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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 133Mast Cell Leukemia and Other Mast Cell Neoplasms

, MD and , MD.

The importance of the mast cell in mediating certain allergic and cutaneous disorders was recognized long before the original identification of a mast cell malignancy by Efrati in 1957.1 He described the case of a 52-year-old female in whom the presence of mast cells in the peripheral blood was associated with mast cell infiltration of the viscera and bone marrow. This patient’s aggressive disease resulted in her death within 5 months of diagnosis. In the past three decades, significant strides have been made in the understanding of mast cell ontogeny and physiology, although a similarly precise understanding of mast cell diseases has been more elusive.

Mast Cell Biology

Morphology

Mast cells are typically 10 to 15 μm in diameter, have a round or oval nucleus, and contain distinctive cytoplasmic granules that are particularly avid for metachromatic dyes, such as toluidine blue, Giemsa, and methylene blue.2 Staining with these cationic dyes occurs because of their affinity for the negatively charged heparin polymer contained in the granules.3 The chloroacetate esterase reagent stains both mast cells and neutrophils, although mast cells may be distinguished cytochemically by avidin-conjugated fluorochrome or aminocaproate esterase staining.4 Although mast cells may be visible on hematoxylin and eosin–stained preparations of routinely fixed tissues, the previously described dye and enzyme–based approaches are required to definitively characterize these cells.

Ontogeny

Although mature mast cells are typically located in tissues having primary contact with foreign antigens, such as the skin and gastrointestinal and respiratory tracts, they originate in the bone marrow. Mast cells can be restored to mice with acquired or congenital absence of tissue mast cells by bone marrow transplantation from normal mice.5 Human mast cells appear to be derived from pluripotent (CD34-positive) hematopoietic stem cells,6 under the influence of molecules such as interleukin-3, (IL-3) stem cell factor,7,8 and eotaxin.9 Moreover, mast cells display surface antigens in common with other hematopoietic cells, including monocytes/macrophages.10

Although they share a common lineage, mast cells are highly heterogeneous. Subpopulations can be defined on the basis of response specificity,11 granule content,12,13 or tissue migration patterns.12,13 For example, the so-called T mast cells, which predominate in the lung and intestinal mucosa, contain a different amount of tryptase and chymase (vasoactive proteases that function as mast cell–specific mediators) in their granules than do the TC mast cells found mainly in the skin and intestinal submucosa.13 The relative amount of tryptase and chymase in mast cells may be regulated by cytokines, such as IL-4.14

Physiology

Mast cells play a central role in the manifestations of the acute hypersensitivity reaction. A number of immune and nonimmune stimuli cause mast cell granules to fuse with the cell membrane, thereby releasing mediators of anaphylaxis into the surrounding area. Such stimuli include antigen-IgE complexes, which may bind to high-affinity IgE receptors found on the mast cell surface,15 complement anaphylotoxins C3a and C5a,16 adenosine analogues,17 and gastrin.18 Mast cell granules contain substances subclassified as primary mediators or newly generated mediators, which regulate the vasoactive (increase in capillary permeability, vasodilatation) and inflammatory (recruitment of other effector cells) processes that are characteristic of allergic phenomena. Primary mediators, including the proteoglycans heparin and chondroitin sulfate, biogenic amines, acid hydrolases, and neutral proteases,19,20 are preformed prior to mast cell stimulation. The newly generated mediators, such as platelet activating factor and the arachidonic acid metabolites, leukotrienes (B4, C4, and D4), and prostaglandin D2, are synthesized at the time of mast cell activation.19,20 Furthermore, activated mast cells or mast cell leukemic cell lines produce (1) cytokines and/or chemokines, such as tumor necrosis factor (TNF), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage (GM)-CSF, IL-3, IL-4, IL-5, IL-6, IL-8, RANTES, MCP1, and MIP1a,20–22 (2) adhesion molecules, such as ICAM1, which play a crucial role in inflammation due to their ability to cause the activation and proliferation of white blood cells and their precursors,22 and (3) angiogenic substances such as basic fibroblast growth factor.23

Since GM-CSF, IL-3, IL-4, IL-10, and stem cell factor (the soluble fragment of the proto-oncogene c-kit ligand) are mitogenic for mast cells,24–26 an autocrine feedback loop may exist between mast cell activation and proliferation. Insofar as blasts from certain patients with acute myeloid leukemia retain the capacity to proliferate in response to growth factors (which they also may produce), a similar mechanism of autocrine stimulation could play a role in the generation and/or maintenance of malignant mast cell neoplasms.

