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MD Consult: Books: Goldman: Cecil Medicine: Chapter 276 – DRUG ALLERGY

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 276 – MASTOCYTOSIS

Cem Akin

Definition

Mastocytosis is a heterogeneous group of disorders characterized by pathologic accumulation of mast cells in tissues such as skin and bone marrow. According to the classification of the World Health Organization (WHO), based on clinical presentation and pathologic findings, there are seven distinct categories of mastocytosis ( Table 276-1 ). The term “cutaneous mastocytosis” describes skin disease alone without any evidence of internal organ involvement, whereas the term “systemic mastocytosis” describes the disorder when it involves internal organs (most commonly the bone marrow) with or without skin disease.


TABLE 276-1   — 
WORLD HEALTH ORGANIZATION CLASSIFICATION OF MASTOCYTOSIS

Cutaneous mastocytosis
Indolent systemic mastocytosis
Systemic mastocytosis with associated clonal hematologic non–mast cell lineage disease
Aggressive systemic mastocytosis
Mast cell leukemia
Mast cell sarcoma
Extracutaneous mastocytoma

From Valent P, Horny H-P, Li CY, et al: Mastocytosis (mast cell disease). In Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization (WHO) Classification of Tumours: Pathology and Genetics. Tumours of Haematopoi-etic and Lymphoid Tissues. France, Lyon, International Agency for Research on Cancer, 2001, pp 291–302.

Epidemiology

Mastocytosis can be diagnosed at any age. Pediatric-onset and adult-onset forms are distinguished based on the age of the patient at initial diagnosis. These forms display differences in their clinical course, molecular pathology, and prognosis. The most common clinical scenario leading to diagnosis in the pediatric population is a child presenting with skin lesions of cutaneous mastocytosis within the first year of life. Patients with a later onset of skin lesions are more likely to have systemic mastocytosis, as are most patients with adult-onset mastocytosis. The disease has been diagnosed in all ethnic populations. Pediatric-onset mastocytosis appears to be diagnosed more commonly in males (approximately 60%). Estimates of the prevalence of patients with cutaneous mastocytosis range from 1 in 500 to 1 in 8000 patients presenting in dermatology clinics. The prevalence of systemic mastocytosis is more difficult to estimate, because the diagnosis requires biopsy of an involved tissue and a high degree of clinical suspicion. Systemic mastocytosis is likely to be underdiagnosed, considering the fact that there are neither physical examination findings nor routine hematologic or chemistry laboratory abnormalities specifically associated with the disease. Consequently, it is not unusual to encounter several years’ delay after the onset of symptoms in many patients before a diagnosis of mastocytosis is reached. The disease is sporadic, although rare cases of familial occurrence have been described.

Pathobiology

Pathogenesis

The pathogenesis of mastocytosis involves the accumulation of mast cells in tissues, with mediators released by activated mast cells. The primary reason for the increased mast cell numbers in tissues appears to be defective apoptosis rather than uncontrolled proliferation. It is unusual to see increased mitotic activity in biopsies from patients with mastocytosis, and, in most patients, the disease follows an indolent course. Tissue microenvironment and altered chemotaxis may also contribute to the final level of tissue mast cell burden.

Genetics

Mast cells are derived from hematopoietic progenitors. Systemic mastocytosis is associated with somatic gain-of-function point mutations in the KIT (formerly c-kit) gene of the mast cell progenitor, leading to a clonal neoplastic expansion of mast cells. KIT encodes a transmembrane receptor (Kit), whose intracellular portion functions as a tyrosine kinase enzyme. The extracellular portion of Kit binds the cytokine stem cell factor (SCF or Kit ligand). The interaction between SCF and Kit provides the single most important growth and differentiation stimulus for mast cells from their progenitors. Under physiologic conditions, homodimeric SCF binds and cross-links two Kit receptor molecules, which leads to autophosphorylation of the tyrosine amino acids of the intracellular portion of the Kit molecule. Phosphorylated tyrosine residues in turn act as docking sites for downstream adaptor and signal transduction molecules, such as phosphatidylinositol 3 (PI3) kinase, Janus kinase 2 (JAK2), signal transducer and activator of transcription 1 (STAT1) and STAT5, Lyn, phospholipase C-γ (PLC-γ), and Src homology 2 domain–containing inositol-5-phosphatase 1 (SHIP1). These molecules regulate the differentiation, proliferation, chemotaxis, and functional activation of mast cells.

