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Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis

Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis
Authors:
Mariana C Castells, MD, PhD
Cem Akin, MD, PhD
Section Editor:
Sarbjit Saini, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Jul 2022. | This topic last updated: Jul 15, 2021.

INTRODUCTION — Mastocytosis describes a group of rare disorders in which there is pathologic accumulation of mast cells in tissues. These diseases can be limited to the skin (cutaneous mastocytosis [CM]) or involve extracutaneous tissues (systemic mastocytosis [SM]).

The evaluation and diagnosis of the different forms of CM and SM in post-pubescent adolescents and adults are reviewed here. The evaluation and diagnosis in children, the treatment of mastocytosis, and the biology of mast cells are discussed separately:

(See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)

(See "Cutaneous mastocytosis: Treatment, monitoring, and prognosis".)

(See "Systemic mastocytosis: Determining the subtype of disease".)

(See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)

(See "Advanced systemic mastocytosis: Management and prognosis".)

(See "Mast cell disorders: An overview".)

(See "Mast cells: Development, identification, and physiologic roles".)

OVERVIEW — Mastocytosis is diagnosed according to the World Health Organization's (WHO) published diagnostic criteria for cutaneous and systemic forms of mastocytosis (table 1) [1].

The diagnosis of cutaneous mastocytosis (CM) in a patient with an appropriate clinical presentation is based upon characteristic skin findings, supported by findings on skin biopsy. Evidence for systemic disease must be absent.

The diagnosis of systemic mastocytosis (SM) requires the presence of the major criterion plus one minor criterion, or the presence of three minor criteria (table 1). In a patient with an appropriate clinical presentation, fulfilling these criteria requires both laboratory testing and biopsy of one or more involved tissues (most commonly bone marrow). SM is further classified into five subtypes (table 2) [2,3]. An approach to determining the subtype of SM is discussed separately. (See "Systemic mastocytosis: Determining the subtype of disease".)

The diagnostic criteria for cutaneous and systemic mastocytosis are discussed in more detail below. (See 'Diagnosis' below.)

Most adults with mastocytosis have systemic forms of the disease and should therefore undergo a full evaluation for systemic involvement. Note that it is difficult to distinguish adults with isolated CM from those with systemic involvement on clinical grounds, because both groups can have the same skin lesions, systemic symptoms, and complications (eg, osteoporosis).

EPIDEMIOLOGY — Mastocytosis, in all of its forms, is a rare disorder with an estimated prevalence of 1 per 10,000 persons [4]. Both sexes are affected with a slight predominance of females in adulthood [5]. Adults who develop mastocytosis more often have systemic forms of the disease, which tend to be persistent [6]. Cutaneous forms of mastocytosis account for less than 5 percent of all adult cases. In contrast, >90 percent of children with mastocytosis have disease limited to the skin, which improves or resolves during puberty in the majority of patients. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis", section on 'Natural history' and "Cutaneous mastocytosis: Treatment, monitoring, and prognosis", section on 'Prognosis'.)

PATHOGENESIS — The pathogenesis of all forms of mastocytosis results from both chronic and episodic mast cell-mediator release and excessive mast cell accumulation in one or more tissues. Mast cells contain a variety of vasoactive mediators and normally function to protect the body from microbial invaders and other insults by releasing these chemicals to generate inflammatory responses. Mediators released from mast cells include histamine, heparin, leukotrienes, prostaglandins, platelet-activating factor, proteases, and cytokines, including tumor necrosis factor (table 3). The signs and symptoms associated with sudden and extensive mast cell-mediator release are similar to those associated with allergic and anaphylactic reactions. In addition to mediator release, some advanced forms of mastocytosis involve signs and symptoms arising from tissue infiltration by mast cells, effects of local accumulations of these cells, and the presence of an associated hematologic neoplasm. (See 'Signs and symptoms' below.)

Molecular abnormalities — The molecular pathogenesis of mastocytosis is incompletely understood. Stem cell factor (SCF), also called kit ligand, is a growth factor that is essential for normal development and expansion of mast cells from hematopoietic progenitors. Mast cells express a receptor for SCF on their surface, the receptor tyrosine kinase KIT (CD117). Many of the molecular defects associated with mastocytosis involve gain-of-function mutations in KIT, the gene encoding KIT [7,8]. There are limited data that SCF overexpression may play a role in some cases [9]. Most other hematopoietic cells express KIT early in their development and then lose it during maturation, becoming unresponsive to SCF. Only mast cells maintain KIT at high levels and remain responsive to SCF throughout the lifetime of the cell. Thus, abnormalities in SCF regulation or KIT preferentially affect the growth, differentiation, apoptosis, and activation of mast cells.

Mutations in KIT – Activating mutations of KIT have been implicated in the pathogenesis of both cutaneous mastocytosis (CM) and systemic mastocytosis (SM) [10-13]. However, no consistent correlation between the type of mutation and either phenotype or prognosis has been recognized [5,14-16]. Greater than 95 percent of adults with SM have exon 17 KIT mutations. The most common KIT mutation is an adenine-to-thymine base substitution (A>T) at nucleotide position 2468, which results in an aspartic acid-to-valine change in the protein. This is called the Asp816Val or D816V mutation. D816V is present in most patients with SM and in some patients with different forms of CM [14,17-22]. D816V KIT mutations are also common in skin lesions of adults with systemic disease, although data are more limited. In children with CM, the D816V mutation has been found in skin lesions in at least 20 percent [23]. One study of 59 adults with mastocytosis in the skin that developed in adulthood found that 58 of 59 patients had D816V KIT mutations in bone marrow cells, although only 74 percent had the mutation demonstrable in lesional skin [22]. Several other KIT mutations have been reported as well [12,13,23,24].

D816V results in a putative-activating loop in the kinase domain. In transfection studies, it causes ligand-independent autophosphorylation of KIT and induces constitutive activation of the Stat5-PI3K-Akt signaling cascade [25]. A more precise mechanism by which KIT-activating mutations enhance signaling is not fully characterized, but these defects lead to SCF-independent activation [26]. Clonal expansion and apoptotic defects of KIT-mutated mast cells are thought to provide the basis for pathologic accumulation of mast cells in tissues [27]. Reduction in mast cell burden and symptomatology with drugs targeting mutated KIT D816V provide further evidence that the mutation drives disease. Mast cell signal transduction is reviewed separately. (See "Mast cells: Surface receptors and signal transduction", section on 'Signal transduction'.)

Increased expression of SCF, the ligand for KIT, has been linked to mastocytosis lesions in the skin in a group of adults and children with cutaneous forms of mastocytosis [9]. Local mast cell hyperplasia was linked to increased free SCF in the dermis and the extracellular spaces between keratinocytes in skin samples, suggesting the increased presence of soluble SCF, although SCF in the peripheral blood was not elevated, and the messenger RNA sequence was not mutated [9]. However, another study demonstrated no differences in SCF levels in peripheral blood and skin [28], so this abnormality appears to be variable. In other studies of patients with SM, increased mast cell numbers could be attributable to autocrine secretion of SCF by mast cells [29,30].

Other factors – Abnormalities in several other molecules have been noted in patients with mastocytosis or cell lines derived from such patients, although their pathologic importance requires further study:

Constitutive expression of the stress-related survival factor heat-shock protein 32 (Hsp32) in a human mast cell tumor line is another finding that may prove relevant to the pathogenesis of SM [31]. Unregulated expression of Hsp32 has also been implicated in chronic myeloid leukemia [32].

Additional molecular aberrations were frequently identified in TET2, SRSF2, ASXL1, CBL, RUNX1, DNMT3A, and in the RAS pathway in patients with advanced forms of SM [33-36].

