Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + BASOPHILS Download Section PDF Listen +++ ++ The basophil is the least common granulocyte. Normal basophil count is 0.015 to 0.08 × 109/L. The causes of basopenia (decreased numbers) and basophilia (increased numbers) are listed in Table 33–1. ++Table Graphic Jump LocationTABLE 33–1CONDITIONS ASSOCIATED WITH ALTERATIONS IN NUMBERS OF BASOPHILSView Table||Download (.pdf) TABLE 33–1 CONDITIONS ASSOCIATED WITH ALTERATIONS IN NUMBERS OF BASOPHILS Decreased Numbers (Basopenia) Hereditary absence of basophils (very rare) Elevated levels of glucocorticoids Hyperthyroidism or treatment with thyroid hormones Ovulation Hypersensitivity reactions Urticaria Anaphylaxis Drug-induced reactions Leukocytosis (in association with diverse disorders) Increased Numbers (Basophilia) Allergy or inflammation Ulcerative colitis Drug, food, inhalant hypersensitivity Erythroderma, urticaria Juvenile rheumatoid arthritis Endocrinopathy Diabetes mellitus Estrogen administration Hypothyroidism (myxedema) Infection Chickenpox Influenza Smallpox Tuberculosis Iron deficiency Exposure to ionizing radiation Neoplasia “Basophilic leukemias” (see text) Myeloproliferative neoplasms (especially chronic myelogenous leukemia; also polycythemia vera, primary myelofibrosis, essential thrombocythemia) Carcinoma Source: Williams Hematology, 9th ed, Chap. 63, Table 63–2. + BASOPENIA Download Section PDF Listen +++ ++ Hereditary absence of basophils is very rare. Other causes include high doses of glucocorticoids, hyperthyroidism or therapy with thyroid hormones, ovulation, hypersensitivity reactions, or leukocytosis in association with diverse disorders. + BASOPHILIA Download Section PDF Listen +++ ++ Causes include allergy or inflammation, endocrinopathies (diabetes mellitus, hypothyroidism), infections, iron deficiency, exposure to ionizing radiation, and neoplasias. Basophilia occurs in virtually all patients with chronic myelogenous leukemia (CML). De novo acute basophilic leukemia is very rare, but marrow basophilia may be associated uncommonly with other subtypes of acute myelogenous or acute promyelocytic leukemia. Basophils in acute or chronic clonal myeloid diseases are derived from the malignant clone and occasionally may cause symptoms of histamine release (flushing, pruritus, hypotension) or severe peptic ulcer disease reflecting hypersecretion of gastric acid and pepsin. + MAST CELLS AND SECONDARY CHANGES IN NUMBERS Download Section PDF Listen +++ ++ Mast cells are produced in the marrow and then transit the blood to the tissues where they reside. They cannot be identified in transit in the blood of healthy individuals by standard techniques. Mast cells contain mediators that may be preformed in granules (eg, histamine, heparin, and chemotactic factors) or newly formed (eg, arachidonic acid metabolites, such as prostaglandin D2 and leukotrienes). An increased number of mast cells may be seen in tissues of immunoglobulin E–associated disorders, connective tissue disorders, at infection sites, and in the lymph nodes and marrow in a variety of benign and malignant tumors (see Table 33–2). ++Table Graphic Jump LocationTABLE 33–2CONDITIONS ASSOCIATED WITH SECONDARY CHANGES IN MAST CELL NUMBERSView Table||Download (.pdf) TABLE 33–2 CONDITIONS ASSOCIATED WITH SECONDARY CHANGES IN MAST CELL NUMBERS Decreased Numbers Long-term treatment with glucocorticoids Primary or acquired immunodeficiency disorders (certain mast cell populations) Increased Numbers IgE-associated disorders Allergic rhinitis Asthma Urticaria Connective tissue disorders Rheumatoid arthritis Psoriatic arthritis Scleroderma Systemic lupus erythematosus Infectious diseases Tuberculosis Syphilis Parasitic diseases Neoplastic disorders Lymphoproliferative diseases* (lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, other lymphomas, chronic lymphocytic leukemia) Hematopoietic multipotential progenitor cell diseases* (acute or chronic myelogenous leukemias, myelodysplastic syndromes) Lymph nodes draining areas of tumor growth Osteoporosis* Chronic liver disease* Chronic renal disease* *Indicates increase numbers of mast cells may be principally in marrow. Source: Williams Hematology, 9th ed, Chap. 63, Table 63–4. + SYSTEMIC MASTOCYTOSIS Download Section PDF Listen +++ ++ This encompasses a group of systemic disorders associated with significant increases in mast cell numbers in the skin and internal organs. A consensus classification has been developed to provide prognosis and treatment (see Table 33–3). ++Table