whorls and Charcot-Leyden crystals (see Fig. 63–1C).^1,2 A minor population of small, uniform granules is characteristically located near the nucleus.³⁹ 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 (see Fig. 63–1C).^1,2 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 having many more cytoplasmic filaments and lacking cytoplasmic glycogen deposits. Human mast cells can contain numerous cytoplasmic lipid bodies.

BIOCHEMISTRY AND ROLE IN IMMUNOGLOBULIN E-ASSOCIATED IMMUNE RESPONSES

Mediators

The cytoplasmic granules of basophils and mast cells contain proteoglycans, consisting of sulfated glycosaminoglycans covalently linked to a protein core.⁴⁰ These substances can be stained metachromatically with basic dyes (see Fig. 63–1A and B). In humans and murine species, individual mast cell populations can contain variable mixtures of heparin and chondroitin sulfate proteoglycans.^29,40 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 five patients with myeloid leukemia indicate that such cells may produce solely chondroitin sulfates⁴¹ or a mixture of chondroitin sulfates (50 to 84 percent) and heparin (8 to 43 percent).⁴² Although the biologic functions of basophil and mast cell proteoglycans are not fully understood, in mice, heparin is required for normal packaging of certain neutral proteases in mast cell cytoplasmic granules.^40,43 Both human mast cells and basophils synthesize and store histamine.^1,4 Basophils represent the source of most (if not all) of the histamine present in normal human blood.⁴⁴ Although macrophages,⁴⁵ neutrophils,⁴⁶ and platelets,⁴⁷ as well as basophils,⁴⁴ can produce histamine, mast cells represent the source of virtually all the histamine stored in normal tissues in mice, with the notable exceptions of the glandular stomach and parts of the central nervous system.⁴⁸

In addition to proteoglycans and histamine, basophils and mast cells generate many other products that can influence the course of inflammatory processes (see Table 63–1).^{1,3,4,5,49,50,51} 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 and other metabolites of arachidonic acid, and platelet-activating factor). Appropriately stimulated mouse or human mast cells can release the cytokine tumor necrosis factor α (TNF-α),^52,53 and many other cytokines, chemokines, and growth factors with effects on inflammation, immunity, hematopoiesis, tissue remodeling, and many other biologic processes.^{1,3,4,5,49,50,51} By contrast, the spectrum of basophil-derived cytokines appears to be more limited but includes IL-4 and IL-13, vascular endothelial growth factor (VEGF)-A,⁵⁴ certain chemokines, and, at least in mice, IL-6, TNF-α, and thymic stromal lymphopoietin (TSLP).^4,5,55,56,57

ROLE IN ACUTE REACTIONS

Basophils and mast cells have specific, high-affinity plasma membrane receptors for the Fc region of IgE (FcεRI).^58,59 When IgE antibodies bound to FcεRI on the basophil or mast cell surface are bridged by specific divalent or multivalent antigens, anaphylactic degranulation is triggered.^57,58 The critical signal in this event is the aggregation of FcεRI on the plasma membrane.^57,58 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.^1,2 The complex sequence of biochemical events associated with anaphylactic degranulation, the signaling mechanisms that positively and negatively regulate this response, and the rationale for the pharmacologic manipulation of these processes have been reviewed.^57,58

The sudden, massive release of mediators from basophils and mast cells provokes many of the clinical manifestations of acute immediate hypersensitivity reactions in disorders such as certain forms of bronchial asthma (including fatal asthma, in which basophils can be prominent⁶⁰); urticaria; allergic rhinitis; and anaphylaxis to foods, drugs, insect stings, and other antigens.^{1,5,49,50,55,56,57} Both mast cells and basophils can bind IgG antibodies (as well as IgE), and the binding of IgG or IgG immune complexes can contribute to the activation of these cells (in certain mouse models of anaphylaxis) or, in other circumstances, to the downregulation of their activation (e.g., via FcγRIIB).^{5,55,56,57,61,62,63,64} Other diverse stimuli, including certain complement fragments (anaphylatoxins), neutrophil lysosomal proteins, a variety of basic peptides and peptide hormones, components of insect or reptile venoms, radiocontrast solutions, cold, calcium ionophores, and certain drugs such as narcotics and muscle relaxants, also may initiate rapid release of mediators from basophils and/or mast cells, independently of IgE.^{1,4,5,48,49,54,55,56} The clinical reactions provoked by these agents can closely mimic those of immediate hypersensitivity. Basophils activated via FcεRI or other mechanisms can exhibit increased surface levels of CD63, CD69, and CD203c, and the clinical value of using such findings to monitor basophil activation in vivo (e.g., in the setting of allergic disorders or antigen-specific immunotherapy) is under investigation.⁶⁵

ROLE IN LATE-PHASE REACTIONS

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 recurrence of signs (e.g., cutaneous edema) and symptoms (e.g., bronchoconstriction).^49,50 Much of the morbidity associated with chronic allergic conditions, including allergic asthma, is widely believed to reflect the actions of leukocytes that are recruited to sites of late-phase reactions.^49,50 Studies in mast cell–deficient and mast cell knockin mice (genetically mast cell–deficient mice that have been selectively repaired of their mast cell deficiency) indicate mast cells are responsible for virtually all of the vascular permeability changes and leukocyte infiltration associated with IgE-dependent cutaneous late-phase reactions^66,67 and that TNF-α can, importantly, contribute to these responses.⁶⁶ The extent to which mast cells (or TNF-α) contribute to late-phase reactions in humans, in which such reactions may have components that are either IgE or T-cell dependent (and in which it has been suggested that certain IgE-dependent mechanisms may not involve mast cells⁶³), is not yet clear.^68,69 However, the lymphocytes, basophils, eosinophils, and other leukocytes that are recruited to these reactions likely produce cytokines and other mediators that regulate further development and, ultimately, resolution of these reactions.^4,5,49,50

ROLE IN CHRONIC CHANGES ASSOCIATED WITH ALLERGIC DISORDERS

Studies in mice (see “Genetic Approaches for Analyzing Basophil and Mast Cell Function” below) indicate that mast cells can contribute importantly to many of the features of asthma, as observed in certain mouse models of chronic allergic inflammation involving the lungs. The features include the development of airway hyperreactivity to immunologically nonspecific agonists of bronchoconstriction such as methacholine; infiltration of the airways and lung interstitium with inflammatory cells, including eosinophils, neutrophils, and T cells; increased deposition of collagen in the lungs and hyperplasia and/or hypertrophy of airway smooth muscle; and induction of increased numbers of mucus-producing goblet cells in the large airways.^50,70,71 Thus, such mouse models indicate mast cells and their products can promote the development of much of the pathology and pathophysiologic changes observed in longstanding asthma in humans.^50,70,71 Studies in mice indicate that basophils also can enhance the development of IgE-dependent chronic inflammation of the skin, even in the absence of mast cells or T cells.^56,67

