INTRODUCTION  — Mastocytosis refers to a group of disorders characterized by excessive mast cell accumulation in one or multiple tissues. Mastocytosis is subdivided into two groups of disorders [ 1,2 ]:

• Cutaneous mastocytosis (CM) describes forms of mastocytosis that are limited to the skin.
• Systemic mastocytosis (SM) describes forms of mastocytosis in which mast cells infiltrate extracutaneous organs, with or without skin involvement.

The epidemiology, pathogenesis, classification, and clinical manifestations of cutaneous and systemic mastocytosis will be reviewed here. The evaluation, diagnosis, treatment, and prognosis of mastocytosis are discussed separately. (See«Evaluation and diagnosis of mastocytosis (cutaneous and systemic)» and «Treatment and prognosis of systemic mastocytosis» .)

EPIDEMIOLOGY  — Mastocytosis, in all its forms, is a rare disorder; the exact incidence is unknown. Mastocytosis affects males and females in equal ratios.

• In children, 80 percent of mastocytosis cases appear during the first year of life, and the majority is limited to the skin. Most eventually improve or resolve completely by adolescence [ 3-5 ].
• Adults who develop mastocytosis more often have systemic forms of the disease, and these disorders tend to persist [ 6 ].

PATHOGENESIS  — 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 (TNF) ( table 1 ). The signs and symptoms associated with sudden and extensive mast cell mediator release are those associated with allergic and anaphylactic reactions. (See «Mast cell derived mediators» .)

The clinical features of mastocytosis result from both chronic and episodic mast cell mediator release. In addition, 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 non-mast cell clonal hematologic disease.

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 c-kit (CD 117 or c-kit receptor). Many of the molecular defects associated with mastocytosis involve gain of function mutations in KIT, the gene encoding the c-kit receptor. There are limited data that SCF overexpression may play a role in some cases.

Most other hematopoietic cells express c-kit receptor early in their development and then lose it during maturation, becoming unresponsive to SCF. Only mast cells maintain c-kit receptor and remain responsive to SCF throughout the lifetime of the cell. Thus, abnormalities in SCF regulation or c-kit receptor permanently 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 and systemic mastocytosis [ 1,7-9 ]. The precise mechanism by which KIT activating mutations enhance signaling is not fully characterized, but these defects lead to SCF-independent activation [ 10 ]. Clonal expansion and apoptotic defects of KIT mutated mast cells are thought to provide the basis for pathologic accumulation of mast cells in tissues [ 11 ].

Several KIT mutations have been reported:

• The most common mutation detected in human mast cell disease occurs in the codon 816 and consists of the substitution of valine for aspartate (Asp816Val). Asp816Val is present in most patients with systemic mastocytosis and in some patients with different forms of cutaneous mastocytosis [ 12-16 ]. This mutation results in a putative activating loop in the kinase domain. In transfection studies, it causes ligand-independent autophosphorylation of the c-kit receptor and induces constitutive activation of the Stat5-PI3K-Akt signaling cascade [ 17 ]. Mast cell signal transduction is reviewed separately. (See «Mast cells: Surface receptors and signal transduction», section on ‘Signal transduction’ .)
• Another mutation found in a neoplastic mast cell line (HMC-1) is rare in human disease. It is located at codon 560, in the so-called juxtamembrane domain between transmembrane and intracellular kinase domains. This mutation results in the loss of helical structure, and also induces constitutive activation of c-kit kinase [ 8,18 ].
• Other rare KIT mutations have been reported in mastocytosis [ 9 ]. Non-activating mutations have been reported in some children with cutaneous mastocytosis.

KIT mutations are somatic mutations in most cases [ 16,19 ]; 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 [ 20 ]. Rare familial cases have been reported [ 21 ], but it is not clear if all of these patients had KIT mutations [ 22,23 ]. Ten pairs of monozygotic twins have been described in whom symptoms and onset of disease were concordant, although several other reports describe twins with discordant disease [ 24 ]. Thus, although mastocytosis may be present at birth, it is neither inherited nor passed down to offspring in the great majority of patients.