Mast cells in patients with mastocytosis demonstrate abnormal expression of surface interleukin (IL)-5 receptor, soluble CD25 (soluble IL-2 receptor alpha chain), and soluble KIT [37,38].

Heritability — In the great majority of patients, mastocytosis does not appear to be inherited, although it may be present at birth. It is also not passed down to offspring, except in rare familial cases [39-43]. KIT mutations are somatic mutations in most cases [21,44]. They are rarely found in germline cells and are not polymorphisms but can be found in some hematopoietic progenitor cells and other mature hematopoietic lineages in some patients with advanced forms of SM [45].

CLINICAL MANIFESTATIONS

Signs and symptoms — Signs and symptoms of mastocytosis in adults are summarized in the table (table 4). They may be grouped into categories:

Skin findings (which may be present in both cutaneous and systemic forms of mastocytosis).

Symptoms arising from mediator release (which may be present in both cutaneous and systemic forms of mastocytosis, as well as solid mast cell tumors [rare]).

Symptoms arising from (noncutaneous) organ infiltration (which are only present in systemic forms of mastocytosis).

Symptoms due to an associated non-mast cell hematologic disease in advanced forms, such as anemia, splenomegaly.

Characteristic presentations — There are several characteristic presentations of mastocytosis in adults.

Mastocytosis in the skin — The most common presentation of mastocytosis in adults is the gradual development of maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP), which consists of multiple, monomorphic, reddish brown macules (picture 1A-C). "Mastocytosis in the skin" (MIS) is a term used to refer to the cutaneous findings that can occur in patients with all forms of mastocytosis, rather than a category of disease. MIS describes the presence of skin findings in patients who have not yet been evaluated to determine if they have systemic disease. Most adults with MPCM/UP will prove to have systemic disease, and among adults with systemic mastocytosis (SM), approximately 80 percent have MPCM/UP [46].

MPCM/UP lesions typically begin to appear in young adulthood or middle adulthood, and then they increase in number over several years. Newly formed lesions have an erythematous hue, which becomes more brown with time. The diagnosis of MPCM/UP is often made by dermatologists, based upon skin biopsies. Patients may report urticaria with rubbing of the skin or hot showers. A majority will also note systemic mast cell-mediated symptoms, such as flushing or gastrointestinal symptoms (particularly cramping, hyperacidity, and diarrhea).

Darier's sign — If lesions of MPCM/UP are detected, the examiner may lightly rub, scratch, or stroke a small area of the affected skin. The development of erythema or urticaria over/around the lesion within approximately five minutes is called Darier's sign and is suggestive of the presence of mast cells within the lesion. The examiner should concentrate on younger, reddish lesions, since it can be more difficult to elicit Darier's sign from older, brown-colored, lesions. Darier's sign may not be demonstrable in patients taking antihistamines.

Symptoms related to mast cell mediators without skin lesions — Episodic signs and symptoms of mast cell activation affecting at least two organ systems, such as flushing, tachycardia, diarrhea, fatigue, or musculoskeletal pain, is a common presentation of mastocytosis in adults (table 4). Triggers for these episodes of symptoms include physical factors, medications, medical procedures, and sometimes dietary factors and stress (table 5).

Recurrent severe anaphylactic episodes — Severe anaphylactic reactions in response to Hymenoptera stings (eg, bee, wasp, hornet, etc), exercise, medications given in the perioperative setting or at other times, or unexplained triggers, should raise the suspicion for SM. Reactions characteristically involve hypotensive syncope or near syncope, without hives or angioedema. Some experts recommend a bone marrow biopsy in all such patients [47].

Patients with severe sting reactions should initially have serum tryptase measured, and undergo allergy evaluation for immunoglobulin E (IgE)-mediated venom allergy [48]. Most patients will have demonstrable venom-specific IgE, but if skin testing is negative, it should be repeated in six months. Fifty percent of patients with SM presenting with severe reactions to Hymenoptera stings do not have MIS, so there must be a high index of clinical suspicion.

Less severe symptoms — Patients can also have milder episodes that do not meet criteria for anaphylaxis. These usually involve flushing (rather than hives), tachycardia, or gastrointestinal symptoms occurring daily or several times a week. Food allergy is not increased in mastocytosis, although patients may have nonspecific intolerances, especially to spicy foods. Symptoms typically include flushing, syncope or near-syncope, hypotension, abdominal cramping, and diarrhea. Urticaria and angioedema are not typical. Evaluation typically does not reveal a causative IgE-mediated allergy to explain the symptoms.

Hematologic abnormalities, splenomegaly, fatigue, and weight loss — Cytopenias, such as anemia, leukopenia, and thrombocytopenia, may develop in systemic forms of mastocytosis due to infiltration of the bone marrow by mast cells and interference with normal hematopoiesis. In contrast, patients with myeloproliferative variants of SM with an associated hematologic neoplasm (SM-AHN) more typically present with leukocytosis or thrombocytosis. Hepatomegaly or splenomegaly due to infiltration with either mast cells or cells of the associated hematologic malignancy may also develop. These patients are discovered to have mastocytosis during the workup of the hematologic abnormality, when the bone marrow biopsy reveals another hematologic disorder such as myelodysplastic syndrome or a myeloproliferative neoplasm, in addition to mastocytosis.

Unusual initial presentations — There are other unusual initial presentations of mastocytosis.

An adult with hypotensive anaphylaxis in response to the sting of a Hymenoptera insect – Hypotensive reactions, without urticaria, have been noted in patients (mostly males) with indolent systemic mastocytosis, both with and without skin lesions. Patients typically have baseline serum tryptase levels below 20 ng/mL (and low mast cell burden in the bone marrow when this is biopsied), so this presentation can be easily missed [49-51].

An adult with osteoporosis and pathologic bone fractures, particularly if risk factors for osteoporosis are lacking – Occasionally mastocytosis will present in this manner in a young adult, particularly a male, in whom an evaluation for unusual causes of osteoporosis is undertaken. Patients may have vertebral compression fractures, pathologic fractures of long bones, or diffuse radiographic skeletal abnormalities (lytic or sclerotic lesions) [52,53]. Signs and symptoms of mast cell activation may or may not be present.

An adult with sclerotic or lytic bone lesions on imaging studies, prompting an evaluation for metastatic malignancy – Bone marrow biopsy then reveals mast cell infiltrates [54].

PRESENTATIONS THAT DO NOT SUGGEST MASTOCYTOSIS — An evaluation for mastocytosis is not indicated in patients presenting with:

Chronic urticaria and/or angioedema (see "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history")

Multiple environmental and chemical sensitivities (see "Idiopathic environmental intolerance (multiple chemical sensitivity)")

Multiple food intolerances and/or food aversion not explained by IgE-mediated food allergy, without objective symptoms suggestive of mastocytosis (see "Food intolerance and food allergy in adults: An overview")

Primarily neuropsychiatric symptoms (such as seizures or pseudoseizures, weakness or numbness, motor or sensory complaints, depression, anxiety, psychosis), without other objective findings or symptoms suggestive of mastocytosis

Chronic nonspecific symptoms, such as fatigue, bone/muscle pain, fibromyalgia, headaches in the absence of other symptoms or findings (see "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome")

LABORATORY STUDIES

Initial testing in all patients — The tests discussed in this section should be performed in all adults suspected of having mastocytosis, to detect the presence of mast cell mediators, and to evaluate for abnormalities due to systemic disease or organ infiltration by mast cells:

Serum total tryptase when the patient is in a baseline state – Tryptase is a protease produced predominantly in mast cells, although a small amount is made by basophils and myeloid precursors as well. Total serum tryptase can be measured with a commercially available assay (ImmunoCAP tryptase), which is performed at many clinical laboratories. Normal laboratory reference levels are between 1 and 11.4 ng/mL (although some laboratories consider 15 ng/mL to be the upper limit of normal).