The majority of the mutations reported in systemic mastocytosis involve codon 816 in KIT, resulting in the replacement of an aspartic acid by a valine residue (D816V) in the Kit protein. D816 is a critical residue involved in the kinase activity of Kit. Substitution of the wild-type aspartic acid residue in this location by another amino acid results in constitutive activation and autophosphorylation of the receptor molecule without the need for cross-linking by its ligand, SCF. The D816V mutation has been shown in lesional mast cells from the skin and bone marrow tissue of patients with mastocytosis, as well as from other hematopoietic lineages in patients with extensive disease. This aspect of the pathobiology of systemic mastocytosis is similar to the multilineage involvement observed in myeloproliferative disorders.

Codon 816 KIT mutations have been reported in various categories of mastocytosis, including those with benign and poor prognoses. Most patients with adult-onset mastocytosis were found to carry this mutation when an appropriate tissue sample from an involved site such as skin or bone marrow was analyzed. In contrast, it has been reported in fewer patients with pediatric-onset cutaneous disease (up to 42%, depending on the study and detection method). Other pathogenetic factors, some yet to be determined, appear to be responsible for the final disease phenotype, because the presence of the D816V KIT mutation alone does not explain the remarkable heterogeneity in the clinical presentation and prognosis of the disease. For example, a common polymorphism in the interleukin-4 (IL-4) receptor α-chain (Q576R) has been described as being associated with a milder form of the disease that is limited to the skin.

Symptomatology

The symptomatology of mastocytosis is primarily manifested by the release of mast cell mediators and rarely by a destructive infiltration of mast cells into tissues. Mast cell activation results in the release of various preformed mediators stored in mast cell granules, de novo synthesis of sulfidopeptide leukotrienes such as LTC4 and prostaglandins (mostly PGD2) from membrane lipids, and cytokine synthesis. Preformed mediators stored in mast cell granules include histamine; proteases such as tryptase, chymase, and carboxypeptidase A; and proteoglycans such as heparin and chondroitin sulfate. Vasoactive mediators such as histamine, LTC4, and PGD2 at local or distant tissues cause vasodilation, which may lead to flushing, tachycardia, hypotension, presyncope, and syncope. Histamine also causes pruritus and stimulates gastric acid hypersecretion from parietal cells. Mast cells are rich sources of cytokines. Elevated serum levels of tumor necrosis factor-α (TNF-α) and IL-6 have been found in patients with mastocytosis and may contribute to the pathophysiology of fatigue and accelerated osteoporosis observed in some patients. Rare aggressive categories of mastocytosis may be associated with an extensive destructive infiltration of mast cells into tissues such as the gastrointestinal tract, which may result in malabsorption, and the liver, which may cause portal fibrosis with associated portal hypertension.

Mast cell activation and mediator release may occur after triggers such as temperature changes (e.g., hot showers); exercise; ingestion of alcohol or spicy foods; emotional stress; insect stings; exposure to certain drugs such as opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), or muscle relaxants; and sometimes spontaneously without an obvious trigger. The prevalence of atopic disease in patients with mastocytosis is similar to that of the general population, and the serum immunoglobulin E (IgE) level is often found to be low.