Increased expression of stem cell factor  — Increased expression of SCF, the ligand for c-kit receptor, has been linked to mastocytosis lesions in the skin [ 25 ]. SCF was found free in the dermis and the extracellular spaces between keratinocytes in skin samples of adults and children with cutaneous forms of mastocytosis, suggesting the increased presence of soluble SCF. Local mast cell hyperplasia was linked to increased free SCF. In these cases, there was no elevation of SCF in the peripheral blood and the mRNA sequence was not mutated [ 25 ]. Another study demonstrated no differences in SCF levels in peripheral blood and skin [ 26 ], so this abnormality appears to be variable.

In other studies of patients with systemic mastocytosis, increased mast cell numbers could be attributable to autocrine secretion of SCF by mast cells [ 27,28 ]. SCF was bound to highly immature non-metachromatic mast cells in the peripheral blood. Membrane–bound SCF was also demonstrated in mature spleen and skin mast cells, as well as in bone marrow mast cells [ 28 ].

Other factors  — 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 systemic mastocytosis [29 ]. Unregulated expression of Hsp32 has also been implicated in chronic myeloid leukemia [ 30 ]. Mutations in TET2, a tumor suppressor gene, have been identified in about one-third of patients with systemic mastocytosis, although there was no correlation between these mutations and subtype of disease or prognosis [ 31 ]. Elevated levels of soluble interleukin (IL)-5 receptor α have also been noted, raising the possibility that new therapeutics targeting this molecule may be useful in the future [ 32 ].

CLASSIFICATION SYSTEMS  — A consensus clinical classification was published by the World Health Organization (WHO) in 2001 and updated in 2008, which represents the currently accepted clinical approach to categorizing mastocytosis [ 33-35 ].

Cutaneous mastocytosis  — Cutaneous mastocytosis (CM) describes forms of mastocytosis limited to the skin, in the absence of involvement of other organs. Skin lesions in cutaneous mastocytosis may be subdivided into subtypes:

• Urticaria pigmentosa (UP), also called maculopapular cutaneous mastocytosis, is the most commonly diagnosed form of CM. There are several subtypes of UP:

• Typical UP ( picture 1 )
• Plaque form ( picture 2 )
• Nodular form

• Telangiectasia macularis eruptiva perstans (TMEP) ( picture 3 and picture 4 and picture 5 ).

UP and TMEP represent forms of cutaneous mastocytosis when identified in isolation; however, they may also be found in patients with systemic mastocytosis.

• Diffuse cutaneous mastocytosis (DCM) is rare ( picture 6 ). Bullous forms have been reported ( picture 7 and picture 8 ).
• Solitary mastocytoma(s) of the skin is typically identified in infants and young children ( picture 9 and picture 10 ).

Systemic mastocytosis  — Systemic mastocytosis (SM) is defined as involvement of an extracutaneous site, most commonly the bone marrow, and includes four distinct disorders:

• Indolent systemic mastocytosis (ISM), is the most common form of systemic mastocytosis. As implied by the name, ISM follows a stable or slowly progressing clinical course and carries a good prognosis in most patients. Two rarer provisional subvariants are also classified under ISM:

• Smoldering systemic mastocytosis (SSM): This describes patients with a high mast cell burden as evidenced by involvement of >30 percent of the bone marrow space with mast cells and high tryptase levels >200 ng/mL, liver or spleen enlargement without signs of hypersplenism or functional liver impairment, and subtle signs of myelodysplasia or myeloproliferation without overt diagnostic findings for myelodysplastic syndrome or myeloproliferative disorder.
• Isolated bone marrow mastocytosis (BMM): This describes patients with bone marrow involvement but without skin involvement.

• Systemic mastocytosis with an associated hematologic non-mast cell lineage disorder (SM-AHNMD): The associated disorder may be myeloproliferative, myelodysplastic, or lymphoproliferative.
• Aggressive systemic mastocytosis (ASM): Patients with ASM have tissue dysfunction such as hepatic fibrosis and portal hypertension, malabsorption, or cytopenias due to aggressive tissue infiltration by mast cells.
• Mast cell leukemia (MCL): This is a rare category of SM characterized by presence of greater than 10 percent immature mast cells in the peripheral blood or greater than 20 percent immature mast cells in bone marrow smears in a nonspicular area.