The presence of elevated serum concentrations of tryptase >20 ng/mL is one of the minor criteria for the diagnosis of systemic mastocytosis (SM) [55]. However, elevations of tryptase above normal range (11.4 ng/mL) without reaching 20 ng/mL have been found in 10 to 15 percent of mastocytosis patients. Conversely, serum tryptase >20 ng/mL can be seen in individuals with hereditary alpha tryptasemia who do not have mastocytosis. (See 'Differential diagnosis' below.)

Of note, serum tryptase should be assayed when the patient is in a baseline state (ie, not immediately following an episode of symptoms) for the purposes of diagnosing mastocytosis, because elevations in mediators obtained immediately after a symptomatic episode (such as flushing or syncope) indicate mast cell activation but do not distinguish between anaphylaxis and mastocytosis. Antimediator therapies (ie, antihistamines, antileukotriene drugs, and cromolyn) do not interfere with serum tryptase levels, although prolonged glucocorticoid therapy potentially could. (See 'Differential diagnosis' below.)

Complete blood count (CBC) with differential to evaluate for cytopenias, immature or abnormal myeloid and lymphoid leukocytes, leukocytosis, polycythemia, anemia, thrombocytopenia, thrombocytosis, eosinophilia, and circulating mast cells. A more detailed discussion of hematologic abnormalities found in advanced forms of SM is found separately. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Evaluation'.)

Liver function tests (including serum aminotransferases, gamma glutamyl transpeptidase, and alkaline phosphatase) to evaluate for liver involvement.

KIT mutational analysis on peripheral blood is now performed routinely at some specialty centers and available through a limited number of commercial labs. Assays vary in sensitivity, and less sensitive assays may not detect mutations that are present at a low level. Therefore, a positive result on peripheral blood is helpful and may obviate the need for bone marrow biopsy, but a negative result does not exclude the possibility that a KIT mutation is present. Assay differences and interpretation are discussed below. (See 'KIT mutational analysis' below.)

Findings in cutaneous and systemic disease — Some abnormalities of routine laboratories (eg, CBC, liver function tests) may be seen. When present, these abnormalities usually indicate the presence of organ infiltration by mast cells in systemic forms of the disease (table 4).

Tryptase is usually normal in cutaneous mastocytosis (CM) and elevated in the majority of patients with SM. However, up to 10 percent of patients with SM (with or without maculopapular cutaneous mastocytosis/urticaria pigmentosa [MPCM/UP]) have tryptase levels <20 ng/mL [56,57]. Intermediate values (ie, above normal but <20 ng/mL) are sometimes seen in patients with indolent systemic mastocytosis with a low mast cell burden and in those with mast cell activation disorders. Mast cell activation disorders are discussed separately. (See "Mast cell disorders: An overview", section on 'Monoclonal mast cell activation syndrome' and "Mast cell disorders: An overview", section on 'Idiopathic mast cell activation syndrome'.)

If baseline tryptase is elevated, it should be repeated at least once more. SM should be strongly suspected in patients with adult-onset skin lesions or baseline levels of total tryptase >20 ng/mL on at least two occasions [58]. Some experts are beginning to incorporate genetic testing for hereditary alpha tryptasemia (HaT) in those with less suggestive symptoms (such as hyperacidity and dysautonomic symptoms). (See 'Disorders with similar clinical manifestations' below.)

The absolute level of total tryptase does not predict the category of SM [59]. Aggressive mastocytosis and mastocytosis associated with hematologic malignancies can have similar elevations of tryptase as indolent systemic mastocytosis. However, mast cell leukemia (MCL) is generally associated with extremely elevated tryptase levels, sometimes >1000 ng/mL, and smoldering systemic mastocytosis is associated with tryptase of >200 ng/mL by definition. Smoldering systemic mastocytosis is a rare category with high mast cell burden but without meeting the criteria for advanced disease.

The laboratory abnormalities that may be present in different systemic forms of mastocytosis are discussed separately. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'C findings'.)

The most common form of SM is indolent SM, in which routine laboratories are usually normal. However, when lab abnormalities are present, the most common findings are normochromic, normocytic anemia and mild elevations in alkaline phosphatase (without other liver function test abnormalities), which can be seen in both indolent and advanced forms.

In advanced forms of SM, more extensive cytopenias and/or liver function abnormalities may be seen, depending upon the category of disease present. In patients with leukocytosis, eosinophilia, or findings that suggest another hematologic disorder, additional molecular or cytogenetic testing appropriate for that disorder (including BCR/ABL, JAK2 V617F, and Fip1-like1-platelet-derived growth factor receptor alpha [FIP1L1-PDGFRA] fusion genes) should be performed [10]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Myeloproliferative HES variants'.)

In CM, which represents less than 5 percent of adult cases of mastocytosis, the CBC and differential are typically normal, although a mild eosinophilia is sometimes noted. Liver function tests should be normal. Serum tryptase is usually normal [60-62].

Skin biopsy (if needed) — An experienced clinician can diagnose mastocytosis in the skin (MIS) based upon the characteristic appearance of MPCM/UP lesions. However, if there is any doubt about the nature of the lesion, a punch biopsy should be performed and evaluated with the specific histopathologic stains discussed below. Medications do not interfere with biopsy results.

Specimens should be fixed in formalin and undergo histopathologic staining with Giemsa and/or immunohistochemical staining for tryptase and KIT (also known as CD117, the receptor for stem cell factor), which identify both normal and abnormal mast cells (picture 2). Mast cells also stain positive for chymase and carboxypeptidase A3, although these stains are not routinely performed [63]. Degranulated mast cell can be difficult to identify without these specialized stains. Techniques for identifying mast cells in tissues are presented in more detail separately. (See "Mast cells: Development, identification, and physiologic roles", section on 'Cellular identification'.)

Mast cells in lesions of UP may have irregular shapes, sometimes with bilobed nuclei, which may be seen on light microscopy. Infiltrating eosinophils may also be present.

Mast cells may form small or large clusters or appear in sheets. There are four patterns of mast cell infiltrates that are observed in cutaneous mastocytosis, which only partially correlate with the type of clinical lesion [6]:

Perivascular infiltrates in the papillary and upper dermis

Sheet-like infiltrates in the papillary body and upper reticular dermis

Interstitial infiltrates

Nodular infiltrates

CD25 (interleukin-2 [IL-2] receptor alpha chain) may be aberrantly expressed by a subset of skin mast cells in those with systemic disease [64].

Interpretation — Abnormal skin biopsy findings in the context of the morphologic lesion are diagnostic of MIS (table 1) [65]. However, MIS should not be diagnosed based on biopsy findings alone, without the characteristic skin lesions, because mast cells can be found around blood vessels and in telangiectasias in otherwise healthy skin. In addition, mast cell numbers may be increased in inflammatory or neoplastic skin diseases, such as psoriasis, urticaria, eczema, and dermatofibromas. In addition, skin biopsy does not provide information about systemic involvement. (See 'Disorders with similar skin biopsy findings' below.)

There is no specific cut-off value for numbers of mast cells in the skin that is considered abnormal. However, one study found mast cell numbers of >100 per high power field in lesions of MIS, whereas healthy controls had <100 [28]. Analysis of cutaneous mast cells for the presence of mutations in KIT does not fulfill the diagnostic criteria and is not a standard part of the evaluation of skin biopsies, but it has been performed in investigational protocols [5,14,23]. Instead, KIT mutational analysis is usually performed on peripheral blood or bone marrow. (See 'KIT mutational analysis' below.)