IMMUNOGLOBULIN E-DEPENDENT UPREGULATION OF FcεRI EXPRESSION AND FcεRI-DEPENDENT FUNCTION

As plasma levels of IgE increase (as often occurs in subjects with allergic diseases or parasite infections), levels of FcεRI expression on the surface of basophils and mast cells also increase.^72,73 Compared with cells with low “baseline” levels of FcεRI 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.⁷⁴ Thus, basophils and mast cells in subjects with high levels of IgE may have significantly enhanced ability to express IgE-dependent and/or immunoregulatory functions.^49,74 Exposure of mouse mast cells to certain monoclonal IgE antibodies, in the absence of exposure to the antigen for which the IgE is known to have specificity, can enhance the survival of the cells and, in some cases, induce the cells to release all three classes of mediators (preformed, lipid, cytokines).⁷⁴ Exposure to IgE in the absence of known antigen also can induce enhanced survival and cytokine and chemokine release in in vitro derived human mast cells.⁷⁵ Although the mechanisms responsible for these intriguing findings are not fully understood, some types of IgE antibodies appear to induce aggregation of FcεRI in the absence of known antigen.^74,76 The clinical implications of these findings, if any, remain to be defined.

ROLES IN T-CELL–DEPENDENT RESPONSES NOT INVOLVING IMMUNOGLOBULIN E

Mast cell activation and/or infiltration of affected tissues with circulating basophils can occur during a variety of T-cell–dependent immunologic responses in both humans and experimental animals.^{1,5,49,55,56,57,63,64,77,78,79} However, despite years of study, the importance of the contributions of mast cells or basophils in such settings is not fully understood. In part this may reflect differences in the types of mast cell–deficient mice used to investigate such responses and/or the strain background of such mice, and in part this may reflect differences in the details of the experimental models used to probe the roles of mast cells and basophils in these settings (see “Genetic Approaches for Analyzing Basophil and Mast Cell Function” below). In some of the models of T-cell–dependent responses tested, authors have concluded that mast cell can either enhance or suppress features of the responses, and in some settings evidence has been reported that mast cells can enhance the features of relatively weak responses and suppress features of strong responses.^63,64 It also has been proposed that mast cells and basophils might have immunomodulatory effects on the development or magnitude of certain acquired immune responses (e.g., positive effects via mast cell–dependent enhancement of dendritic cell migration or activation or negative effects via the production of IL-10 by mast cells).^{5,55,56,57,63,64,78,79,80} However, some of the findings in this area are considered controversial.^5,63,64,79

BIOLOGIC FUNCTIONS OF BASOPHILS AND MAST CELLS

Roles in Host Defense

Parasites

Basophils and mast cells may have critical roles in the expression of host resistance to certain parasites. Whether basophils, mast cells, or both represent major effector cell types in these responses appears to vary according to factors such as species of parasite, species of host, and site of infection. Thus, in the guinea pig, basophils appear to be required for expression of immune resistance to infestation of the skin by larval ixodid Amblyomma americanum ticks,^77,81 whereas expression of IgE-dependent immune resistance to the cutaneous infestation of larval Haemaphysalis longicornis ticks in mice is dependent on mast cells and basophils, and IgE.^57,82 Such findings support the notion that basophils and mast cells express similar or complementary functions as effector cells in host defense against parasites and other agents.

Bacterial Infections

Studies in mast cell–deficient and “mast cell knockin mice” (see “Genetic Approaches for Analyzing Basophil and Mast Cell Function” below) or in mice that lack TNF-α or certain mast cell–associated proteases indicate that mast cells can contribute to “innate” host defense against some experimental bacterial infections.^63,64,83 Depending on the model system tested, the beneficial role of the mast cell in such models of “innate immunity” in mice may partly reflect complement-dependent, toll-like receptor (TLR) 4-dependent, endothelin-1–dependent, or neurotensin-dependent activation of mast cells, inducing the release of mast cell–derived mediators, which, in turn, can contribute to enhanced local recruitment or activation of neutrophils and enhanced clearance of bacteria, or which may reduce harmful levels of TNF-α.^63,64,83 Studies in mice indicate mast cells can phagocytose bacteria,⁸³ and mouse and human mast cells can produce antimicrobial peptides (cathelicidin LL-37 in humans).⁸⁴ However, mast cells also may contribute to survival during bacterial infection in mice by additional mechanisms, such as protease-dependent degradation of endothelin-1,^85,86 neurotensin,⁸⁷ and perhaps other endogenous peptides that are produced during infections and which contribute to the pathology associated with the disorders.⁶³ On the other hand, some mast cell functions that may be expressed during bacterial infections in mice, such as the ability of mast cells to degrade IL-6 via dipeptidyl peptidase 1⁸⁸ or to produce IL-10 that suppresses host acquired immunity,⁸⁹ may have detrimental consequences. Thus, mast cells may have complex roles in innate immune responses, with some actions promoting host defense and survival and others enhancing the pathology associated with the response.

Viral Infections

Mast cell progenitors^90,91,92 and basophils⁹³ can become infected with “M tropic” strains of HIV. Although mature mast cells appear to be resistant to such infection, mast cells that matured from infected progenitors while harboring latent infection exhibited enhanced viral replication upon stimulation with ligands for TLR2, TLR4, or TLR9,^91,92 or via an IgE-dependent mechanism.⁹² At least one HIV-derived protein, glycoprotein 120 (gp120), can induce mast cell or basophil mediator release (histamine and, in basophils, IL-4 and IL-13) by binding to and crosslinking cell-surface-bound IgE.⁹³ Many patients infected with HIV develop high levels of IgE and can exhibit exacerbation of the symptoms and signs of their allergic disorders.⁹³ However, the clinical significance of such findings in HIV-infected patients remains to be determined. Many potential secreted products of mast cells or basophils may have effects that enhance (or suppress) host responses to a variety of viruses or contribute to the pathology associated with the infections.⁹⁴ However, the extent to which mast cells contribute to host defense or pathology during viral infections is not clear.