Solid mast cell tumors  — There are two types of solid mast cell tumors, which are rare and are not categorized as either cutaneous or systemic mastocytosis:

• Mast cell sarcoma (MCS): These malignant tumors have been reported in the tibia, skull, and other bones [ 36,37 ].
• Extracutaneous mastocytoma: These benign tumors are composed of mature mast cells and are located in a tissue other than skin, such as the lung or skull, sometimes in older-aged patients [ 38,39 ].

CLINICAL FEATURES  — Signs and symptoms of mastocytosis may be grouped as follows:

• 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).
• Symptoms arising from (non-cutaneous) organ infiltration (which are only present in systemic forms of mastocytosis).

Darier’s sign  — Darier’s sign is defined as the development of urticaria and erythema (within about five minutes) of rubbing, scratching, or stroking skin or skin lesions that are heavily infiltrated with mast cells [ 40 ]. This finding arises when physical irritation triggers the localized release of mast cell mediators. Darier’s sign is present in various forms of mastocytosis involving the skin, including UP, diffuse cutaneous mastocytosis, and mastocytomas (although the latter should not be purposefully rubbed, as this can precipitate symptoms).

Skin findings and symptoms  — Accumulations of mast cells in the skin may present as urticaria pigmentosa (eg, maculopapular CM), diffuse cutaneous mastocytosis, or cutaneous mastocytoma, as mentioned previously [ 40,41 ]. The most common complaint is pruritus, especially after exposure to a trigger such as physical irritation or heat [ 22 ]. Patients and caregivers may also report flushing or blister formation. Urticaria is uncommon and recurrent prominent urticaria should prompt consideration of other allergic disorders.

Urticaria pigmentosa  — Urticaria pigmentosa (UP) is the most common manifestation of mastocytosis in children and adults [ 42 ]. Lesions of UP are characterized by small yellow-tan to reddish–brown macules or slightly raised papules ( picture 1 ). Nodules or plaque-like lesions may also occur ( picture 2 ). The upper and lower extremities are most commonly affected, followed by the thorax and abdomen. In adults, the palms, soles, face, scalp, and other sun exposed areas generally remain free of lesions. In children, the face and scalp may be involved.

Pruritus associated with urticaria pigmentosa may be exacerbated by changes in temperature, exercise, hot showers, local friction, ingestion of hot beverages, spicy food, ethanol, emotional stress, or certain drugs. Bullous eruptions with hemorrhage can also occur in children, a feature that is shared with diffuse cutaneous mastocytosis.

As stated previously, UP can represent a form of cutaneous mastocytosis, or may be a cutaneous manifestation in patients with systemic mastocytosis. In those with systemic disease, UP is more typical of the less aggressive forms. Specifically, UP is found in over 90 percent of patients with systemic indolent mastocytosis, but in less than 50 percent of those with mastocytosis associated with a hematologic disorder (SM-AHNMD) or with ASM [ 40 ].

Various KIT mutations have been identified in patients with UP, none of which predict an association with systemic disease. The Asp816Val mutation has been found in skin mast cells of adult patients with UP, and in some affected children [ 15,43 ]. (See ‘Mutations in KIT’ above.)

• Telangiectasia macularis eruptiva perstans — Telangiectasia macularis eruptiva perstans (TMEP) is the least frequent form of cutaneous mastocytosis, accounting for less than 1 percent of cases. It occurs mainly in adults and is characterized by tan to brown macules with telangiectasias ( picture 3 and picture 4 and picture 5 ) [ 44 ]. There is an increase in the mast cells around capillaries and venules of the superficial vascular plexus. Pruritus and blisters are not seen. Rarely, it is associated with systemic involvement.

  The diagnosis of TMEP should NOT be based on the findings in a skin biopsy alone without observation of the physical lesion, as mast cells can be found around blood vessels in healthy or inflamed skin.

Mastocytomas of the skin  — Solitary or multiple mastocytomas of the skin are less common than UP and usually present in childhood ( picture 9 and picture 10 ). Spontaneous involution is frequently observed.