Clinical Manifestations

Mastocytosis is a disease with protean clinical manifestations. Although in some patients the only complaint is the cosmetic appearance of urticaria pigmentosa lesions, others suffer from frequent episodes of vascular instability or have life-threatening hematologic disease. In general, patients with mastocytosis belong to one of two broad categories, according to the site of tissue involvement: those with cutaneous disease alone, and those with systemic disease with or without skin involvement. Cutaneous mastocytosis (i.e., disease limited to the skin in the absence of internal organ involvement) is commonly diagnosed in children within the first year of life, whereas systemic mastocytosis is mostly diagnosed in adults by a bone marrow biopsy and aspirate.

Cutaneous Manifestations

Skin lesions of urticaria pigmentosa are the most common presentation of cutaneous mastocytosis ( Fig. 276-1 ). They are also present in 50 to 90% of patients with systemic mastocytosis, depending on the disease category. Remarkably different in appearance from urticaria or hives, lesions of urticaria pigmentosa are fixed, tan- to salmon-colored, maculopapular lesions varying in size from a few millimeters to a few centimeters. They are most prominently observed on the trunk and extremities and tend to spare the face and the sun-exposed areas of the skin, although facial involvement may be seen in children. Blistering of the lesions may occur in children in the first 3 years of life. The lesions are generally not pruritic at rest but may urticate after exposure to a number of triggers (see Pathobiology). Many patients note that the skin lesions become more prominent after exposure to heat or after physical irritation such as rubbing. The lesions may be found concentrated in skin areas that are prone to irritation, such as the axillae and groin.

FIGURE 276-1  Urticaria pigmentosa.

Uncommon presentations of cutaneous mastocytosis include mastocytomas, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans (TMEP). Mastocytomas are benign and generally solitary mast cell tumors, although they have been known to precede urticaria pigmentosa lesions in some cases. They occur almost exclusively in children, and physical irritation of the lesion may result in generalized flushing and other symptoms of mast cell mediator release. Diffuse cutaneous mastocytosis (DCM) is another form of skin involvement seen exclusively in children. It is characterized by diffuse thickening of the skin and appendages with a peau d’orange appearance without individual urticaria pigmentosa lesions. TMEP is a rare form of cutaneous mastocytosis characterized by the presence of diffuse telangiectatic macules. Because TMEP lesions are generally seen in the presence of urticaria pigmentosa, there is debate about whether TMEP represents a distinct form of cutaneous mastocytosis.

Patients with cutaneous mastocytosis may manifest systemic symptoms such as abdominal pain or diarrhea. They also may experience hypotensive episodes resulting from triggered or spontaneous mast cell mediator release, even in the absence of histopathologic mast cell infiltration in the internal organs.

Systemic Manifestations

Symptoms caused by mast cell degranulation may be experienced as brief, recurrent, and self-limited episodes with multiorgan manifestations or as chronic complaints over a prolonged time course. A typical mast cell degranulation episode may variably involve flushing, conjunctival hyperemia, nausea, vomiting, abdominal cramping, diarrhea, tachycardia, and lightheadedness. Hypotension may develop, and the episode may progress to full loss of consciousness in some patients. Therefore, mastocytosis should be ruled out in all patients with recurrent anaphylaxis before a diagnosis of idiopathic anaphylaxis can be made. Tryptase, a protease stored in mast cell granules, may be elevated above the patient’s baseline level in the serum or plasma if measured within 3 hours after the onset of the episode in patients with suspected mast cell degranulation or anaphylaxis, regardless of the cause. Angioedema, hives, and wheezing are uncommon in mastocytosis, in contrast to idiopathic anaphylaxis. Flushing usually involves the face and upper chest area. A consistent trigger can be identified in only a small number of patients (see Pathobiology). The episodes usually last for 30 minutes to a few hours. Patients with systemic mastocytosis frequently complain of fatigue, which may last several hours to days after an episode; impaired memory; irritability; and depressed mood. The pathogenesis of these problems is poorly understood, but it may be related to mediators or cytokines released from mast cells, or it may represent the psychological manifestations of having a chronic illness. Hypotensive episodes can be life-threatening, particularly in the presence of comorbidities such as cardiac or pulmonary disease.