Mast Cell Leukemia and Other Mast Cell Neoplasms

Mastocytosis represents a spectrum of disorders characterized by mast cell hyperplasia (Table 133.1). These disorders may be reactive or neoplastic and range from benign syndromes with cutaneous involvement to malignant variants with mast cell infiltration of multiple organs, including the bone marrow. Approximately 15% of patients with malignant mastocytosis develop mast cell leukemia,27 a very rare variant of acute myeloid leukemia.

Table 133.1. Spectrum of Mast Cell Proliferation.

Table 133.1

Spectrum of Mast Cell Proliferation.

Reactive mastocytosis

Mast cell hyperplasia frequently occurs in tissues involved in immediate or delayed type hypersensitivity reactions, such as in the nasal mucosa during allergic rhinitis.20 Increased numbers of mast cells in the bone marrow have been noted in association with a wide range of malignant disorders, including lymphomas,28 hairy-cell-leukemia,29 and myeloid neoplasms.30,31 The mast cells in such patients appear to be reactive, rather than derived from the malignant clone.32,33 Skin infiltration with mast cells, simulating urticaria pigmentosa, was the presenting sign in two patients with acute lymphoblastic leukemia.34

Urticaria Pigmentosa and Systemic Mastocytosis

Urticaria pigmentosa is by far the most common type of neoplastic mast cell proliferation, accounting for the vast majority of all mastocytoses.35–37 This disorder, characterized by mast cell infiltration of the skin, usually presents in infancy and remits at the onset of puberty.38 Familial clusters have been described.39 The typical eruption of urticaria pigmentosa consists of multiple discrete hyperpigmented nodulopapular lesions and portends a benign clinical course. The likelihood of systemic involvement varies directly with age. The patient with urticaria pigmentosa usually presents with a variable number of flat or slightly elevated red-brown lesions 0.5 cm to several centimeters in diameter, although nodules and bullae may also be seen. In 15% of cases the typically diffuse cutaneous involvement may be localized.19,27 Cutaneous symptoms may include the classic urticarial wheals because of mast cell degranulation occurring due to mechanical insult (Darier’s sign), pruritis, or episodic flushing. Very rarely, cutaneous infiltration by mast cells may be limited to a single lesion, the mastocytoma or mast cell nevus.19,27

The serum tryptase level, a specific indicator of mast cell activation, is typically elevated in urticaria pigmentosa to a degree similar to that noted in patients with anaphylactic reactions.40 Furthermore, the levels of histamine and its metabolites, tryptase, heparin, calcitonin, and prostaglandin D2, may also be elevated.41–43 In tissue sections, mast cell disease can be distinguished from other neoplasms by characteristic tryptase positivity,44 with a CD68-positive and CD20-negative phenotype.45 Mast cell growth factor mRNA is expressed by cultured dermal keratinocytes and fibroblasts obtained from patients with cutaneous mastocytosis, suggesting that mast cell proliferation in this entity may be a reactive process, rather than a clonal neoplasm.46

A blurred distinction exists between urticaria pigmentosa and benign systemic mastocytosis, an indolent disorder in which mast cells may also be found in extracutaneous sites.19,35 Neither condition is characterized by unregulated clonal proliferation.47 Some studies have classified patients displaying focal mast cell marrow infiltrates and/or increased urinary excretion of histamine metabolites as having systemic mastocytosis rather than urticaria pigmentosa,48 but bone marrow involvement is frequent in either condition (60%) and not ominous.49 Such bone marrow mast cell infiltration may be accompanied by eosinophils,48 lymphoid aggregates,49 or fibrosis and sclerotic thickening of the bony trabeculae.27 Children with urticaria pigmentosa rarely develop systemic involvement,50 although adults with this entity frequently have nonprogressive mast cell infiltration of the liver, spleen, lymph nodes, and gastrointestinal tract in addition to the skin and bone marrow.20