REFERRAL — Generalists should perform a history and physical examination (with careful attention to the skin) and obtain the initial laboratory studies mentioned above. (See 'Initial testing in all patients' above.)

Further evaluation and skin biopsy usually requires specialty referral. When feasible, the following patients should be referred to an allergy/immunology, dermatology, or hematology expert with knowledge of mast cell disorders:

Any patient with suspected or confirmed maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP), because most adults with MPCM/UP will prove to have systemic mastocytosis (SM).

Patients with signs or symptoms suggestive of systemic disease (eg, recurrent episodic flushing attacks with tachycardia, lightheadedness, and abdominal complaints).

Patients with elevated tryptase levels (>20 ng/mL). If the patient also has clear symptoms of mast cell activation, such as syncope or hypotensive episodes, a lower threshold for referral is appropriate (>11.4 ng/mL).

Patients with recurrent unexplained anaphylaxis that includes hypotension.

ADDITIONAL EVALUATION AND BONE MARROW BIOPSY

Presentation guides further evaluation — The patient's presentation guides additional testing and the need for bone marrow biopsy [10,66]. The evaluation of adults with and without skin lesions of maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP) is summarized in algorithmic form and discussed in this section (algorithm 1 and algorithm 2).

MPCM/Urticaria pigmentosa — Nearly all adults with MPCM/UP will prove to have systemic mastocytosis (SM) [67]. Therefore, adults with MPCM/UP should have the laboratory studies mentioned above and undergo a bone marrow examination (algorithm 1) [10]. (See 'Laboratory studies' above and 'Bone marrow examination' below.)

Recurrent severe allergic or anaphylactic reactions — All patients with recurrent anaphylaxis should undergo a thorough allergy evaluation if an underlying allergy seems possible from the clinical history [68]. The evaluation of idiopathic anaphylaxis is reviewed separately. (See "Idiopathic anaphylaxis", section on 'Diagnosis'.)

For patients with anaphylactic reactions with hypotension and lacking hives or angioedema in response to Hymenoptera stings, medications, or unexplained, we suggest genotyping for hereditary alpha tryptasemia (HaT), assessment for the presence of mutations in the KIT gene in peripheral blood (discussed below), and a bone marrow biopsy to evaluate for systemic disease or monoclonal mast cell activation syndrome (algorithm 2) [47]. (See 'Differential diagnosis' below.)

Symptoms related to mast cell mediators without skin lesions — In patients with symptoms less severe than anaphylaxis, such as flushing and persistent gastrointestinal symptoms, the initial laboratories mentioned previously should be performed, as well as genetic testing to evaluate for HaT. In addition, if tryptase levels are >20 ng/mL on at least two occasions, we perform a bone marrow examination (algorithm 2). Note that patients can have both HaT and SM [69].

In adults with symptoms of mast cell activation but without MPCM/UP, validated clinical and laboratory criteria have been defined that predict the presence of clonal mast cells in the bone marrow or SM [70,71]. These criteria are used to generate a "REMA score" (named for the Spanish Network on Mastocytosis), which ranges from –4 to +7. A REMA score ≥2 is associated with a high probability of the presence of clonal mast cell in the bone marrow or SM, and is thus an indication for a bone marrow biopsy in patients presenting in this manner:

Sex: Male (+1), female (–1)

Clinical symptoms: Absence of urticaria, pruritus and angioedema (+1), presence of urticaria, pruritus and/or angioedema (–2), presyncope and/or syncope (+3)

Baseline serum tryptase: <15 ng/mL (–1), >25 ng/mL (+2)

A REMA score ≥2 was shown to have a sensitivity and specificity of 84 and 74 percent, respectively, for the presence of clonal mast cells in the bone marrow, and a sensitivity and specificity of 87 and 73 percent, respectively for SM [70].

Other presentations — Patients with the physical findings or laboratory features below may be considered for evaluation for SM regardless of the presence of skin lesions, particularly if there is an elevated baseline tryptase level:  

Unexplained peripheral blood abnormalities, such as liver function abnormalities or cytopenias

Unexplained splenomegaly, or lymphadenopathy

Unexplained pathologic bone fractures, osteopenia, osteoporosis, or osteosclerosis

Shifting definition of normal tryptase — The level of tryptase that is considered elevated is evolving. The World Health Organization diagnostic criteria for SM specifies a level about 20 ng/mL as a minor criterion for SM. Different commercial laboratories set the upper limit of normal at either 11.4 or 15 ng/mL, as mentioned above. Patients with HaT have levels above 7.5 ng/mL and as high as 60 ng/mL (see 'Disorders with similar clinical manifestations' below). The inclusion of individuals with HaT in the general population may have skewed the previous definitions of normal upwards. There is growing evidence that individuals without HaT or any mast cell disorder have serum tryptase levels significantly lower (ie, typically <8 ng/mL). Because of these areas of uncertainty, the authors consider levels above 10 ng/mL to be potentially abnormal when considering which individuals to monitor more closely.

However, in patients without skin lesions or symptoms of mast cell activation, in whom a bone marrow biopsy is being considered because of an elevated tryptase, other nonmast cell etiologies (such as renal disease) or HaT should be explored before proceeding to bone marrow biopsy. (See 'Other causes of elevated tryptase' below.)

KIT mutational analysis — The presence of a mutation in the KIT gene (which codes the receptor for stem cell factor) is one of the minor criteria for SM (table 1). KIT mutational analysis can be performed on bone marrow, peripheral blood, or other tissues. Bone marrow testing is the gold standard, but peripheral blood testing can be helpful in patients in whom a bone marrow biopsy could not be obtained. Reports of mutational analysis from some commercial laboratories also provide information about the frequency of the mutation (ie, mutational burden), which can be useful for monitoring the disorder and for assessing response to therapy.

Bone marrow lesional tissue has the highest sensitivity for detection of somatic KIT mutations due to the higher concentration of mast cell precursors and mature mast cells, and a bone marrow evaluation is the most useful means of evaluating for KIT mutations. The evaluation of patients with MPCM and elevated baseline serum tryptase should proceed directly to bone marrow biopsy, as this will provide all the information required for diagnosis.

All adults suspected of having SM should undergo a mutational analysis of KIT by allele-specific polymerase chain reaction (PCR), which can be performed either on peripheral blood or bone marrow (and occasionally on other tissues) [72,73]. It is available through at least two commercial laboratories in the United States [74] and in many other countries. One situation in which the peripheral blood KIT analysis can be helpful is the evaluation of a patient with normal or slightly elevated serum tryptase, no suggestive skin lesions, and persistent clinical suspicion for SM, as a positive result would allow the patient to avoid the need for bone marrow biopsy, although a negative result would not necessarily rule out SM (algorithm 2) [67]. Peripheral blood KIT testing is also useful in the evaluation of monoclonal and idiopathic mast cell activation syndromes. (See "Mast cell disorders: An overview", section on 'Monoclonal mast cell activation syndrome' and "Mast cell disorders: An overview", section on 'Idiopathic mast cell activation syndrome'.)

The tests performed by commercial laboratories for diagnosis of mastocytosis only detect the most common KIT mutation (D816V) and will miss less common mutations [74]. Mutational assays using D816V allele-specific PCR primers have the highest sensitivity of detection and usually can detect <0.1 percent of the mutated allele in a sample, whereas sequencing-based techniques have poor sensitivity and should not be used for routine mutational analysis. However, sequencing of the entire KIT exome is recommended in patients with advanced forms of SM when KIT D816V-specific testing is negative, as the results can also inform treatment with targeted therapies [75]. (See "Systemic mastocytosis: Determining the subtype of disease".)