Graphic Jump LocationTABLE 33–3WORLD HEALTH ORGANIZATION CLASSIFICATION OF SYSTEMIC MASTOCYTOSISView Table||Download (.pdf) TABLE 33–3 WORLD HEALTH ORGANIZATION CLASSIFICATION OF SYSTEMIC MASTOCYTOSIS Cutaneous mastocytosis (CM) Urticaria pigmentosa (UP)/Maculopapular cutaneous mastocytosis (MPCM) Diffuse cutaneous mastocytosis Solitary mastocytoma of skin Indolent systemic mastocytosis (ISM) Systemic mastocytosis with associated clonal, hematologic non–mast-cell lineage disease (SM-AHNMD) Aggressive systemic mastocytosis (ASM) Mast cell leukemia (MCL) Mast cell sarcoma (MCS) Extracutaneous mastocytoma Modified with permission from Swerdlow SH, Campo E, Harris NL: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC Press; 2008. +++ Clinical Features ++ The clinical pattern and prognosis vary substantially among patients. Half the patients are older than 60 years of age at the time of diagnosis. Malaise, weight loss, and fever are frequent. Symptoms of mediator release include urticaria, pruritus, dermatographism, abdominal cramps, diarrhea, nausea, vomiting, musculoskeletal pain, flushing, headaches, dizziness, palpitations, dyspnea, hypotension, syncope, and shock. +++ Organ Involvement ++ The organs most frequently involved are the skin, lymph nodes, liver, spleen, marrow, and gastrointestinal tract. Skin involvement is typically characterized by urticaria pigmentosa (UP) and is diagnosed before age 2 years in 50% of cases. Dermal accumulations of mast cells results in brown papules symmetrically distributed, especially over the trunk. Intense pruritus and urticaria may occur from mild friction of the skin (Darier sign). It typically subsides at puberty but can continue into adulthood (see Figure 33–1). Adults with UP usually have extracutaneous involvement by mastocytosis. Lymphadenopathy, hepatomegaly, splenomegaly, and bone pain are frequently present, especially in aggressive disease. The majority of adults have focal mast cell lesions in the marrow, but this is much less common in children. Osteoporosis may accompany systemic disease, and pathologic fractures may occur. ++ FIGURE 33–1 Urticaria pigmentosa in an adult man with indolent systemic mastocytosis. Multiple pigmented macules are present. If local pressure is applied to the skin, individual lesions show urtication and become raised, pruritic, and erythematous. (Source: Williams Hematology, 8th ed, Chap. 63, Fig. 63–2, p. 924.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Laboratory Features ++ Anemia is present in about 50% of cases at the time of diagnosis. Marrow biopsy shows an increase in mast cells in about 90% of patients. Immunohistochemical staining for mast cell tryptase is best for visualizing and quantifying mast cell involvement. Mast cells in paraffin tissues are strongly positive for CD117, as are a subset of leukemic myeloblasts. Mast cells, unlike the latter, are not positive for peroxidase, however. Mast cells in the blood indicate a transformation to leukemia. Elevated alkaline phosphatase, aminotransaminases, and γ-glutamyltranspeptidase reflect liver involvement in about 50% of patients. Skin biopsy shows mast cell accumulations. Osteoporosis, osteoblastic, or osteolytic lesions are common on bone imaging studies. Aberrant mast cell phenotype by flow cytometry: high side scatter cells (granular) with surface IgE, and CD2+, CD25+, CD35+, CD117+, and CD34– immunophenotype. Finding of elevated plasma histamine levels and urinary excretion of the histamine metabolite 1-methyl-4-imidazoleacetic acid are useful diagnostic tests. Elevated mast cell tryptase in the serum is an important confirmatory finding. Elevated serum or urine histamine or serum tryptase is not pathognomonic of mastocytosis, however, and needs to be integrated with the clinical findings. Gain-of-function KIT gene mutation, Asp816Val, is a virtually universal finding in adults and many children with mastocytosis. Table 33–4 lists the diagnostic criteria for systemic mastocytosis. ++Table Graphic Jump LocationTABLE 33–4DIAGNOSTIC CRITERIA FOR SYSTEMIC MASTOCYTOSISView Table||Download (.pdf) TABLE 33–4 DIAGNOSTIC CRITERIA FOR SYSTEMIC MASTOCYTOSIS Major Criteria Multifocal, dense infiltrates of mast cells (≥15 mast cells in an aggregate) detected in sections of marrow and/or other extracutaneous organ(s) Minor Criteria In biopsy sections of marrow or other extracutaneous organs, > 25% of the mast cells in the infiltrate are spindle shaped or have atypical morphology, or, of all mast cells in marrow aspirate smears, > 25% are