Venoms

The venoms of many animals contain substances that can activate mast cells via innate mechanisms and/or can induce specific IgE responses to venom components.^95,96 Many humans have IgE antibodies against components of honeybee or wasp venom, but only a small fraction of such “venom-sensitized” individuals have a history of anaphylaxis or other serious clinical response to such venoms.⁹⁷ Work in mast cell–deficient, mast cell knockin, and mast cell protease-deficient mice indicates that mast cells can enhance the resistance of mice to diverse animal venoms and/or their toxic components, including the venoms of three poisonous snakes,⁹⁶ the honey bee,^96,98 the Gila monster,⁹⁹ and two species of scorpions,⁹⁹ as well as to sarafotoxin 6b, a major toxin in Israeli mole viper snake venom⁸⁶ and helodermin, a toxin in Gila monster venom.⁹⁹

Notably, carboxypeptidase A3 (CPA3) or mouse mast cell protease (mMCP-4, the functional counterpart in the mouse to human chymase) appeared to account for much or all of the protective effects against various venoms that were attributable to mast cells.^86,96,98,99 CPA3 and mMCP-4 can degrade both endogenous biologically active peptides (endothelin-1 [ET-1]^86,96 and vasoactive intestinal polypeptide [VIP],⁹⁹ respectively) and similar peptides present in animal venoms (sarafotoxin 6b and helodermin, respectively), which are thought to act in mammals via the same receptors that bind the similar endogenous peptides. Work in mice deficient in mast cells, IgE, or components of the FcεRI suggests that mast cells also can contribute to the IgE antibody- and FcεRI-dependent enhanced resistance to challenge with potentially lethal amounts of honeybee venom that is observed in animals after an initial exposure to a sublethal amount of that venom.⁹⁸ Indeed, it has been hypothesized that the ability to participate in innate and acquired immune defenses against components of venoms and other toxins are important functions of mast cells and, in the case of acquired immunity, of IgE antibodies.^95,96,100

GENETIC APPROACHES FOR ANALYZING BASOPHIL AND MAST CELL FUNCTION

Factors capable of inducing basophil infiltration, mast cell proliferation, and/or basophil or mast cell activation are generated during a wide variety of immunologic or pathologic processes, including immune responses to parasites.^{1,5,30,49,50,51,55,56,57,77} As a result, speculation is considerable that basophils and mast cells express critical roles in diverse biologic responses. On the other hand, the precise functions of basophils and mast cells in most of the biologic responses in which the cells have been implicated are obscure. Studies of basophil function in guinea pigs⁸¹ and mice^55,56,57 have employed antibodies to deplete basophils, and such approaches also have been used to deplete mast cells in mice¹⁰¹; however, the antibodies used may also influence other cell types.^{5,55,56,57,63,64,79} Various mutant or transgenic mice that exhibit constitutive or inducible depletion of some or all mast cell populations, as well as mast cell–deficient mice that have been selectively engrafted with wild-type or genetically altered mast cells (so-called mast cell knockin mice), have been used in efforts to define and quantify the contributions of mast cells to many different biologic responses.^63,64,79 Transgenic mice also are now available that exhibit constitutive or inducible depletion of basophils, or that lack certain mast cell–associated products either globally or in selected cell populations.^{5,55,56,57,63,64,79} As has been extensively reviewed,^{5,54,55,56,74,75,76} the availability of such models has the potential to advance substantially our understanding of the roles of mast cells and basophils in health and disease in mice, including ascertaining the importance of strain background on some of the findings. In evaluating the results of such studies, one should keep in mind that such genetic models can have various advantages and disadvantages, and that even very strong evidence that mast cells or basophils have particular roles in mice does not prove that the cells have identical functions in humans.

No humans devoid of mast cells have been reported. In addition, the clinical findings in the rare patients who express a deficiency of basophils are not easy to interpret. One 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. However, 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

The normal blood basophil count is difficult to define precisely, but several studies place the normal range between approximately 14 to 20 and 80 to 90/μL (approximately 0.014 to 0.020 and 0.080 to 0.090 × 10⁹/L).^8,9,10,102 The blood basophil count reportedly varies by age,¹⁰³ gender (in one study¹⁰³ but not in another⁹), and season.¹⁰⁴

BASOPHILOPENIA

Because numbers of blood basophils can be very low even in apparently normal individuals,^8,9,10,102 determining whether examples of basophilopenia reflect pathologic processes as opposed to normal variation can be difficult. Nevertheless, reduced numbers of circulating basophils have been reported in several disorders (Table 63–2). Basophilopenia has been recorded in association with urticaria and anaphylaxis,^105,106 but the extent to which the latter 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 also are associated with eosinophilopenia. These conditions often are associated with increased secretion of adrenal glucocorticoids.^102,107,108 Basophil counts may diminish, sometimes markedly, during leukocytosis accompanying infection, inflammatory states, immunologic reactions, neoplasia, or hemorrhage.¹⁰⁷ Basophil counts also are diminished in thyrotoxicosis or after pharmacologic administration of thyroid hormones. Conversely, basophil counts may be increased in myxedema or after ablation of thyroid function.¹⁰⁷ A rapid and significant drop in blood basophil levels of up to 50 percent has been documented at ovulation.¹⁰⁸ A few patients with an apparent total lack of basophils have been reported.^32,34

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.

BASOPHILIA

Table 63–2 lists conditions associated with increased numbers of blood basophils (basophilia).

Inflammatory and Immunologic Responses

An increased number of basophils is commonly associated with chronic, IgE-associated hypersensitivity disorders. These disorders often are accompanied by increased levels of IgE. Although serum IgE levels and basophil numbers are not directly related,¹⁰⁹ increased IgE levels are associated with increased expression of FcεRI on the surfaces of both basophils and mast cells.^72,73,110 Moreover, basophils can be recruited into tissues at sites of IgE-associated and other immunologic responses.^{1,4,5,55,56,57,77} Basophil levels may be elevated in ulcerative colitis¹¹¹ and juvenile rheumatoid arthritis,¹¹² whereas many inflammatory conditions that cause a leukocytosis are associated with basophilopenia. Basophilia can occur in subjects exposed to ionizing radiation.¹¹³