Gastrointestinal Symptoms

Gastrointestinal symptoms are observed in more than 50% of patients with mastocytosis. Epigastric pain, lower abdominal cramping, nausea, vomiting, or diarrhea can occur episodically in the context of an acute mast cell degranulation episode or on a chronic basis. Gastric acid hypersecretion induced by mast cell–derived histamine may lead to esophagitis, gastritis, and peptic ulcer disease, although measurements of basal acid output have shown great variability in different studies, ranging from hypersecretion in the range of Zollinger-Ellison syndrome to achlorhydria. Mucosal edema, thickened gastric or duodenal mucosal folds, or nodular lesions may be observed in radiographic or endoscopic evaluations. Diarrhea alternating with constipation may be seen. Severe persistent diarrhea may be complicated by clinically significant malabsorption in patients with aggressive systemic mastocytosis. Hematochezia, hematemesis, and melena are uncommon symptoms and should prompt endoscopic evaluation to rule out coexisting pathology. Mast cells are constituents of the normal lamina propria in gastrointestinal mucosa, and their numbers may be increased in inflammatory states affecting the gastrointestinal tract. However, quantitation of mast cell numbers in gastrointestinal biopsies is generally not helpful, and diagnosis of mast cell disease via a gastrointestinal biopsy, in the absence of typical bone marrow findings, should be avoided. Mild to moderate hepatomegaly with or without abnormalities in serum transaminases may be observed, although portal hypertension and ascites are rare and indicate the presence of advanced categories of mastocytosis. Jaundice and findings on cholangiography resembling those of primary sclerosing cholangitis have been reported in some patients.

Musculoskeletal Symptoms

Musculoskeletal pain is common in patients with mastocytosis and is mostly caused by soft tissue pain resembling fibromyalgia. Accelerated osteoporosis may be seen in a subgroup of patients, particularly in those with other risk factors, such as postmenopausal women, and in those receiving glucocorticoid therapy. Mastocytosis should be considered in the differential diagnosis of patients with premature osteoporosis or pathologic fractures, because the initial clinical finding in some patients is compression fractures of the vertebrae. A bone densitometry measurement should be recommended as part of the standard evaluation of women with mastocytosis and of any patient with a history of pathologic fractures. Radiographic abnormalities have been reported in up to 75% of patients with mastocytosis. In addition to generalized osteoporosis, bone surveys may show a mixture of sclerotic or lytic lesions, and skeletal scintigraphy may reveal focal or diffuse radiotracer uptake.

Hematologic Manifestations

Peripheral blood abnormalities have been noted in up to 50% of patients with systemic mastocytosis. Mild normochromic normocytic anemia is the most common abnormality, followed by thrombocytopenia, eosinophilia, monocytosis, and leukopenia. Eosinophilia in mastocytosis rarely causes organ damage, as is observed in chronic eosinophilic leukemia or idiopathic hypereosinophilic syndrome (see Chapter 176 ). It is important to differentiate a primary eosinophilic disorder from mastocytosis with eosinophilia. Some cases of chronic eosinophilic leukemia are associated with the FIP1L1-PDGFRA fusion gene and respond to the drug imatinib, whereas systemic mastocytosis is associated with codon 816 point mutations of the KIT gene, which confers resistance to this drug.

Approximately 20% of the patients with systemic mastocytosis have been reported to display evidence of another clonal non–mast cell hematologic disease in various case series. These patients usually come to the physician’s attention because of an unexplained abnormality in peripheral blood count, hepatosplenomegaly, or lymphadenopathy; mastocytosis is discovered incidentally during the hematologic work-up. Non–mast cell clonal hematologic neoplasms associated with mastocytosis are commonly myeloid in nature (myeloproliferative disorders, myelodysplastic syndromes, or myeloid leukemias) but may also involve lymphoproliferative disorders such as lymphomas, myelomas, and lymphocytic leukemias.

