Chapter 35: Basophils and Mast Cells and Their Diseases

• Normal basophil count is 0.015 to 0.08 × 10⁹/L.

• The causes of basophilia are listed in Table 35–1.

• An increase in the absolute basophil count among other blood cell abnormalities may be a useful sign of a chronic clonal myeloid disease (see Table 35–1).

• In chronic myelogenous leukemia (CML), an increased absolute basophil count occurs in virtually all patients.

• 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 (see Table 35–2).

• 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.

• The causes of basophilopenia are listed in Table 35–1.

• Mast cells are produced in the marrow, 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 (e.g., histamine, heparin, and chemotactic factors) or newly formed (e.g., arachidonic acid metabolites, such as prostaglandin D₂ and leukotrienes).

• An increased number of mast cells may be seen in any tissue involved in a hypersensitivity reaction.

• An increased number may be seen in the lymph nodes and marrow as a reaction to a variety of benign and malignant tumors.

• Cutaneous mastocytosis may be expressed as a solitary lesion in infants or as multiple nodules in older children.

• Urticaria pigmentosa occurs before age 2 years in 50 percent of cases and is characterized by dermal accumulations of mast cells resulting in brown papules symmetrically distributed, especially over the trunk.

• Intense pruritus and urticaria may occur from mild friction of the skin (Darier sign).

• Demonstration of infiltrates of mast cells on the skin biopsy is diagnostic.

• Urticaria pigmentosa usually subsides at puberty but can continue into adulthood (see Fig. 35–1), and later patients may develop systemic mastocytosis.

• A 10-fold increase in mast cells in skin biopsies of chronic inflammatory sites is considered consistent with cutaneous mastocytosis.

• Table 35–3 lists causes of alterations in mast cell numbers.

Clinical Features

• Affects men and women equally.

• 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.

• Hyperpigmented skin lesions may be present.

• Lymphadenopathy, hepatomegaly, splenomegaly, and bone pain are frequently present, especially in aggressive disease.

• Osteoporosis complicated by fractures occurs in half the patients.

• Table 35–4 contains a classification of systemic mast cell disease.

Laboratory Features

• Anemia is present in about half the cases at the time of diagnosis.

• Marrow biopsy shows an increase in mast cells in about 90 percent 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 later, are not positive for peroxidase, however.

• Mast cells in the blood indicate a transformation to leukemia.

• Elevated alkaline phosphatase, aminotransaminases, γ-glutamyltranspeptidase in about 50 percent of patients, reflect liver involvement.

• 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 35–5 lists the diagnostic criteria for systemic mastocytosis.

Management

• Local lesions may be excised.

• Avoid triggers such as temperature extremes, physical exertion, or in some cases opiate analgesics, nonsteroidal antiinflammatory drugs, ingestion of ethanol containing drinks.

• Anaphylaxis may follow stings by venomous insects. 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 that insect stings are prevalent. Patients with mastocytosis can also have anaphylaxis from iodinated contrast material.

• Mastocytosis currently has no curative therapy and symptomatic therapy, although transiently helpful, does not alter course of the disease.

• Histamine-2 (H₂)-receptor antagonists (e.g., 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 (e.g., 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.

• Ketotifen may ameliorate pruritus and wheal formation and may minimize osteoporosis.

• Diphosphonates have also been used to stop or reverse osteopenia.

• Cutaneous glucocorticoids and 8-methoxypsoralen and ultraviolet light (PUVA) have been reported to decrease pruritus or improve the appearance of skin lesions.

• Oral glucocorticoids can be used for malabsorption or ascites. In adults, the doses used to start therapy are approximately 0.75 mg/kg 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 cladrabine, for progressive mastocytosis. Chemotherapy, generally, has been disappointing in cases of aggressive systemic disease.

• Allogeneic stem cell transplantation has been used very infrequently, especially if an associated clonal myeloid disease coexists, but the mastocytic component of disease seems not to have been benefitted, usually.

• 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.

• Avoid mast cell stimulants such as alcohol, anticholinergics, aspirin, other nonsteroidal antiinflammatory agents, and morphine derivatives.

• Inhibitors of mutant KIT-encoded tyrosine kinase (e.g., imatinib mesylate) have been generally unsuccessful in therapy because the most prevalent KIT mutation at codon 816 (Asp816Val) is resistant to these drugs. Rare mutations such as KIT (Phe522Cys) are responsive. Some diseases not technically mastocytosis but with elevated mast cells and elevated serum tryptase and with the FIPIL1-PDGFRA fusion gene do respond. (e.g., chronic eosinophilic leukemia, see Chaps. 34 and 47). If possible, mutational analysis on the mastocytosis cells should be done to determine if a drug-sensitive mutated kinase is present.

Course and Prognosis

• Symptoms range from absent to progressive and disabling. Patients with urticaria pigmentosa 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 percent.

• Patients may have fever, constitutional symptoms, and severe clinical manifestations of mediator release (see above).

• Hepatomegaly, splenomegaly, and lymphadenopathy are common.

• Anemia and thrombocytopenia are nearly always present; the white count varies from 10.0 to 150 × 10⁹/L, and mast cells make up 5 to 90 percent of the blood leukocytes.

• Marrow shows a striking increase in mast cells, sometimes up to 90 percent of cells.

• A rare tumor, characterized by nodules at various cutaneous and mucosal sites; subsequently, almost every organ becomes involved by extensive mast cell infiltration; terminally, the blood cells are nearly all immature mast cells with a monocytoid appearance.