Clonal Myeloid Diseases

Myeloproliferative Neoplasms

The concentration of blood basophils is slightly increased in many patients with polycythemia vera (Chap. 84), primary myelofibrosis (Chap. 86), and essential thrombocythemia (Chap. 85). A slight increase in the absolute basophil count may be a useful early sign of a myeloproliferative neoplasm. An increased absolute basophil count occurs in virtually all patients with chronic myelogenous leukemia (CML).^114,115,116 In some patients, basophils can represent 20 to 90 percent of blood leukocytes (Chap. 89). Exaggerated basophilia of this type is a poor prognostic sign and may herald transformation to the accelerated phase of CML.¹¹⁷ The basophil in myeloproliferative neoplasms is derived from the malignant clone and in CML can contain the Philadelphia (Ph) chromosome.¹¹⁸ The basophils in CML exhibit a variety of ultrastructural and biochemical abnormalities.^119,120 In some cases, the abnormalities obscure the typical distinctions between basophils and mast cells.^{121,122,123,124} Release of basophil-associated histamine can lead to episodes of flushing, pruritus, and hypotension in occasional patients with basophilic CML.^125,126 Severe peptic ulcer of the stomach and duodenum can occur in association with hypersecretion of gastric acid and pepsin.^127,128 Ph chromosome–positive acute basophilic leukemia may be a presenting manifestation of CML.¹²⁹

Basophilic Leukemias

The basis for designating some cases as basophilic leukemias as opposed to examples of other more typical myelogenous leukemias with an associated pronounced basophilia is not always clear. Accordingly, we refer to these conditions herein as leukemias associated with basophilia. Table 63–3 lists the leukemias associated with basophilia. In addition to extreme basophilia in the chronic phase CML or as a manifestation of the accelerated phase of CML, acute basophilic leukemia can rarely occur de novo.^{130,131,132,133,134,135,136} Thus, acute basophilic leukemia is included in the World Health Organization classification of acute myeloid leukemias (AMLs),¹³⁷ but the entity is poorly defined.^135,136,138 Some cases are recognized only by electron microscopy, a procedure not used routinely in the diagnosis or classification of leukemias. One report suggests that the detection of a CD123-positive, CD203c-positive, and CD117-negative blast cell immunophenotype may be useful in making a diagnosis of acute basophilic leukemia.¹³⁹ The best defined entity of acute basophilic leukemia appears to occur in male infants and is associated with t(X;6)(p11.2;q23.3), resulting in the fusion of MYB and GATA1.^140,141

Other types of AML that have an associated increase in basophils are more prevalent than acute basophilic leukemia. Such acute leukemias most commonly have t(9;22), t(6;9), t(3;6), or 12p abnormalities.^{142,143,144,145} The t(9;22) AMLs have features similar to blast crisis of CML, but studies show that de novo cases are associated with deletion of antigen receptor genes.¹⁴⁶ The t(6;9) AML often is associated with erythroid hyperplasia and dysplasia, a high frequency of FLT3 mutations, and poor prognosis.^147,148,149

AML with inv(16) or t(16;16) are characteristically associated with cells having large basophilic granules, but the cells containing these granules are generally thought to represent abnormal eosinophils rather than basophils.¹⁵⁰

Although the clinical and pathologic features of acute basophilic leukemia are largely similar to those of AML, affected patients occasionally exhibit symptoms that result from release of mediators (especially histamine) from degranulating or dying basophils.^{125,126,132,151} Remission induction therapy is similar to the therapy used for other types of AML, but management can be complicated by shock resulting from massive release of histamine and other mediators associated with acute cytolysis.

Chapter 88 provides further details on the acute leukemias associated with basophilia.

NORMAL MAST CELL LEVELS

Mast cells cannot be identified in the blood of healthy individuals using standard techniques. However, mast cells can be observed in the blood of monkeys that have been treated chronically with large amounts of the KIT ligand SCF²² and in the blood of some patients with systemic mastocytosis.¹⁵² Increases in tissue mast cells can occur by a combination of enhanced progenitor influx and proliferation of resident mast cells in tissues.^16,153 Human mast cells have been classified according to their content of neutral proteases as MC_T, because the granules contain tryptase but not detectable chymase, and MC_TC, whose secretory granules contain both enzymes.²⁹ The former mast cell type ordinarily predominates in lung and gastrointestinal mucosal tissues, and the latter type in dermis and submucosal tissues.^154,155,156 Mast cells that express chymase but little or no tryptase (MC_C) also have been described.¹⁵⁷

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,¹⁵⁸ no clinical disorder whose primary feature is a reduction in levels of tissue mast cells has been reported. Studies of small numbers of patients indicate that certain mast cell populations, namely, the MC_T mast cells in the gastrointestinal mucosa, can be strikingly reduced in numbers in subjects with genetically determined or acquired (HIV-induced) immunodeficiency.¹⁵⁹ Human mast cell precursors can be infected in vitro with so-called M tropic strains of HIV^90,91,93; and in vivo may comprise a long-lived inducible reservoir of persistent HIV.⁹² Whether mast cell infection with HIV contributes to the reduction in gastrointestinal mast cells observed in some subjects with HIV infection remains to be determined.

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 63–4). Tissues at sites of recurrent allergic reactions often exhibit increases in mast cell numbers, to levels as high as approximately fourfold normal.^154,160 Small increases in mast cell numbers have been observed at sites of pathology in rheumatoid arthritis, psoriatic arthritis, scleroderma, and systemic lupus erythematosus.^{154,160,161,162} Mast cells are reported to be increased in osteoporosis,¹⁶³ but the extent to which this increase reflects decreases in other cell types and/or a decrease in bone matrix is unclear. Numbers of marrow mast cells can be increased in patients with chronic liver or renal diseases.¹⁶⁴ Increases in mast cells also have 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.¹⁶⁵ In such settings, mast cell numbers 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^164,166 and in subjects with stem cell diseases and lymphoproliferative diseases, including lymphoma in the marrow and in association with CML.^{164,167,168,169}

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 report of a primary mast cell disorder is attributed to Unna¹⁷⁰ who, in 1887, reported that the skin lesions of urticaria pigmentosa (UP)^171,172 contained numerous mast cells. Ellis¹⁷³ recognized the systemic nature of the disorder in 1949. In addition to the systemic disorders classified as mastocytosis, localized cutaneous aggregates of mast cells, ranging from mast cell nevi and mastocytomas in infants and children to multiple nodules in older children, may occur.^174,175

The clinical pattern of disease in mastocytosis and its prognosis can vary substantially among patients (see “Course and Prognosis” below). A consensus classification for mastocytosis has been developed to address the issue and to provide guidelines regarding prognosis and treatment (Table 63–5).¹⁷⁶ Patients with indolent disease, who compose the great majority of subjects with mastocytosis, can expect a normal life span. Patients with systemic mastocytosis with associated clonal, hematologic non–mast-cell-lineage disease (SM-AHNMD) have a prognosis determined by the associated hematologic disorder. Patients with aggressive systemic mastocytosis (ASM) generally have a 3- to 5-year survival. Mast cell leukemia (MCL) is often rapidly fatal.