Diagnosis

The diagnosis and classification of mastocytosis is carried out according to the guidelines published by the WHO. A suggested algorithm for the diagnosis of mastocytosis is shown in Figure 276-2 .

FIGURE 276-2  Suggested diagnostic algorithm for mastocytosis. CBC=complete blood count.

Cutaneous Mastocytosis

Diagnosis of cutaneous mastocytosis is made by observing the typical hyperpigmented maculopapular lesions of urticaria pigmentosa and is confirmed by skin biopsy, which shows infiltration of mast cells in the upper dermis, particularly in perivascular locations. It should be noted that mild increases in mast cell numbers can be observed in inflammatory and neoplastic skin diseases, and establishing a diagnosis of cutaneous mastocytosis by a blind skin biopsy or biopsy of a lesion that does not have the typical appearance of urticaria pigmentosa should be avoided. A localized wheal-and-flare reaction limited to the lesional skin within a few minutes after rubbing or scratching the skin is known as “Darier’s sign.” Diagnosis of urticaria pigmentosa in adults should always prompt investigation of possible systemic mastocytosis.

Systemic Mastocytosis

Biopsy

A bone marrow biopsy and aspiration is the recommended diagnostic procedure to evaluate the presence of WHO diagnostic criteria for systemic disease (discussed later). This procedure is recommended for all patients with adult-onset urticaria pigmentosa, patients with recurrent symptoms suggestive of mast cell degranulation (such as flushing and hypotension accompanied by abdominal complaints), patients with unexplained osteoporosis, and patients with suspected hematologic disease (see Clinical Manifestations). Children with an onset of lesions within the first year of life usually do not require a bone marrow biopsy unless they have an abnormal complete blood count, lymphadenopathy, hepatomegaly, or splenomegaly. Children with late-onset skin lesions and those who experience persistence of urticaria pigmentosa into adulthood should be considered for diagnostic evaluation for systemic disease.

World Health Organization Diagnostic Criteria

WHO guidelines for diagnosis of systemic mastocytosis consist of one major and four minor criteria ( Table 276-2 ). Presence of the major criterion with at least one minor criterion, or demonstration of three minor criteria in the absence of the major criterion, is needed to establish a diagnosis of systemic mastocytosis and distinguish it from reactive mast cell hyperplasia. The major diagnostic criterion is the presence of multifocal, dense aggregates of 15 or more mast cells in bone marrow or other extracutaneous tissue biopsy sections ( Fig. 276-3A ). Such clusters are frequently observed around blood vessels and next to bone trabeculae in bone marrow biopsies. Immunohistochemical staining for tryptase is the recommended method for visualization of mast cells. Routine hematoxylin and eosin or metachromatic stains such as toluidine blue are not sufficiently sensitive to demonstrate subtle mast cell infiltrates or abnormal morphologic features of mast cells within the infiltrates in decalcified bone marrow biopsy sections.


TABLE 276-2   — 
WORLD HEALTH ORGANIZATION DIAGNOSTIC CRITERIA FOR SYSTEMIC MASTOCYTOSIS

MAJOR
Multifocal, dense infiltrates of mast cells consisting of 15 or more mast cells in aggregates detected in sections of bone marrow and/or other extracutaneous organs, confirmed by tryptase immunohistochemistry or other special stains
MINOR
More than 25% of mast cells in biopsy sections or bone marrow aspirate smears showing spindle shape or atypical morphology
Detection of a KIT codon 816 point mutation in bone marrow, blood, or other extracutaneous organs
Expression of CD2 and/or CD25 by mast cells in bone marrow, blood, or extracutaneous organs
Persistent elevation of serum total tryptase >20 ng/mL[*]

From Valent P, Horny H-P, Li CY, et al: Mastocytosis (mast cell disease). In Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization (WHO) Classification of Tumours: Pathology and Genetics. Tumours of Haematopoi-etic and Lymphoid Tissues. Lyon, France, International Agency for Research on Cancer, 2001, pp 291–302.