If the KIT D816V mutation is detected in peripheral blood in the evaluation of an adult who presents without skin lesions, then bone marrow should be performed to evaluate for additional diagnostic criteria. If the mutation is not detected in peripheral blood (which is common in patients with low mast cell burden) and there is a high index of suspicion due to compatible clinical symptoms, then a bone marrow biopsy should be performed to obtain material for the evaluation of the KIT D816V and to look for other diagnostic criteria. In contrast, if the result is negative and the clinical suspicion is low or moderate, the bone marrow biopsy could reasonably be deferred while other explanations for the symptoms are explored. (See 'Bone marrow examination' below.)

Bone marrow examination — Bone marrow examination is performed to determine if abnormal mast cells are present (algorithm 3). Evaluation includes histology of the core sample and of aspirated cells. Both types of samples should be examined for morphologically abnormal mast cells (eg, spindle-shaped, hypogranular forms). Certain bone marrow findings constitute the major criterion for the diagnosis of SM (table 1). (See 'Major criterion' below.)

In patients with SM, there is a good correlation between an elevated total tryptase level and the mast cell burden in the bone marrow biopsy. A simple bone marrow biopsy with routine histologic studies is more likely to be diagnostic of mastocytosis in patients with serum tryptase levels >20 ng/mL. However, even in patients with elevated serum tryptase levels, the bone marrow may have relatively low numbers of pathologic mast cells and the disease may not be detected due to sampling of uninvolved areas, and thus the diagnosis can require some expertise [76]. Such patients should be offered referral to a center with expertise in diagnosing mastocytosis if there is a strong suspicion of SM based on the presentation [77].

Histochemistry – Mast cells (both normal and abnormal) within the bone marrow core biopsy specimen are identified by immunohistochemical staining with antibodies to tryptase and/or KIT (CD117). Mast cells in other tissues stain with metachromatic dyes, such as Giemsa or toluidine blue, but mast cells in the bone marrow core sections may not, because fixation and decalcification of the specimen can interfere with these stains. In addition, degranulated mast cells may lose their metachromatic staining properties. For these reasons, bone marrow mast cells are best identified with specialized monoclonal antibodies that recognize CD117 and tryptase [78].

Stains to detect CD25 (interleukin-2 [IL-2] receptor alpha chain) and CD2 (lymphocyte function antigen-2 [LFA-2]) should also be performed, as mast cells from patients with SM inappropriately express these surface markers, while normal or reactive mast cells do not [10,79]. The typical phenotype in SM is an increase in mast cells that are positive for CD117, tryptase, and CD25 [80]. Staining for CD25 can be done on histopathology sections in most hospital pathology laboratories using formalin-fixed bone marrow tissue. CD2 stains usually yield weaker results than CD25. The expression of one or both of these markers is a minor criterion for the diagnosis (see 'Diagnosis' below). The functionality of CD2 and CD25 expression is unknown, although CD2 may be involved in clustering of mast cells. CD30 (TNFRSF8) is aberrantly expressed in approximately 80 percent of patients with SM and may be of additional diagnostic value in individuals with well-differentiated SM (WDSM) [81]. (See 'Well-differentiated systemic mastocytosis' below.)

Normal bone marrow mast cells are round cells with small central nuclei and granulated cytoplasm and have a morphology similar to mature mast cells in other tissues. In patients with SM, bone marrow mast cells often have a spindle or fusiform shape, cytoplasmic projections, eccentric, oval nuclei, hypogranular cytoplasm with focal accumulation of granules with or without granule fusion, and a high nucleus to cytoplasm ratio [82]. Mast cells in SM may also appear immature (multilobated or clefted nuclei, hypogranulated). Paratrabecular and perivascular localization is common, with thickened bony trabeculae, although interstitial infiltrates are also observed.

The major criterion for SM is the presence of multifocal aggregates of spindle-shaped mast cells that contain at least 15 mast cells per aggregate. Smaller aggregates with round mast cells of normal morphology, as well as diffuse increases of mast cells, may also be observed (picture 3). One of the minor criteria is the presence of mast cells with a spindle-shape or atypical morphology that comprise >25 percent of the mast cells in the bone marrow aspirate or in the infiltrate (either in aggregated or interstitially distributed mast cells) on a bone marrow section (figure 1).

In healthy individuals, bone marrow mast cells represent less than 1 percent of all nucleated cells [83]. In patients with SM, the bone marrow ranges from normocellular to markedly hypercellular [82,84]. The clinical significance of the marrow burden of mast cells is unclear, but advanced forms of disease, such as aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL), are associated with extensive bone marrow infiltration. Morphologically immature bone marrow mast cells comprising more than 20 percent of cells in a nonspicular area of the bone marrow smear or >10 percent in peripheral blood is diagnostic for MCL [1,82]. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Mast cell leukemia'.)

Flow cytometry – Analysis of the bone marrow aspirate by flow cytometry (ie, fluorescence activated cell sorting [FACS]) should be performed if possible. Mast cells make up less than 1 percent of cells in bone marrow aspirate samples and are identified as a CD117high immunoglobulin E (IgE)positive population [79,85,86]. Acquisition of at least 1 million cell events is preferred to capture enough mast cells. Expression of CD2 and CD25 should also be assessed [85]. CD2 expression may be variable or absent in advanced disease, whereas CD25 is more reliable. Double-positive cells expressing both KIT (CD117) and CD25 are considered aberrant mast cells, which fulfills a World Health Organization (WHO) minor criteria. CD30 is also helpful, as it is a marker of WDSM, and is also expressed in most typical SM lesions and may be incorporated into future revisions of the diagnostic criteria. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Evaluation'.)

Mutational analysis – Analysis for mutations in the KIT gene should be performed on bone marrow aspirate samples. D816V KIT mutational analysis is commercially available in the United States, and it is also performed at several academic centers [77]. The assay of choice is a PCR assay using a mutation-specific primer with a sensitivity of <0.1 percent or better [73]. Whole cell sequencing-based methods should not be done because they have a low sensitivity and frequently yield false-negative results.

The presence of this mutation is one of the minor criteria for SM and clonal mast cell expansion [87,88]. When appropriate tissues are analyzed with a highly sensitive method, the D816V KIT mutation is identified in more than 90 percent of patients with SM [13]. Cells from skin or other organs, including the gastrointestinal tract, are sometimes used when bone marrow is not readily available, although there are limitations to using these tissues [89,90]. (See 'Other studies' below.)

Other studies — Other studies are sometimes obtained before the diagnosis of mastocytosis is considered or as part of an evaluation of specific signs and symptoms. Although these are not components of the diagnostic criteria for cutaneous mastocytosis (CM) or SM, they are useful to determine the extent of disease and can be helpful once the diagnosis of SM has been made, to determine the degree of systemic involvement. Other tissues (such as spleen or lymph nodes) are occasionally used as a source of mast cells if they have been removed as part of evaluation or treatment. (See "Systemic mastocytosis: Determining the subtype of disease".)

Gastrointestinal biopsy — Increased mast cell numbers in gastrointestinal biopsies should not be interpreted as diagnostic of a systemic mast cell disease unless the increase is sufficient to fulfill a major or minor criterion (table 1). Interpretation of gastrointestinal tract biopsies is problematic because mast cells are normally abundant in these tissues, and it can be difficult to appreciate relative increases in mast cell concentration or the presence of mast cell aggregates [91]. For example, the number of mast cells in a normal colon biopsy sample can be as high as 40 per high power field. The number of mast cells normally present in different parts of the gastrointestinal tract was investigated in a 2014 study, providing a much needed baseline for interpretation of gastrointestinal biopsies [89]. In addition, increased mast cell numbers can also be found in gastrointestinal biopsies from patients with inflammatory bowel diseases and bacterial and parasitic infections.