Lesions are similar in quality to those of urticaria pigmentosa, but can be larger (up to several centimeters) [ 45 ]. Some mastocytomas have a yellow to orange coloration [ 41 ]. Bullae may be present, with typical localization in the extremities. Flushing may also occur, particularly after physical irritation of the tumor, so lesions should NOT be vigorously rubbed. Instead, the patient or caregiver can usually provide the history that flushing occurs if the lesions are disturbed.

Diffuse cutaneous mastocytosis  — Diffuse cutaneous mastocytosis is the result of a diffuse mast cell infiltration in the dermis. Discrete lesions are not described. The skin appears either normal in color or possibly yellowish-brown, with increased thickness ( picture 6 ). Involvement of the whole skin has been observed.

• Bullous eruptions — Bullous eruptions with hemorrhage can occur in patients with diffuse cutaneous mastocytosis and urticaria pigmentosa ( picture 7 and picture 8 ). Eruptions can be spontaneous or triggered by infections or vaccinations. Blister fluid contains histamine, prostaglandins, and platelet activating factor. Blisters can be present at birth, and cutaneous mastocytosis should be considered in the differential of neonatal blistering disorders [ 46 ]. (See «Vesiculobullous and pustular lesions in the newborn» .)

Symptoms arising from mediator release  — Mast cell mediators induce vasodilation, hypotension, flushing, pruritus, syncope, abdominal pain, nausea, vomiting, diarrhea, fatigue, headache, cachexia, local anticoagulation, and/ortissue remodeling and fibrosis ( table 1 ) [ 47,48 ].

In patients with either CM or SM, release of mast cell mediators may occur in explosive episodes, presenting as apparent «allergic» reactions and anaphylaxis, or on a chronic basis, giving rise to problems such as chronic gastrointestinal complaints.

Triggers for mediator release  — The release of mast cell mediators in patients with cutaneous and systemic mastocytosis may be precipitated by a variety of stimuli, although not all triggers cause mast cell degranulation in all patients. A careful history is often helpful in determining what can or cannot be tolerated by individual patients. Potential triggers include the following ( table 2 ) [ 49-54 ]:

• Medications, including narcotics, opioids, NSAIDs, iodinated contrast agents, vancomycin and other antibiotics, and muscle relaxants used in anesthesia
• Physical factors, such as exercise, massage or friction applied to the skin, extremes of temperature, sudden temperature changes, and very spicy foods
• Surgical procedures or instrumentation (including biopsies or endoscopy)
• Alcohol ingestion
• Infections, including viral, bacterial, and parasitic
• Emotional stress
• Hymenoptera stings, either through non-allergic or IgE-mediated allergic mechanisms (see ‘Concomitant allergic disease’ below)
• Toxic exposures, such as stings of jellyfish, snake bites, etc

Anaphylaxis  — Anaphylaxis can be observed in both cutaneous and systemic mastocytosis. Symptoms typically include flushing, syncope, gastrointestinal symptoms, and vascular collapse. Urticaria and angioedema occur less frequently [ 55 ]. These reactions may result from either IgE-mediated allergy or non-specific activation of mast cells.

• A subset of patients with recurrent anaphylaxis, but without mastocytosis, has been reported to carry clonal markers of mast cell disease including D816V KIT mutation [ 56 ].
• Anaphylaxis without identified IgE-mediated allergies appears to be particularly prevalent in males with indolent systemic mastocytosis [ 57 ].
• Systemic anaphylaxis to insect stings with negative skin and in vitro tests for venom-specific immunoglobulin E (IgE) has been described, and fatalities have been reported [ 58,59 ]. (See «Fatal anaphylaxis» and «Treatment and prognosis of systemic mastocytosis» .)

Gastrointestinal complaints  — Gastrointestinal dysfunction caused by release of mast cell mediators can be observed in both cutaneous and systemic mastocytosis [ 60 ]. Gastrointestinal symptoms can be precipitated by the same triggers that cause systemic symptoms ( table 2 ). Signs and symptoms include abdominal pain, diarrhea, nausea, vomiting, peptic ulcer disease, and gastrointestinal bleeding.

Abdominal pain and diarrhea were reported in up to 80 percent of patients with systemic mastocytosis, with duodenal ulceration and severe duodenitis in 30 to 50 percent of untreated cases [ 61 ].