ETIOLOGY AND PATHOGENESIS

Activating mutations in KIT, which encodes the SCF receptor, a member of the type III receptor tyrosine kinase family, have been documented in patients with mastocytosis. Several lines of evidence indicate such mutations can be involved in the pathogenesis of the disease. The most common of these mutations (Asp816Val), which results in ligand-independent activation of the KIT receptor, was first identified in a long-term cell line derived from a patient with MCL.¹⁷⁷ It then was detected in mononuclear cells in the blood of patients with mastocytosis who had an associated hematologic disorder,¹⁷⁸ 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 UP,¹⁷⁹ and in the skin, but not the marrow and blood, of an 11-month-old child with mastocytosis.¹⁸⁰

Together these findings suggest the mutation occurs initially in a mast cell progenitor and that, as the clone expands, it becomes detectable in the marrow, blood, and skin lesions. The Asp816Val mutation, or similar 816 activating mutations that result in the substitution of phenylalanine or tyrosine for aspartate, now are believed to occur in more than 90 percent of adult patients with mastocytosis.¹⁸¹ Mutations at codon 816 have been identified in a subset of pediatric patients, whereas other pediatric patients exhibit KIT mutations elsewhere, including within the extracellular domain. These other mutations also cause constitutive activation in KIT to a varying degree.¹⁸¹

The extent to which the presence of various KIT mutations, and the anatomical distribution of the affected cells, can be used to predict prognosis or disease severity in patients with mastocytosis remains under investigation. Moreover, additional “gain-of-function” mutations of KIT in human subjects with mastocytosis have been reported. For example, a novel form of mastocytosis with a KIT mutation in the transmembrane domain (Phe522Cys) has been described.¹⁸² In a second example, a PRKG2-PDGFRB fusion was identified in a patient presenting with increased numbers of mast cells and peripheral basophilia.¹⁸³ The latter case falls within the World Health Organization category of myeloid neoplasms with PDGFRB rearrangements, rather than being categorized as a subvariant of mastocytosis. Gain-of-function mutations of KIT also have been reported in gastrointestinal stromal tumors.¹⁸⁴ Additional genetic lesions have been reported in aggressive mastocytosis and in patients with SM-AHNMD, including mutations in JAK2, TET2, NRAS, and KRAS.¹⁸⁵

CLINICAL FEATURES

The organs most frequently involved in systemic mastocytosis are the skin, lymph nodes, liver, spleen, marrow, and gastrointestinal tract.

The Skin

The usual presenting lesion of mastocytosis in the skin is UP/maculopapular cutaneous mastocytosis. UP lesions appear as small yellowish-tan to reddish-brown macules or slightly raised papules (Fig. 63–2), which can exhibit the Darier sign, that is, urticaria after mild friction of the skin.¹⁷⁴ The palms, soles, face, and scalp generally remain free of lesions. In many cases, UP develops before age 2 years and subsides by puberty. Adults with UP usually have extracutaneous involvement by mastocytosis. However, some patients, particularly those with SM-AHNMD, ASM, or MCL, lack cutaneous lesions. In such cases, other organs must be biopsied to make the diagnosis. Diffuse cutaneous mastocytosis is an unusual manifestation of mastocytosis.^175,186 The skin appears yellowish-brown and is thickened. Young children with cutaneous disease may have bullous eruptions with hemorrhage.¹⁷⁵ Some adults develop prominent vascularity in association with the skin lesions, a condition that has been termed telangiectasia macularis eruptiva perstans.¹⁷⁵

Lymph Nodes

In one series, peripheral lymphadenopathy occurred in 26 percent and central lymphadenopathy in 19 percent of patients at diagnosis.¹⁸⁷ Lymphadenopathy is most prominent in patients with SM-AHNMD or ASM. Mast cell infiltrates are observed in the node’s paracortex, follicles, medullary cords, and sinuses. Additional findings include infiltrates of eosinophils, blood vessel proliferation in association with mast cells in the paracortical areas, and extramedullary hematopoiesis. In hematoxylin-and-eosin (H&E)–stained sections, mast cell infiltrates in the lymph nodes may resemble T-cell lymphomas in their pericortical distribution, the clear cytoplasm that is sometimes exhibited by the mast cells, and the associated vascular proliferation and eosinophilia.¹⁸⁷ Alternatively, when mast cells replace lymphoid follicles, the pattern may resemble follicular hyperplasia or follicular lymphoma.¹⁸⁷ Fibrosis may be observed in lymph nodes involved by mast cell infiltrates.

Liver

Patients frequently exhibit infiltration of the liver with mast cells. Many of these individuals have some associated liver pathology, but severe liver disease is uncommon. When severe liver disease does occur, it typically affects patients with SM-AHNMD or ASM. In one series of 41 patients, 61 percent had some liver disease.¹⁸⁸ Elevated serum levels of alkaline phosphatase, aminotransaminases, 5′-nucleotidase, or γ-glutamyl transpeptidase was detected in 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; some of these patients also had ascites or portal hypertension. Portal fibrosis was observed in 68 percent and was positively correlated with hepatic inflammation and mast cell infiltrates. Venopathy and associated venoocclusive 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 patients with systemic disease.^187,189 Mast cells most commonly occurred in a paratrabecular distribution, followed by perifollicular, follicular, and diffuse infiltrates. Trabecular and capsular fibrosis and eosinophilic infiltration also were observed, and extramedullary hematopoiesis was present in most cases. On H&E stained sections, the infiltrates of mast cells produced lesions that may resemble those of T-cell lymphoma, follicular hyperplasia, follicular lymphoma, myeloproliferative neoplasms, hairy cell leukemia, or a granulomatous process. Splenomegaly has also been reported in the absence of infiltration of the spleen by mast cells.¹⁹⁰ Increased splenic weights greater than 700 g generally occurred in patients within unfavorable categories of mastocytosis.