Systemic mastocytosis may present with a variety of constitutional and/or gastrointestinal symptoms, each of which can be attributed to excessive elaboration of mast cell mediators. Such symptoms, which may also present to a lesser degree in patients with urticaria pigmentosa, include rhinitis, asthma, nausea, vomiting, diarrhea, syncope, chest pain, bone pain, and rectal discomfort.19,20 Although usually associated with obvious mast cell infiltration of the skin, constitutional and histamine excess–related symptoms may occasionally arise in the setting of subclinical cutaneous lesions.19 Over 70% of patients afflicted with systemic mastocytosis have infiltrative splenomegaly;51 mast cell infiltration of the gut mucosa and submucosa is also common. Moreover, peptic ulcer disease may occur with increased frequency in those with systemic mastocytosis due to the histamine-mediated release of gastric acid.19 Skeletal involvement is frequent and is characterized by both sclerotic and osteoporotic lesions.52 Hematologic abnormalities, affecting up to 50% of patients with systemic mastocytosis, include anemia, thrombocytopenia, and eosinophilia.19,35 Mortality is unusual.53 Avoidance of mast cell stimulants, such as anesthetics,54 alcohol, aspirin, and morphine,55 as well as the use of H1 and H2 histamine antagonists,56,57 interferon alpha,58,59 or disodium cromoglycate,60 may offer palliative relief for those patients with histamine-related symptoms, including flushing, pruritis, and diarrhea.20 Radiation therapy has been used to control localized disease, apparently without causing histamine release.61

Malignant Mastocytosis

Malignant mastocytosis is an aggressive variant of systemic mastocytosis characterized by a much less favorable clinical course.19,35 Unlike (benign) systemic mastocytosis, in which an affected patient has a normal life expectancy, survival beyond 1 to 2 years after diagnosis of malignant mastocytosis is uncommon. Adults are most commonly affected with an onset usually occurring during the sixth or seventh decade of life.27 Up to one-third of adults with urticaria pigmentosa develop malignant mastocytosis; however, this aggressive entity can also be seen without a history of prior mast cell disease. About 30% of patients with malignant mastocytosis have no prior or concomitant cutaneous involvement;27 patients presenting with isolated eosinophilia62 or mediastinal germ cell tumor63 have been described. The bone marrow is always involved, eosinophilia and cytopenias are common, and adenopathy and/or organomegaly due to infiltration of the spleen, liver, and lymph nodes is frequently noted.27,51,64 Portal hypertension, due to visceral fibrosis19,27,64 or apparent autoimmune cholangitis,65 can be a cause of mortality. Lymph nodes obtained from patients with malignant mastocytosis may exhibit mast cell atypia and leukemic infiltrates and extramedullary hematopoiesis.35

In addition to differences in clinical course, benign and malignant mast cell disorders can be differentiated cytochemically. For example, the mast cells of malignant mastocytosis have larger nuclei than do mast cells from patients with urticaria pigmentosa. In addition, malignant mast cells have greater avidity for toluidine blue staining at basic pH than do mast cells from those with urticaria pigmentosa,27 a finding believed to be due to disordered glucosaminoglycan biosynthesis in the malignant cells. Malignant mast cells, unlike normal mast cells, may exhibit striking erythrophagocytosis66 and express higher levels of reactivity with PC10, a proliferation-associated monoclonal antibody.67

In 15 to 37% of patients with malignant mastocytosis acute leukemia eventually develops.19,27,68,69 One-third of such transformations become manifest as mast cell leukemia, while the rest are either acute myeloid or chronic myelomonocytic leukemia.70 Furthermore, up to 70% present with or develop myelodysplastic syndromes and myeloproliferative disorders, such as essential thrombocytosis;71–73 these patients fare poorly.74 The development of myeloma,75 Hodgkin’s76 and non–Hodgkin’s lymphoma has also been described.77 Mice reconstituted with bone marrow cells expressing the v-erbB oncogene develop a lethal disease resembling malignant mastocytosis with massive infiltration of the marrow and viscera.78 A subset of patients with myeloproliferative disorders or myelodysplastic syndromes can be shown to exhibit a transformation to a more malignant phenotype characterized by exogenous, stem cell factor–independent mast cell proliferation.79 For example, activation of the c-kit (stem cell factor receptor) by an Asp to Val mutation at position 816 can lead to such autonomous growth in cell lines80 and in mast cells obtained from adult patients with aggressive systemic mastocytosis.81–83 The point mutation has not been found in myeloid blasts from patients with previous point mutation–associated mast cell disease,84 suggesting that the second malignancy did not clonally evolve from the mast cell proliferation.

