Chapter 33: Basophils, Mast Cells, and Related Disorders

• 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.

• 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.

• 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 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).

• 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).

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.

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.

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%.