Studies of mast cell density in the gastrointestinal tracts of patients with SM are conflicting, with some documenting increased mast cells in gastrointestinal biopsies of patients with SM compared to controls [79], and another finding decreased numbers [91].

In contrast to mast cell numbers, expression of CD25 on gastrointestinal mast cells is a useful diagnostic marker for presence of SM and may be helpful when bone marrow sampling is not possible [89,92]. For unclear reasons, pathologic mast cell infiltrates in some gastrointestinal biopsies from patients with SM may stain negative for tryptase, and so biopsy specimens should also be stained for CD117. Obtaining multiple biopsies is also helpful, since gastrointestinal involvement may be patchy. One way in which the diagnosis of SM can be made without a bone marrow biopsy is the combination of a tryptase level persistently >20 ng/mL, the D816V mutation detected in peripheral blood, and a gastrointestinal biopsy fulfilling a WHO major (aggregates of 15 mast cells) or minor criteria (expression of CD25 or spindle shaped mast cells).

Biopsies of other organs — Histologic evaluation of organs other than bone marrow and skin is generally not recommended for diagnosis of SM because bone marrow is almost always involved and the pathologic significance of increased mast cells in other tissues have not been carefully studied. Occasionally, an organ is biopsied because of enlargement or dysfunction [29]. Multifocal aggregates of spindle-shaped mast cells can be found, similar to those in the bone marrow. This can be used to fulfill the World Health Organization major criterion (table 1).

Imaging — Potential findings on imaging studies in patients with SM include hepato- or splenomegaly, lymphadenopathy, ascites, or bony lesions. These may be detected by radiography, computed tomography (CT) scan, magnetic resonance imaging (MRI), or bone scan during evaluation of the patient's symptoms. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Evaluation'.)

DIAGNOSIS — Mastocytosis is diagnosed according to the World Health Organization's (WHO) published diagnostic criteria for cutaneous and systemic forms of mastocytosis (table 1) [1]. Subtypes of both cutaneous mastocytosis (CM) and systemic mastocytosis (SM) are defined (table 6) [1].

Cutaneous mastocytosis — The diagnosis of CM is based upon the presence of suggestive signs and symptoms (table 4), combined with characteristic cutaneous lesions (usually maculopapular cutaneous mastocytosis/urticaria pigmentosa [MPCM/UP]) and findings on skin biopsy (table 1). Bone marrow studies are normal (ie, none of the WHO criteria for SM are fulfilled). Adults with isolated CM can have the same skin lesions and systemic symptoms and the same complications (eg, osteoporosis) as adults with systemic mastocytosis [93].

Historically, the finding of telangiectasias with increased numbers of mast cells, called telangiectasia macularis eruptive perstans (TMEP) (picture 4) was considered a separate form of CM, but these lesions rarely occur in the absence of UP and are now included in MPCM/UP.

Systemic mastocytosis — Mastocytosis is a histopathologic and genetic diagnosis and should not be based solely on clinical presentation. According to the WHO diagnostic criteria, the definitive diagnosis of SM requires either the presence of one major and one minor criteria OR three minor criteria (table 1) [1]:

Major criterion — The major criterion is the presence of multifocal, dense aggregates of greater than 15 mast cells in bone marrow (preferred) or other extracutaneous organs (eg, gastrointestinal tract, lymph nodes, liver, or spleen), as detected with antibodies for tryptase or other special stains (algorithm 3).

Minor criteria — Four minor criteria have been defined:

Atypical morphology or spindle shapes in >25 percent of the mast cells in bone marrow sections, bone marrow aspirate, or other extracutaneous tissues.

Mutational analysis of KIT showing a codon 816 mutation (commonly Asp816Val) in bone marrow, peripheral blood, or extracutaneous organs.

Bone marrow or other extracutaneous mast cells expressing the surface markers CD2, CD25, or both. CD30 may be included in future revisions of the criteria because it is helpful for identifying well-differentiated SM (eg, mast cells are CD30+CD25-).

Serum tryptase levels (when the patient is in a baseline state) >20 ng/mL. Values >11.4 ng/mL are considered elevated in most diagnostic laboratories. However, the WHO criterion is defined as a value >20 ng/mL. Of note, the serum tryptase criterion does not apply to patients with an associated clonal hematologic nonmast cell lineage disorder (AHNMD), since tryptase in such patients can originate from myeloid precursor cells.

Monoclonal mast cell activation syndrome — Patients with MPCM/UP who fulfill one or two of the minor criteria for systemic disease (ie, have a KIT mutation and bone marrow mast cells express CD25) may be diagnosed with monoclonal mast cell activation (MMAS) (table 7). (See 'Disorders with similar clinical manifestations' below.)

Well-differentiated systemic mastocytosis — A rare histopathologic variant called well-differentiated systemic mastocytosis (WDSM) has been described in children with systemic disease (especially diffuse CM) that persists into adulthood [94]. Patients with WDSM do not have aberrant CD25 or CD2 expression, but instead express CD30. (See 'Bone marrow examination' above.)

While the cells in WDSM do form mast cell clusters, atypical spindling is absent. They carry markers of clonality, as detected by X chromosome inactivation or unusual KIT mutations, but may be negative for the typical D816V mutation [95].

Once a patient has been diagnosed with SM, further evaluation is needed to determine the category of disease present. This evaluation is presented separately. (See "Systemic mastocytosis: Determining the subtype of disease".)

DIFFERENTIAL DIAGNOSIS — Mastocytosis can be confused either clinically or histologically with a variety of disorders, although application of the World Health Organization's (WHO) criteria to pathologic samples confirms or rules out the diagnosis of systemic mastocytosis (SM). Common presentations that do not suggest mastocytosis are reviewed above. (See 'Presentations that do NOT suggest mastocytosis' above.)

Disorders with similar clinical manifestations — In addition to mastocytosis, there are other disorders of mast cell activation with overlapping clinical and pathologic features (table 7):

Monoclonal mast cell activation syndrome – The term "monoclonal mast cell activation syndrome" (MMAS) has been accepted by a consensus panel as appropriate for patients who experience episodes of mast cell activation symptoms, such as recurrent flushing, gastrointestinal cramping, and hypotension, and meet one or two of the minor diagnostic criteria for SM (KIT D816V or aberrant CD25 expression on mast cells), but do not fully meet diagnostic criteria for SM (algorithm 2). (See 'Minor criteria' above.)

Patients with MMAS may present with recurrent unexplained anaphylaxis or hypotensive reactions to Hymenoptera stings. Baseline serum tryptase values are normal or mildly increased. Bone marrow findings do not meet the full criteria for SM, although some cells express the aberrant markers CD2 and CD25 and/or KIT mutations. MMAS is reviewed in greater detail separately. (See "Mast cell disorders: An overview".)

Idiopathic mast cell activation syndrome – "Idiopathic mast cell activation syndrome" (IMCAS) is a term proposed to describe an idiopathic disorder in which patients present with symptoms of chronic mast cell activation, in addition to recurrent episodes of signs and symptoms that are consistent with acute mast cell activation and affect at least two organ systems (ie, cutaneous, gastrointestinal, cardiovascular, respiratory, or naso-ocular) (algorithm 2 and table 8) [96]. If the criteria for anaphylaxis are met, then the diagnosis of idiopathic anaphylaxis is more appropriate. An important clinical difference between IMCAS and idiopathic anaphylaxis is that patients with idiopathic anaphylaxis are generally well in between episodes and lack the symptoms of chronic mast cell activation seen in IMCAS.