* Criterion not valid if there is an associated clonal myeloid disorder.

FIGURE 276-3  Diagnostic findings in the bone marrow biopsy and aspirate. A, Characteristic mast cell aggregates on tryptase staining (major criterion) in biopsy section (arrow). B, Mast cells with atypical spindle shapes in aspirate smear (arrow).

Mast cell morphology in bone marrow provides important clues to the diagnosis of systemic mastocytosis. Normal bone marrow mast cells are round cells with a centrally located, round to oval nucleus; a low nucleus-to-cytoplasm ratio; and heavy granulation. They are observed singly in an interstitial distribution in healthy marrow, without any significant clustering. In contrast, bone marrow mast cells in systemic mastocytosis often display atypical morphology, such as an elongated (spindle) shape, hypogranularity, and an eccentric or lobulated nucleus (see Fig. 276-3B ). These atypical mast cells are usually observed in close association with bone marrow spicules in the aspirate smear. Mast cells in mast cell leukemia (MCL) may be very sparsely granulated.

Flow cytometric analysis of the mast cells in a bone marrow aspirate, when performed appropriately, is a very sensitive diagnostic aid. Mast cells are identified in flow cytometric dot plots as cells highly expressing CD117 (Kit) that are also positive for surface IgE but negative for CD34. These staining characteristics allow the differentiation of mast cells from a more abundant CD117-positive bone marrow cell population, including hematopoietic progenitor cells that are intermediately positive for CD117 and CD34 but negative for surface IgE. The mean percentage of mast cells in a healthy bone marrow aspirate is approximately 0.02%, and it does not exceed 1% in most patients with mastocytosis. Therefore, to visualize the mast cell population correctly, the total cell numbers analyzed by flow cytometry should be significantly higher than those in other, more routine evaluations (e.g., leukemia phenotyping). The characteristic flow cytometric finding of systemic mastocytosis is the aberrant expression of CD25 and/or CD2 on mast cells. CD2 expression may show variability among patients, whereas CD25 expression is a more consistent finding.

Serum tryptase level may be elevated in patients with mastocytosis. Currently available commercial tryptase immunoassays measure levels of total tryptase, the sum of mature tryptase and tryptase precursors. Mature tryptase enzyme is a serine protease stored in mast cell granules and is transiently elevated in serum or plasma after mast cell degranulation episodes such as anaphylaxis. In contrast, tryptase precursor proenzymes (α and β protryptases) are constitutively secreted outside the cell, and their serum levels correlate with mast cell burden. Therefore, total tryptase levels measured at baseline (i.e., not after a suspected mast cell degranulation event) primarily reflect protryptase levels and should be determined as part of the diagnostic evaluation of a patient with suspected mastocytosis. The median serum tryptase level in a healthy population is approximately 5 ng/mL. A serum tryptase level higher than 20 ng/mL raises suspicion for systemic mastocytosis in the appropriate clinical setting. It should be noted that a normal tryptase level does not rule out a diagnosis of mastocytosis and that increased tryptase levels can be seen in other conditions, such as myelodysplastic syndromes, acute myeloid leukemias, and chronic eosinophilic leukemia. Metabolites of histamine, such as N-methylhistamine, are found to be elevated in a 24-hour urine specimen but are neither more sensitive nor more specific than the baseline serum tryptase measurement in mastocytosis.

Demonstration of a codon 816 KIT mutation (D816V) may be necessary to fulfill the diagnostic criteria in patients lacking the major criterion (see Pathobiology). Examination of lesional tissues such as skin and bone marrow affords the highest sensitivity, in contrast to peripheral blood, which yields positive results only in patients with extensive disease variants. Codon 816 KIT mutations have been detected in a variety of other neoplastic diseases, such as core factor–binding acute myeloid leukemias, sinonasal lymphomas, and seminomas, in addition to mastocytosis.