Marrow

The majority of adults with systemic mast cell disease have focal mast cell lesions in the marrow,^{189,191,192,193,194} typically appearing as foci of spindle-shaped mast cells in a fibrotic background (Fig. 63–3), sometimes with associated eosinophils and T and B lymphocytes. These focal mast cell lesions are the major criterion in the diagnosis of systemic mastocytosis (Table 63–6).¹⁷⁶ Reticulin staining may be increased, and Masson trichome staining may reveal collagen deposition. In specimens extensively involved by mast cell lesions, the bony trabeculae may be moderately to markedly thickened. Aggressive variants of mastocytosis, such as MCL, should be considered if the percentage of mast cells in the marrow aspirate film exceeds 20 percent of all nucleated cells. In the typical leukemic variant of MCL, mast cells account for 10 percent or more of blood leukocytes.¹⁷⁶ This type of MCL should be distinguished from an aleukemic variant of MCL where circulating mast cells account for less than 10 percent of white blood cells.¹⁹⁵

In H&E–stained sections, the mast cells typically exhibit a spindle-shaped or oval nucleus (see Fig. 63–3A and B), and fine eosinophilic granules are apparent in the cytoplasm at high-power magnification (see Fig. 63–3B). Mast cells with bilobed nuclei may be seen in these lesions and is a finding associated with a poor prognosis.¹⁸⁹ Mast cells stain positively for chloracetate esterase and aminocaproate esterase, and for mast cell tryptase by immunohistochemistry (see Fig. 63–3D). The latter is the procedure of choice for visualizing mast cells. Mast cells exhibit immunoreactivity for a variety of paraffin section markers.¹⁹⁶ The more specific mast cell markers in paraffin sections are CD117 (KIT) (see Fig. 63–3C) and mast cell tryptase (see Fig. 63–3D). Strong CD117 membrane staining is equally sensitive for mast cells as tryptase but is less specific.

Films of marrow aspirates or clot sections alone cannot be used to diagnose mast cell disease in the marrow. Although increased numbers of mast cells may be present in marrow aspirate films of patients with systemic mast cell diseases, similar findings have been reported in patients without mast cell disorders or in patients with a reactive increase in marrow mast cells. However, mast cells in reactive lesions usually are not spindle shaped, nor do they typically exhibit evidence of degranulation. On marrow films, a normal mast cell has a round or oval shape, a round and centrally located, nonlobated nucleus, and a fully granulated cytoplasm. Mast cells from patients with mastocytosis may exhibit phenotypic aberrations, such as a spindle shape, cytoplasmic projections, and hypogranulation. A multilobular and/or eccentrically located nucleus may be observed.¹⁷⁶ If at least 25 percent of all mast cells on aspirate smears have aberrant morphology, the findings are considered to support the diagnosis of systemic mastocytosis (minor criterion).¹⁷⁶ An aberrant mast cell phenotype also may be detected on flow cytometric analysis of the marrow aspirate. In patients with mastocytosis, mast cells may express CD2, CD25 (minor criterion), and CD33.¹⁹⁷

Marrow involvement is much less common in children. In a study 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 marrow aspirate films were noted in 5.¹⁹³ The focal lesions found in children usually are small and perivascular.

Progression of marrow involvement in systemic mast cell disease is variable. Some adults with indolent disease appear to have stable, or even decreasing, marrow involvement over time.¹⁸⁹ In contrast, a progressive increase in focal mast cell lesions is more commonly observed in patients with more aggressive patterns of disease.

CLINICAL PRESENTATION

Even though individuals may differ in the specific pathogenesis of their disease, all patients within a given category of mastocytosis (see Table 63–5) tend to exhibit similar clinical features. Manifestations of the disease largely reflect the local and systemic consequences of mediator release from tissue mast cells. Effects caused by disruption of normal structures by local collections of mast cells also may be seen.

At presentation, patients with mastocytosis may complain of vague and nonspecific constitutional symptoms, such as fatigue, weakness, flushing, and musculoskeletal pain. Some patients experience fever and/or weight loss.^152,186 A subset of patients may present with recurrent episodes of unexplained anaphylaxis.¹⁹⁸ However, most patients with mastocytosis and a hematologic disorder are diagnosed based on marrow biopsy findings, during the investigation of their hematologic disease.^187,189 Patients with aggressive disease often present with unexplained lymphadenopathy and splenomegaly and/or hepatomegaly.

Gastrointestinal disease and associated symptoms are commonly associated with systemic mastocytosis, either at presentation or as the disease progresses.^174,199 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 patients with systemic disease.¹⁹⁹ With progressive disease, patients may develop mild malabsorption.¹⁹⁹

If systemic involvement is advanced at the time of diagnosis, patients may exhibit lymphadenopathy, hepatomegaly, and splenomegaly during the initial evaluation.¹⁵² Because osteoporosis may accompany systemic disease, pathologic fractures may occur.

LABORATORY FEATURES

When systemic mastocytosis is suspected in patients based on a combination of: reports of symptoms consistent with mediator release, identification of classical skin lesions showing a 10-fold or greater increase in mast cell numbers, an elevation in serum tryptase of greater than 20 ng/mL²⁰⁰ and documentation of organomegaly, an appropriate next step is to perform a marrow biopsy and aspirate.^152,176,201 Additional studies, including a gastrointestinal evaluation involving radiographic studies of the upper gastrointestinal tract and small intestines, computed tomographic scan of the abdomen, and endoscopy, also may be justified.

Plasma and/or urinary histamine levels may be increased in systemic mastocytosis.¹⁸⁶ However, the isolated findings of increased levels of histamine or histamine metabolites may reflect a number of other situations, including anaphylaxis. Furthermore, the accuracy of laboratory measurement of histamine depends on the assay used. Urine histamine levels may be falsely elevated as a result of bacterial contamination, pharmacologic agents and their metabolites excreted in the urine, or diets rich in histamine or histamine precursors. Similarly, serum tryptase may be elevated after anaphylaxis. Thus, no single laboratory test showing an elevation in a mast cell mediator is diagnostic of mastocytosis. Rather, the demonstration of such mediators in blood or urine should prompt the clinician to investigate further for the presence of mastocytosis.

There are patients who have symptoms of mediator release but no mastocytosis in the skin or organomegaly. Some of these patients may have experienced venom-induced anaphylaxis. These patients may also exhibit elevations in tryptase but below the 20 ng/mL which is used as a minor diagnostic criterion. In such situations, reports have suggested the detection of the D816V mutation in blood using a highly sensitive allele-specific quantitative polymerase chain reaction (qPCR) may be useful as a diagnostic parameter.²⁰¹ At the time of writing of this chapter, this test is not widely available and it is being used largely in referral centers.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of systemic mastocytosis includes allergic diseases; hereditary or acquired angioneurotic edema; idiopathic flushing, urticaria, and anaphylaxis; carcinoid tumor; and idiopathic capillary leak syndrome. When episodic hypertension is a major finding, pheochromocytoma should be considered. Significant unexplained gastroduodenal ulcer disease requires that Zollinger-Ellison gastrinoma syndrome be ruled out. Helicobacter pylori infection should be considered in all patients with ulcer disease, including patients with mastocytosis.