In addition, elevations in mast cell mediators in serum or urine should be documented as follows:

A serum tryptase level obtained within four hours of the suspected mast cell activation episode showing a value greater than Baseline + 0.2 x baseline + 2 ng/mL is preferred as a proof of mast cell activation [97].

Elevations in a 24-hour urine N-methylhistamine or prostaglandin D2 (PGD2) (or its metabolite 11-beta-prostaglandin F2-alpha [PGF2-alpha]) should be demonstrated on at least two occasions during a symptomatic period. However, these mediators (especially PGD2 and PGF2-alpha) are less specific to mast cell activation.

Finally, patients should exhibit a favorable clinical response to medications that counteract mast cell mediators, including H1 and H2 antihistamines, antileukotriene medications, or oral cromolyn sodium.

Mast cell activation syndrome (MCAS) can be further classified into clonal and nonclonal subtypes. MCAS is reviewed in more detail separately. (See "Mast cell disorders: An overview".)

Anaphylaxis – Clinical criteria for the diagnosis of anaphylaxis have been defined (table 8). Patients with anaphylaxis may have elevations of serum beta tryptase during (or for several hours after) acute events. In contrast, patients with SM have persistent elevations in total tryptase in the baseline state, which increase further during anaphylaxis. We suggest that patients with Hymenoptera anaphylaxis should be evaluated with a baseline serum tryptase. If the tryptase is greater than 11.4 ng/mL, or if the patient experienced hypotensive syncope (regardless of the tryptase level), then an evaluation for both HaT and SM should be performed. Idiopathic anaphylaxis is a diagnosis of exclusion. (See "Idiopathic anaphylaxis".)

During an anaphylactic event (in a patient without SM), beta tryptase rises and, if sufficiently high, can result in elevations of total tryptase. Beta tryptase levels >1 ng/mL and a ratio of total to mature of <10 are each consistent with systemic anaphylaxis (table 9). The interpretation of tryptase levels in patients with suspected anaphylaxis is reviewed in detail separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

Tryptase measurements are useful in distinguishing systemic mastocytosis from the mast cell activation seen in anaphylaxis (table 9):

Total tryptase – Normal levels are between 1 and 11.4 ng/mL (some laboratories consider 15 ng/mL to be the upper limit of normal) (table 9). SM should be strongly suspected in patients with baseline levels of total tryptase greater than 20 ng/mL on at least two occasions [58].

Beta tryptase – Measurement of beta tryptase is not required to make the diagnosis of mastocytosis, although it allows for an estimate of the total (alpha + beta) to beta ratio, which is sometimes helpful in confirming anaphylaxis (table 9). Beta tryptase is stored in mast cell granules and is elevated in serum in mast cell activation. An assay for beta tryptase is performed at Virginia Commonwealth University (Richmond, Virginia) [98]. The serum level of beta tryptase in healthy blood donors is less than 1 ng/mL. During mast cell activation and systemic anaphylaxis, levels of beta tryptase rise above 1 ng/mL, reaching a peak approximately one hour after the event and generally returning to baseline after four hours. Beta tryptase levels are usually normal in patients with SM, unless they have just experienced an episode of massive mast cell activation.

Ratio of total to beta tryptase – If both measurements are available, the ratio of total to beta tryptase can be calculated [59]. In patients with SM this ratio is >20, whereas it is often <10 in systemic anaphylaxis (table 9).

The next group of disorders described below, which can have some clinical features similar to mastocytosis, do not involve mast cell activation. Therefore, serum tryptase and urinary histamine are not elevated:

Hereditary/acquired angioedema – Patients with hereditary or acquired angioedema due to deficiency of C1 inhibitor present with episodes of angioedema (generally painful) affecting the skin, larynx, and/or walls of the bowel. In contrast, laryngeal edema is unusual in mastocytosis, and C1 inhibitor and complement studies are typically within normal range in mastocytosis. (See "An overview of angioedema: Clinical features, diagnosis, and management".)

Carcinoid syndrome – The presence of episodic flushing and diarrhea may raise suspicion for mastocytosis among patients with the carcinoid syndrome. Elevation of 5-hydroxyindoleacetic acid (5-HIAA), a breakdown product of serotonin, in a 24-hour urine sample is indicative of carcinoid syndrome, whereas this mediator is normal in mastocytosis. (See "Diagnosis of carcinoid syndrome and tumor localization".)

Pheochromocytoma – Patients with pheochromocytoma may present with flushing and paroxysmal episodes of hypertension, whereas patients with mastocytosis generally develop hypotension during an acute mast cell degranulation episode. (See "Clinical presentation and diagnosis of pheochromocytoma".)

Metastatic disease to bone – Bone lesions of SM are frequently misinterpreted radiographically as metastatic lesions to bone. However, elevated serum tryptase and urinary histamine are absent in most malignancies. Thus, histopathologic diagnosis is required to differentiate between these two disorders.

Vasoactive intestinal peptide-secreting tumors – Symptoms found in both SM and vasoactive intestinal peptide (VIP)-secreting tumors include flushing episodes and particularly diarrhea. VIP-secreting tumors are associated with increased levels of VIP. (See "VIPoma: Clinical manifestations, diagnosis, and management".)

Zollinger-Ellison syndrome – A significant number of patients with the Zollinger-Ellison syndrome present with diarrhea. Some affected individuals may also have metastatic disease to bone. However, Zollinger-Ellison syndrome is not associated with elevated levels of histamine or tryptase. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)

Medullary thyroid cancer – This neuroendocrine tumor of the thyroid parafollicular or C cells can present with recurrent flushing and diarrhea. Most patients also have a solitary thyroid nodule. Serum calcitonin levels may be elevated. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)

Other causes of elevated tryptase — Persistent tryptase elevations can be detected in conditions other than mast cell disorders and HaT, including myeloproliferative or myelodysplastic disease, chronic renal or liver failure, and chronic eosinophilic leukemia [99]. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Elevations of tryptase in nonanaphylactic patients'.)

Hereditary alpha-tryptasemia — Hereditary alpha-tryptasemia (HaT) is an autosomal dominant genetic condition which was described in 2014 and may be present in as many as 6 percent of individuals of European ancestry, making it the most common reason for an elevation in baseline total tryptase. Baseline serum tryptase is between 7.5 and 60 ng/mL in the patients reported to date. The genetic basis is a copy number increase in the TPSAB1 gene [100,101]. Most patients have increased copy numbers of the allele encoding alpha tryptase, but duplications of the allele encoding beta tryptase have also been described [102]. In studies of patients with HaT who had been referred to allergy clinics, there was a high incidence of severe anaphylaxis due to Hymenoptera insect stings or unknown causes, suggesting that the presence of HaT may augment the severity of allergic reactions [103-105]. HaT can also coexist with SM, and the presence of maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP) does not exclude concomitant HaT [69,106]. In a study of 180 mastocytosis patients, 17 percent had concomitant HaT [106]. Genetic testing for HaT is discussed in more detail separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Hereditary alpha tryptasemia'.)

Disorders with similar bone marrow manifestations — A few disorders have increased and/or aberrantly shaped mast cells in the bone marrow, similar to those observed in patients with SM. These include myeloproliferative disorders, especially chronic eosinophilic leukemia, primary myelofibrosis, and reactive mastocytosis, which are distinguished from mastocytosis by differences on bone marrow biopsy as well as the presence or absence of characteristic clinical and laboratory features.