World Health Organization Disease Categories

Each patient diagnosed with mastocytosis should be assigned a category of disease according to the WHO classification (see Table 276-1 ). Cutaneous mastocytosis in the absence of bone marrow and internal organ involvement is the most common category in patients with pediatric-onset disease.

Systemic mastocytosis is divided into the categories of indolent systemic mastocytosis, systemic mastocytosis with associated clonal hematologic non–mast cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis, and MCL. An algorithm for classification of systemic mastocytosis is presented in Figure 276-4 . Indolent systemic mastocytosis is the most common category in adults. Patients in this category usually do not have a decreased life expectancy due to the mast cell disease, although they experience symptoms related to release of mast cell mediators. Indolent systemic mastocytosis follows a persistent course, and progression to a more advanced category is unusual. SM-AHNMD is the second most common category in adults, and a non–mast cell hematologic disease is usually diagnosed at the time that the diagnosis of mastocytosis is made. Therefore, bone marrow biopsy and aspirate specimens should be carefully evaluated for the presence of other hematologic disease in every patient with newly diagnosed systemic mastocytosis. Aggressive systemic mastocytosis is a rare category characterized by the presence of organ dysfunction resulting from destructive mast cell infiltration. Aggressive systemic mastocytosis may involve the hematopoietic, gastrointestinal, and skeletal systems in the form of cytopenias, hypersplenism, malabsorption with weight loss, hepatomegaly with portal hypertension and ascites, and large osteolytic lesions with pathologic fractures. MCL is characterized by 10% or more mast cells in the peripheral circulation or 20% or more mast cells in bone marrow aspirate smears, or both. To diagnose MCL, the mast cell percentage in bone marrow aspirate smears should be assessed in an area of the slide that is sufficiently distant from the spicules. Typical diagnostic features of MCL include a diffuse bone marrow infiltration with atypical immature mast cells and significantly elevated serum tryptase levels. Mast cell sarcoma and extracutaneous mastocytoma are rare diagnoses characterized by malignant and benign solid mast cell collections respectively.

FIGURE 276-4  An algorithm for classification of systemic mastocytosis. ASM, aggressive systemic mastocytosis; ISM, indolent systemic mastocytosis; MDS, myelodysplastic syndromes; MPD, myeloproliferative disorders; SM-AHNMD, systemic mastocytosis with associated clonal hematologic non–mast cell lineage disease.

Treatment

The major goal of treatment for all categories of mastocytosis is symptom control. A reduction in mast cell numbers is considered only in disease categories with a poor prognosis (i.e., SM-AHNMD, aggressive systemic mastocytosis, MCL, and mast cell sarcoma). Current treatment modalities have not been shown to change the natural course of the disease.

Medical Therapy

Pruritus in mastocytosis usually responds to scheduled doses of H1 antihistamines such as fexofenadine and/or cetirizine. Sedating antihistamines such as hydroxyzine or diphenhydramine may be used before bedtime. Photochemotherapy (oral psoralen plus ultraviolet A) may be helpful in patients with refractory pruritus; it results in symptomatic improvement and temporary fading of the pigmented skin lesions in up to 50% of the patients. The side effects of phototherapy, including increased risk of skin cancer, should be taken into account when this treatment is considered.

H2 antihistamines such as ranitidine or famotidine are usually prescribed as a first-line treatment for patients with gastrointestinal complaints such as heartburn, nausea, and abdominal pain. Proton pump inhibitors may be added in patients whose abdominal symptoms are refractory to H2 antihistamines. Oral cromolyn sodium, at a dose of 200 mg four times daily, has been effective in reducing abdominal pain, diarrhea, nausea, vomiting, and pruritus in various studies, although the beneficial effects are variable among patients. Finally, low to moderate doses of systemic glucocorticoids can be beneficial in unusual cases of aggressive mastocytosis present-ing with recalcitrant diarrhea associated with malabsorption or hepatomegaly with ascites.