Some diseases have hematologic findings that overlap with those of systemic mastocytosis. These disorders include tryptase-positive AML, CML with accumulation of tryptase-positive cells, primary myelofibrosis with mast cell accumulation, and acute or chronic basophilic leukemia.

A somatic mutation in KIT at codon 816 (most commonly Asp816Val) is associated especially with adult-onset systemic mastocytosis. Demonstration of a codon 816 gain-of-function mutation, where the most sensitive approach is to look for its presence in sorted marrow-derived mast cells, is a minor criterion in the diagnosis of mastocytosis (see Table 63–6).

THERAPY

Mastocytosis currently has no cure.²⁰² In addition, no evidence indicates that symptomatic therapy significantly alters the course of the underlying disease.

Avoiding Triggers

Management of mastocytosis includes instructing the patient on the avoidance of factors that may trigger symptoms (presumably by direct or indirect activation of mast cell mediator production). Such factors can include temperature extremes, physical exertion, or, in some unusual cases, ingestion of ethanol, nonsteroidal antiinflammatory drugs, or opiate analgesics.¹⁷⁴

Epinephrine and H₁ or H₂ Antihistamines

Anaphylaxis may follow insect stings, even in the absence of evidence of allergic sensitivity.¹⁹⁸ Epinephrine-filled syringes and instructions on their use can be given to patients considered at risk for such a reaction. Patients with mast cell disease and a history of anaphylaxis should be advised to carry epinephrine-filled syringes, instructed on their use, and taught to self-medicate, if necessary. These patients also may benefit from the concurrent use of H₁ and H₂ antihistamines prophylactically. Patients may experience severe reactions to iodinated contrast materials. Thus, consideration should be given to premedicating mastocytosis patients with H₁ and H₂ antihistamines and prednisone. Nonsedative H₁ antihistamines decrease skin irritability and pruritus.^186,202 Pruritus may be relieved by approaches that maintain skin hydration. H₂ antihistamines, including ranitidine and famotidine, are used to treat the gastritis and peptic ulcer disease associated with mastocytosis.^{186,202,203,204} H₂ antihistamines may be titrated based on symptom control or to a particular level of gastric secretion. Proton pump inhibitors are useful for management of gastric hypersecretion.^199,204

OTHER DRUG THERAPY

Disodium Cromoglycate; Ketotifen

Oral administration of disodium cromoglycate may be useful for treatment of gastrointestinal cramping and diarrhea.^186,202,205 The agent has been beneficial in cutaneous mast cell disease in children and infants.¹⁸⁶ Other symptoms, including headache, have improved with administration of cromolyn sodium. Ketotifen reportedly has been effective in relieving pruritus and wheal formation in cutaneous mastocytosis.²⁰⁶ By contrast, one pediatric study found ketotifen was no more effective than hydroxyzine.²⁰⁷

Bisphosphonates

Osteoporosis in patients with mastocytosis may be unrecognized and thus undertreated, especially in patients with milder forms of disease. It is thus important to utilize dual-energy x-ray absorptiometry (DEXA) scanning in the evaluation of those with mastocytosis. Recommended approaches for the treatment of osteoporosis include calcium supplementation, consideration of estrogen replacement in postmenopausal women, and use of bisphosphonates.²⁰⁴

Nonsteroidal Antiinflammatory Agents

Nonsteroidal antiinflammatory agents have been useful in some patients whose primary manifestations are recurrent episodes of flushing, syncope, or both.^202,204 It should be noted that these agents may exacerbate ulcer disease. Patients with a history of aspirin sensitivity should not be placed on this therapy unless they first undergo desensitization.

Glucocorticoids; Methoxypsoralen

Cutaneous lesions have been treated with either glucocorticoids²⁰⁸ or 8-methoxypsoralen plus ultraviolet A (PUVA),²⁰⁹ largely to reduce pruritus or for cosmetic improvement. No evidence indicates such approaches alter the progression of systemic disease. Relapses 3 to 6 months after cessation of PUVA therapy are common. Patients may experience a decrease in the intensity of lesions after exposure to natural sunlight. Repeated or extensive application of glucocorticoids may result in cutaneous atrophy or adrenocortical suppression.²⁰⁸

Systemic glucocorticoids are used to decrease significant malabsorption and ascites²¹⁰ in patients with advanced disease. In adults, oral prednisone (40 to 60 mg/day) usually results in decreased symptoms over a 2- to 3-week period. After initial improvement, steroids usually can be tapered to an alternate-day regimen. However, with time, the ascites frequently recurs. Such patients reportedly can benefit from a portacaval shunt.

Interferon-α Cladribine

Patients with more advanced categories of systemic mastocytosis may be candidates for approaches directed at reducing the mast cell burden. None of these approaches has resulted in cure of the disease. For severe disease, some limited success has been reported for interferon α (IFN-α) and it is often considered to be a first-line drug of choice along with cladribine.^204,211,212 It is presumed to act by restricting the proliferation of hematopoietic progenitor cells. Studies with IFN-α, often in combination with glucocorticoids, have reported variable success, with unchanged or modest reductions in marrow infiltration with mast cells, and in tryptase levels. Many patients do report symptomatic benefits. Resolutions of ascites and increased bone remineralization also have been reported. Use of IFN-α is often limited by side effects such as fever, fatigue, and cytopenias. Its use is not routinely recommended for patients with indolent systemic disease, unless there is concomitant severe osteoporosis.

Cladribine (2-chlorodeoxyadenosine), a nucleoside analogue, does not require cells in active cell cycle to exert its cytotoxic activity and may be beneficial in slowly progressing neoplastic processes. The drug has myelosuppressive and immunosuppressive properties and thus cannot be recommended for patients with indolent disease.²⁰⁴

Hematopoietic Stem Cell Transplantation

Allogeneic stem cell transplantation (SCT) has been employed as a treatment option for patients with advanced categories of mastocytosis associated with poor survival. SCT has been used to treat a hematologic disorder associated with mastocytosis in relatively few cases.^{213,214,215,216} Although these studies reported favorable responses of the associated hematologic disorders, complete remission of the mast cell disease was reported in only one study, which used non–T-cell-depleted blood SCT in a patient with an associated myeloproliferative neoplasm.²¹⁵ The value of allogeneic SCT in mastocytosis may result from the immunotherapeutic effects of the donor marrow rather than the myeloablative conditioning regimen.²¹³ One study using nonmyeloablative blood SCT for treatment of advanced systemic mastocytosis in three patients with advanced mastocytosis reported no effect on mastocytosis progression despite the induction of a graft-versus-mast-cell response.²¹⁶ Perhaps performing targeted therapy directed at the mast cell compartment before transplantation would improve outcome.