Mast Cell Leukemia

Mast cell leukemia represents a rare and aggressive subtype of malignant mastocytosis characterized by the presence of large numbers of atypical mast cells in the peripheral blood.1,69,85–88 Patients with mast cell leukemia have a median survival of less than 6 months, in contrast to those with the nonleukemic type of malignant mastocytosis, who tend to survive for a longer time.27,69 The majority of reported cases of mast cell leukemia arise in patients with pre-existing malignant mast cell disease.27,69,87 Criteria required for the diagnosis of mast cell leukemia (Table 133.2), outlined in a study by Travis and colleagues,69 who reviewed the nine cases reported between 1954 and 1986, are (1) the percentage of mast cells in the peripheral white blood cell differential must be 10% or greater, (2) the leukemic mast cells should display features of morphologic atypia, and (3) cytochemical properties of the leukemic cells must be typical of mast cell derivation (presence of metachromatic granules staining with chloroacetate esterase, but not with peroxidase). Blast crises in patients with chronic granulocytic leukemia may also satisfy the criteria for mast cell leukemia,89,90 often in association with basophilia, thereby providing further evidence for the derivation of mast cells (and the related basophils) from a pluripotent hematopoietic stem cell. The use of immunophenotypic studies88 and a cytochemical panel including peroxidase, toluidine blue, chloroacetate esterase, and aminocaproate esterase can aid in distinguishing between mast cell leukemia and other leukemias in which blasts contain numerous cytoplasmic granules (Fig. 133.1).91

Table 133.2. Comparison of Findings in Various Types of Mast Cell Disease*.

Table 133.2

Comparison of Findings in Various Types of Mast Cell Disease*.

Figure 133.1. A.

Figure 133.1

A. Bone marrow findings from a patient with mast cell leukemia. Deeply basophilic granules in mast cells infiltrating the marrow (Giemsa stain, 800 ×). B. Metachromatic granules in malignant mast cells (Toluidine Blue stain, 800 ×). Source: (more...)

Although pruritus and flushing occasionally occur, the typical cutaneous mast cell infiltrates of urticaria pigmentosa are usually not present before, during, or after diagnosis in patients who have mast cell leukemia.69 Constitutional symptoms, such as fever, weight loss, and weakness, are more common presenting manifestations of mast cell leukemia than are histamine-related complaints. However, most patients have had symptoms and/or laboratory features consistent with a diagnosis of peptic ulcer prior to the diagnosis of mast cell leukemia.69,86 Hepatosplenomegaly and peripheral lymphadenopathy are usually present at the time of diagnosis.

Although bone marrow infiltration with atypical mast cells is always present in mast cell leukemia, hematologic findings at the time of diagnosis can vary widely. While a mild to moderate degree of anemia is always present, initial leukocyte counts have ranged from normal to 66,300/μL.69 The percentage of atypical mast cells (hypogranulated metachromatically staining cells with fragmentation, cytoplasmic tails, and multiple nuclei) may be relatively low (but greater than 10%) but almost always increases substantially with time. Patients with nonleukemic malignant mastocytosis who also may have extensive mast cell infiltration of the bone marrow35 consistently exhibit fewer than 10% circulating mast cells, unlike those with mast cell leukemia. Karyotypic studies in several patients with mast cell leukemia have been normal, although the lack of dividing cells for metaphase analysis frequently precluded cytogenetic evaluation.69,85–87 Bone marrow cells from patients with systemic mastocytosis often display cytogenetic abnormalities, such as trisomy 8, monosomy 7/7q-, 20q-, typical of those with myeloproliferative disorders.88

Due in part to the rarity of this condition, no standard treatment approaches exist for those with mast cell leukemia. Immunotherapy with antihuman IgE raised in sheep resulted in a transient decrease in the numbers of circulating mast cells in one patient with mast cell leukemia.85 Although splenectomy has led to brief responses in patients with mast cell leukemia,69,87 no firm conclusions as to the efficacy of this treatment are possible. The several reported patients who received chemotherapeutic agents did poorly,69,92 perhaps, in part, because malignant mast cells overexpress the anti-apoptosis gene, bcl-2.93 Insofar as mast cell leukemia is presumably a clonal disorder of hematopoietic myeloid stem cells, therapy with agents proven successful in other forms of acute myeloid leukemia may be of benefit. Therefore, strong consideration should be given to the administration of an anthracycline in combination with cytosine arabinoside as initial therapy in patients with mast cell leukemia. If remission is achieved, depending on the precise clinical situation, additional therapy with curative intent involving intensive chemotherapy and/or bone marrow transplantation might be attempted.

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Bookshelf ID: NBK20767

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