immature or atypical mast cells Detection of a point mutation in KIT at codon 816 (Asp816V) in marrow, blood, or other extracutaneous organ Mast cells in marrow, blood, or other extracutaneous organs that co-express CD117 with CD2 and/or CD25 Serum total tryptase persistently > 20 μg/L (if there is an associated clonal myeloid disorder, this criterion is not valid) The diagnosis of systemic mastocytosis can be made if one major and one minor criterion are present or if three minor criteria are met. Source: Williams Hematology, 9th ed, Chap. 63, Table 63–6. +++ Treatment ++ Mastocytosis currently has no curative therapy. Symptomatic therapy, although transiently helpful, does not alter course of the disease. Local lesions may be excised. Avoid triggers such as temperature extremes; physical exertion; or in some cases, opiate analgesics, nonsteroidal anti-inflammatory drugs, and ingestion of ethanol-containing drinks. Anaphylaxis may follow insect stings. Epinephrine-filled syringes and instructions for self-administration should be carried by patients considered at risk. These patients may also benefit from prophylactic antihistamines in settings and during seasons in which insect stings are prevalent. Patients with mastocytosis can also have anaphylaxis from iodinated contrast material. Cutaneous glucocorticoids and 8-methoxypsoralen and ultraviolet light (PUVA) have been reported to decrease pruritus or improve the appearance of skin lesions. Histamine-2 (H2)-receptor antagonists (eg, cimetidine, ranitidine, famotidine) can decrease gastric hyperacidity and can be used to treat gastritis or peptic ulcer. Proton pump inhibitors may also be useful in treating gastric hypersecretion. They may, in combination with histamine-1 (H1)-receptor antagonists, contribute to ameliorating mast cell constituent release–related signs and symptoms. H1-receptor antagonists (eg, diphenhydramine, chlorpheniramine, tricyclic antidepressants) can decrease flushing, vasodilation, and headache. More potent H1-receptor blockers (hydroxyzine and doxepin) may be useful in more severe cases. Oral disodium cromoglycate may alleviate gastrointestinal cramping, diarrhea, and headache. It has also been useful in childhood cutaneous mast cell disease. Calcium supplementation, estrogen replacement in postmenopausal women, and bisphosphonates may be used to prevent/treat underlying osteopenia/osteoporosis. Oral glucocorticoids can be used for malabsorption or ascites. In adults, the doses used to start therapy are approximately 40 to 60 mg/d for 2 to 3 weeks and then they are tapered, eventuating in alternate-day use, if they are helpful. Insufficient data are available to determine the usefulness of cytotoxic agents, such as cladribine, for progressive mastocytosis. Chemotherapy, generally, has been disappointing in cases of aggressive systemic disease. Allogeneic stem cell transplantation has been used for patients with advanced categories of mastocytosis; however, although the associated hematologic disorder may respond, complete remission of mast cell disease is uncommon. Tyrosine kinase inhibitors may be useful. Rare mutations such as KIT (Phe522Cys) are responsive to imatinib. Tyrosine kinase inhibitors, including midostaurin and dasatinib, that inhibit the most prevalent KIT mutation at codon 816 (Asp816Val) are in clinical trials. If possible, mutational analysis on the mastocytosis cells should be done to determine if a drug-sensitive mutated kinase is present. In all the therapy noted above, success is unpredictable, the treatment has its own consequential side effects, and one must exercise judgment continually about whether the treatment is resulting in a net benefit to the patient. +++ Course and Prognosis ++ Symptoms range from absent to progressive and disabling. Patients with UP and indolent systemic mast cell disease may live a normal life span with symptomatic treatment. Progression to advanced disease is rare, and some improve spontaneously. About one-third of patients have systemic mastocytosis with an associated hematologic malignancy. In these cases, the prognosis is related to the ability to manage the hematologic disease. Usually this combination portends a foreshortened life span. Elevated serum lactic dehydrogenase and more advanced age tend to be poor prognostic findings. Overall 3-year survival is about 50%. ++ For a more detailed discussion, see Stephen J. Galli, Dean D. Metcalf, Daniel A. Arber, Ann M. Dvorak: Basophils, Mast Cells and Related Disorders, Chap. 63 in Williams Hematology, 9th ed.