Chronic eosinophilic leukemia or myeloproliferative variant of hypereosinophilic syndrome – These disorders are characterized by a modest elevation in serum tryptase and atypical spindle-shaped mast cells expressing surface CD25. However, molecular diagnostic studies reveal the presence of abnormalities in the genes for Fip1-like1 (FIP1L1) and platelet-derived growth factor receptor alpha (PDGFRA), instead of a D816V KIT mutation. The typical patient is a male without MPCM/UP skin lesions and with a hypercellular (myeloproliferative) bone marrow with elevated serum vitamin B12 levels. This is a stem cell disorder affecting multiple hematopoietic lineages, including the mast cell, but the clinical disease manifestations are due to eosinophil-related pathology rather than increased mast cells. Some patients may meet the diagnostic criteria of both disorders (SM associated with chronic eosinophilic leukemia). These patients respond well to imatinib, whereas patients with typical mastocytosis and D816V KIT mutations do not. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis" and "Hypereosinophilic syndromes: Treatment".)

Primary myelofibrosis – Bone marrow biopsy in patients with primary myelofibrosis typically reveals extensive fibrosis, which may be accompanied by spindle-shaped mast cells. These findings can also be observed with mastocytosis in the setting of extensive mast cell infiltration. However, the mast cell increase in myelofibrosis is usually diffuse and interstitial rather than forming clusters. Also, mast cells in myelofibrosis lack pathologic CD25 expression and the KIT D816V mutation. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

Reactive mastocytosis – Reactive mastocytosis in tissues and bone marrow can be seen in patients with solid tumors, such as breast cancer, Hodgkin lymphoma, and in diseases variably associated with increased expression of stem cell factor (eg, aplastic anemia and some hematologic, soft tissue, and gastrointestinal neoplasms). Reactive mast cells generally have a mature appearance (round in shape and fully granulated) and lack significant clustering, aberrant surface expression of CD2 and CD25, or KIT mutations.

Disorders with similar skin biopsy findings — Increased mast cell numbers can be found in other inflammatory and neoplastic conditions of the skin, such as dermatofibromas, psoriasis, atopic dermatitis, and nevi. However, these disorders are also associated with additional characteristic pathologic changes in the skin that differ from those of mastocytosis.

Extracutaneous mastocytomas — Benign mast cell tumors (mastocytomas) are rare. These lesions can cause excessive symptoms of mediator release and are usually cured with surgical excision alone.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mast cell disorders".)

SUMMARY AND RECOMMENDATIONS

Epidemiology and pathogenesis – Mastocytosis describes a group of rare disorders in which pathologic mast cells accumulate in tissues. These diseases can be limited to the skin (cutaneous mastocytosis [CM]) or involve extracutaneous tissues (systemic mastocytosis [SM]). Patients who develop symptoms during adulthood usually have systemic disease, but it is difficult to distinguish CM from SM on clinical grounds, because both disorders can have the same skin lesions, systemic symptoms, and complications. The molecular pathogenesis of mastocytosis is incompletely understood, although mutations in the gene for the receptor tyrosine kinase KIT (CD117), the receptor for stem cell factor, are identifiable in most patients. Stem cell factor is critical for the growth, differentiation, and activation of mast cells, and mutated KIT may lead to constitutive activation of mast cells and accumulation in tissues. (See 'Pathogenesis' above.)

Characteristic presentations – Adults usually present with either skin lesions of maculopapular cutaneous mastocytosis, previously called urticaria pigmentosa (MPCM/UP) (picture 1A-B), or episodic signs and symptoms of mast cell-mediator release without skin lesions (table 4). Another presentation is severe or recurrent hypotensive anaphylaxis in response to Hymenoptera stings (eg, bee, wasp, hornet, etc), medications, and other triggers (table 5). (See 'Characteristic presentations' above.)

Initial evaluation – Initial evaluation involves laboratory studies to detect systemic involvement and/or organ infiltration, and a serum total tryptase level, which is usually normal in CM and elevated (>20 ng/mL) in SM. If there is uncertainty about the skin lesions, skin biopsy should be performed. A test to detect mutations in KIT can be obtained on a sample of peripheral blood, although this is not always available. (See 'Laboratory studies' above.)

Referral – In most cases, referral to an allergy/immunology, dermatology, or hematology expert with knowledge of mast cell disorders will be needed for definitive diagnosis. (See 'Referral' above.)

Bone marrow evaluation – Bone marrow biopsy and aspiration are indicated in adult patients with MPCM/UP, an elevated serum tryptase level, or signs and symptoms of systemic involvement (algorithm 1 and algorithm 2). Most adult patients require bone marrow evaluation. Bone marrow sections should be stained for tryptase, CD117 and CD25, and aspirate analyzed for D816V KIT mutation (algorithm 3). (See 'Bone marrow examination' above.)

Diagnosis – Diagnostic criteria have been established (table 1).

In CM, laboratory studies are typically normal, the bone marrow is normal, and the diagnosis is confirmed by skin biopsy findings. (See 'Cutaneous mastocytosis' above.)

In SM, abnormalities include a persistently elevated total tryptase (>20 ng/mL), characteristic bone marrow findings, and variable other findings of systemic involvement (algorithm 3). The diagnosis of SM requires either the presence of the major criterion and one of the minor criteria, or three of the minor criteria (in the absence of the major criterion) (table 1). (See 'Systemic mastocytosis' above.)

Differential diagnosis – The differential diagnosis of mastocytosis is broad. An important disorder to exclude is hereditary alpha tryptasemia, which is significantly more common than mastocytosis and can also coexist with mastocytosis. Disorders that can mimic mastocytosis may be divided into those with similar clinical manifestations, those with similar bone marrow findings, and other causes of elevated tryptase. (See 'Differential diagnosis' above.)

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  74. In the United States, testing is available through Quest Diagnostics (CPT code 81402) and Mayo Clinic Laboratories (Test code KITB).
  75. In the United States, testing is available through Quest Diagnostics (CPT code 82402) and Mayo Clinic Laboratories. (Accessed on November 02, 2015).
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  77. Some centers with extensive experience in the United States include Brigham and Women's Hospital, the National Institutes of Health (NIH), Mayo Clinic, and MD Anderson Cancer Center.
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  94. Akin C, Fumo G, Yavuz AS, et al. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood 2004; 103:3222.
  95. Álvarez-Twose I, Jara-Acevedo M, Morgado JM, et al. Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. J Allergy Clin Immunol 2016; 137:168.
  96. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: Proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126:1099.
  97. Valent P, Akin C, Arock M, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012; 157:215.
  98. The laboratory can be contacted at (804) 828-9685.
  99. Sperr WR, El-Samahi A, Kundi M, et al. Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematology. Eur J Clin Invest 2009; 39:914.
  100. Lyons JJ, Yu X, Hughes JD, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet 2016; 48:1564.
  101. Robey RC, Wilcock A, Bonin H, et al. Hereditary Alpha-Tryptasemia: UK Prevalence and Variability in Disease Expression. J Allergy Clin Immunol Pract 2020; 8:3549.
  102. Chollet M, Kovalski A, Akin C. A novel case of beta-tryptase/TPSB2 allele duplication [Abstract 431]. J Allergy Clin Immunol 2020; 147:AB135.
  103. Chollet MB, Akin C. Hereditary alpha tryptasemia is not associated with specific clinical phenotypes. J Allergy Clin Immunol 2022; 149:728.
  104. Wu R, Lyons JJ. Hereditary Alpha-Tryptasemia: a Commonly Inherited Modifier of Anaphylaxis. Curr Allergy Asthma Rep 2021; 21:33.
  105. Giannetti MP, Weller E, Bormans C, et al. Hereditary alpha-tryptasemia in 101 patients with mast cell activation-related symptomatology including anaphylaxis. Ann Allergy Asthma Immunol 2021; 126:655.
  106. Greiner G, Sprinzl B, Górska A, et al. Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis. Blood 2021; 137:238.
Topic 4784 Version 27.0

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