Tyrosine Kinase Inhibitors

The availability of low-molecular-weight inhibitors of tyrosine kinases suggested the mutated KIT tyrosine kinases in mastocytosis as a therapeutic target. Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) currently is the only such drug available. It has a specific inhibition profile that includes ABL1, KIT, and PDGFR (platelet-derived growth factor receptor) tyrosine kinases.^217,218 Although the drug inhibits wild-type KIT and KIT bearing juxtamembrane-activating mutations similar to those found in gastrointestinal stromal tumors, it does not inhibit KIT bearing the codon 816 mutations associated with most common forms of systemic mastocytosis.^219,220 This finding is attributed to a conformational change in KIT bearing the codon 816 mutation, which interferes with the association of the drug with the ATP-binding domains of the receptor. Consistent with these observations, imatinib mesylate showed a strong in vitro cytotoxic effect on mast cells bearing wild-type KIT. Mast cells bearing a codon 816 mutation isolated from marrow of patients with mastocytosis were fairly resistant to the drug.²²¹ These studies suggest imatinib mesylate is unlikely to be an effective therapy for patients who carry codon 816 mutations. However, the drug appears to be of value when there is an imatinib-sensitive mutation or in KIT816-unmutated patients. For example, a patient with an unusual form of systemic mastocytosis associated with a KIT mutation (Phe522Cys) affecting the transmembrane region of the receptor responded to treatment with imatinib.¹⁸² Accordingly, a careful mutational analysis of a sample enriched for lesional mast cells appears to be essential in patients with mastocytosis before contemplating imatinib therapy. Other tyrosine kinase inhibitors that decrease the activity of KIT with codon 816 mutations including midostaurin (PKC412) and dasatinib are in clinical trials.^222,223 Studies to date suggest that midostaurin may produce significant decreases in mast cell burden in some patients.²²²

Some patients with a variant of chronic eosinophilic leukemia (clonal hypereosinophilic syndrome) and FIPIL1-PDGFRA fusions exhibit elevated serum tryptase levels, increased numbers of mast cells in the marrow, some of which can appear atypical and spindle shaped, tissue fibrosis, and, like other patients who have the FIPIL1-PDGFRA fusion gene, are responsive to imatinib mesylate.^224,225 Such cases are classified within the World Health Organization category of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1.

Monoclonal Mast Cell Activation Syndrome

Monoclonal mast cell activation syndrome (MMAS) is a term adopted by a consensus conference to be applied to patients who are found to have one or two minor diagnostic criteria for mastocytosis but lack the full diagnostic criteria for systemic disease.²²⁶ Patients with such findings have been identified within groups of patients diagnosed with idiopathic anaphylaxis and patients with anaphylaxis to stinging insects. It is possible that these studies are identifying patients with a progressive clonal mast cell disorder that may one day meet the diagnostic criteria for systemic mastocytosis. For now, such patients are treated symptomatically and for anaphylaxis. Followup at yearly intervals is recommended to determine if there is evidence of an expanding mast cell compartment.

Mast Cell Activation Syndrome

The term mast cell activation syndrome (MCAS) is sometimes applied as a diagnosis for patients with episodic allergic-like signs and symptoms, including flushing, urticaria, diarrhea, and wheezing, involving two or more organ systems; and where an extensive medical evaluation has failed to identify an etiology.^227,228 The assumption is that individuals to whom this diagnosis is applied are having episodes caused by release of mediators associated with hyperreactivity of mast cells that then activate spontaneously.

Diagnostic criteria have been proposed to separate this proposed entity from other causes of such clinical findings. These criteria include response to antimediator therapy and an elevation in a marker of mast cell activation, such as serum tryptase, with an episode.²²⁷ Primary (clonal) and other clinical disorders associated with mast cell activation, as well as other conditions associated with vasoactive mediator release, must be eliminated as possible causes of the clinical findings, including allergic diseases, mast cell activation associated with chronic inflammatory or neoplastic disorders and chronic autoimmune urticaria. Once the diagnostic criteria are met, therapy is symptomatic. Patients must be followed regularly in the event that one of the diagnoses eliminated during the initial evaluation reaches the level of diagnosis.

Splenectomy

Splenectomy has been performed on patients with severe aggressive mastocytosis in an attempt to improve their limiting cytopenias.²²⁹ Based on comparisons to historical controls, splenectomy increased survival by an average of 12 months. Patients who had undergone splenectomy appeared to be better able to tolerate chemotherapy. Splenectomy is of no value in the management of indolent mast cell disease.

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 indolent systemic mastocytosis (ISM) have a chronic protracted course that responds to symptomatic medical management. A normal life span is expected. Few of these patients progress to more severe forms of the disease; some patients may even experience a diminution in the severity of skin lesions in later years, while their marrow findings remain unchanged.²³⁰ However, elevated serum lactate dehydrogenase levels, a late age of onset, and, in patients with SM-AHNMD, 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.¹⁸⁹ The prognosis for patients with SM-AHNMD depends on the course of the associated hematologic disorder.

Mast Cell Leukemia

MCL is relatively rare and prognosis is poor.^195,222 A major differential diagnosis to MCL is myelomastocytic leukemia (MML).²³¹ Patients with MCL may have fever, anorexia, weight loss, fatigue, severe abdominal cramping, nausea, vomiting, diarrhea, flushing, hypotension, pruritus, or bone pain. Peptic ulcer and gastrointestinal bleeding, hepatomegaly, splenomegaly, and lymph node enlargement are frequent findings. Anemia is a constant feature, and thrombocytopenia is nearly always present. The total leukocyte count varies from 10,000 to 150,000/μL (10 to 150 × 10⁹/L), and mast cells compose 10 to 90 percent of leukocytes. Marrow biopsy shows a striking increase in mast cells, sometimes up to 90 percent of marrow cells, although the leukemic mast cells often are hypogranular or agranular.^195,231

Mast Cell Sarcoma

This is an exceedingly rare tumor, characterized by nodules at various cutaneous and mucosal sites.^164,176