Cysteinyl leukotrienes, such as LTC4, that are produced after mast cell activation are thought to contribute to symptoms in mastocytosis. Therefore, drugs targeting the synthesis or receptor binding of leukotrienes are usually added to the treatment regimens of patients who derive suboptimal relief of itching and abdominal pain from histamine receptor–blocking therapy. However, there have been no controlled studies evaluating the clinical efficacy of this class of drugs in patients with mastocytosis.

Self-administered epinephrine should be prescribed to patients who have a history of hypotensive episodes resulting in presyncope or syncope from acute mast cell degranulation. These episodes should be treated like systemic anaphylaxis (see Chapter 274 ).

Ancillary and Other Therapies

Avoidance of the triggers of mast cell degranulation is an important adjunct to the pharmacologic treatment of symptoms. These show remarkable individual variation among patients (see Pathobiology), and the individual medical history can be helpful in identifying such triggers. General anesthesia and surgery impose an additional risk to patients with mastocytosis, because several agents that are used perioperatively such as muscle relaxants, opioid analgesics, and NSAIDs, can induce acute mast cell degranulation. Prior surgical and anesthesia records should be obtained if available, and an appropriate strategy for the anesthetic management of the patient should be determined, with close communication involving the patient, anesthesiologist, surgeon, and an allergist.

Cytoreductive therapy, considered in aggressive disease variants associated with poor prognosis, has yielded disappointing results thus far. Approaches to cytoreductive treatment of mastocytosis have included interferon (IFN)-α 2b and the nucleoside analog 2-chlorodeoxyadenosine (2-CDA). IFN-α2b (0.5 to 5 million units, three to five times per week), alone or with prednisone, has been reported to partially improve clinical and laboratory abnormalities in approximately 50% of patients with aggressive systemic mastocytosis, patients with osteoporosis and pathologic fractures, and patients with recalcitrant recurrent anaphylaxis, although complete histopathologic and molecular remissions appear to be rare. IFN-α is difficult to tolerate because of its many side effects, including flu-like symptoms, bone pain, and depression. A regimen of 2-CDA (0.10 to 0.14 mg/kg/day for 5 days, repeated at intervals of 4 to 8 weeks) has been reported to result in partial and transient responses in patients with advanced categories of disease in case reports and small series. MCL usually is treated with polychemotherapy as acute myeloid leukemia, although a successful treatment regimen has not yet been identified.

Non–mast cell clonal hematologic disorders associated with mastocytosis should be treated according to the standard-of-care guidelines for that disorder, regardless of the presence of mastocytosis. Bone marrow transplantation has yielded generally disappointing results for the treatment of mast cell disease, although occasional cases resulting in complete remission have been reported.

Recent availability of tyrosine kinase inhibitors has generated interest in use of these agents as investigational therapies targeting the mutated Kit protein with constitutively increased activity in mastocytosis. The currently available tyrosine kinase inhibitor imatinib does not inhibit D816V KIT and therefore is not predicted to be effective in patients with mastocytosis, with the exception of rare cases without this mutation. Newer kinase inhibitors with potential to inhibit the mutated KIT gene product are currently in clinical development.

Prognosis

The prognosis for mastocytosis varies by the category of disease. At least 50% of patients with pediatric-onset cutaneous mastocytosis have complete resolution of the disease by adolescence, and the rest of those patients experience improvement or fading of the skin lesions. Indolent systemic mastocytosis is a persistent disease but has a good prognosis without a decrease in life expectancy, and progression to a more aggressive disease category is rare. Factors associated with poorer prognosis have been reported as the absence of urticaria pigmentosa, older age at onset of symptoms, elevated serum lactate dehydrogenase or alkaline phosphatase, thrombocytopenia, anemia, peripheral blood smear abnormalities, and detectability of the D816V KIT mutation in peripheral blood. The prognosis for SM-AHNMD is determined by the prognosis for the associated hematologic disorder. Aggressive systemic mastocytosis and MCL have poor prognoses, with median survival times of approximately less than 3 years and less than 1 year, respectively.

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