Histamine and other mediators, released from local and distant mast cells, increase gastric acid secretion. Serum histamine concentrations may be elevated, particularly in the setting of ulcer disease, suggesting that circulating histamine contributes to basal acid hypersecretion [ 60,61 ].

Diarrhea can result from increased motility induced by prostaglandin D2 (PGD2) secretion or from decreased rectal compliance and overactive rectal contractility.

Neuropsychiatric symptoms  — Neuropsychiatric manifestations, including depression, mood changes, lack of concentration, increased somnolence, irritability, and emotional instability, are frequently observed in patients with mastocytosis [ 49,62 ]. These symptoms are sometimes referred to as «mixed organic brain syndrome.» These are typically ignored or undertreated before the diagnosis of mastocytosis is established. The precise cause of many of these manifestations is not known, although PGD2 is thought to increase somnolence.

Musculoskeletal symptoms  — Diffuse musculoskeletal pain of the long bones and a pain syndrome resembling fibromyalgia may be reported in patients with systemic mastocytosis.

Osteopenia and osteoporosis  — A subset of patients appears to be at increased risk of developing osteopenia and osteoporosis [ 63-65 ]. This can be observed even in young adult men [ 66,67 ]. Osteoporosis is fairly common in patients with indolent systemic mastocytosis (ISM) and may be due to effects of mast cell mediators such as histamine, tryptase, heparin and cytokines (TNF, IL-6, TGF-beta) on bone turnover [ 68,69 ]. A bone densitometry is recommended to evaluate for osteoporosis in all patients with systemic mastocytosis.

Patients with SM may also experience bone pain or fractures, especially of the vertebrae. Nerve damage can follow vertebral compression fractures, even in patients with ISM. Evaluation of these symptoms can reveal osteolytic, osteosclerotic, and/or osteopenic lesions [ 70,71 ]. These presentations may be confused with metastatic malignancy. Skeletal scintigraphy and bone survey may be helpful in characterizing the extent of disease in selected patients [ 72]. The long bones and vertebrae are commonly affected.

Concomitant allergic disease  — Patients with mastocytosis may have concomitant IgE-mediated allergic diseases, including allergic rhinitis, food and drug allergies, and Hymenoptera allergy [ 73,74 ]. They may also have asthma. The prevalence of allergic disorders in patients with mastocytosis (both cutaneous and systemic) appears to be similar to that of the general population (ie, between 20 and 30 percent in westernized nations) [ 57,73,74 ]. Total IgE levels are usually decreased in patients with mastocytosis, possibly due to binding to an increased number of mast cells [ 74 ].

Patients with mastocytosis are more susceptible to anaphylaxis during allergic reactions, particularly in response to Hymenoptera stings [ 75 ]. A prospective study found elevated baseline tryptase levels in 12 percent of patients with a history of systemic reactions to hymenoptera stings. Within this subset of patients with elevated baseline tryptase, 70 percent had anaphylactic reactions and 80 percent had diagnostic or subdiagnostic accumulations of aberrant mast cells in the bone marrow [ 76 ].

Symptoms arising from organ infiltration  — Infiltration and/or proliferation of mast cells in specific organs can be seen in some forms of systemic mastocytosis. Non-cutaneous organs are not involved in cutaneous mastocytosis. The organ systems most often affected are the bone marrow, gastrointestinal tract, lymph nodes, liver, spleen, skeletal system, and genitourinary tract with the following clinical manifestations [ 62,77,78 ]:

• Anemia and thrombocytopenia
• Hepatosplenomegaly, portal hypertension, and hypersplenism
• Malabsorption
• Lytic bone lesions and pathologic fractures

In contrast, the respiratory and endocrine systems are seldom involved in patients with systemic mastocytosis, although patients with SM may have concomitant asthma at rates similar to the general population. The incidence of bacterial, fungal, or viral infections is not increased and patients are not immunocompromised unless there is an associated hematologic disorder affecting other cell lines (ie, neutrophils).

Hematologic  — The most common hematologic abnormality is a mild to moderate anemia, which occurs in up to 50 percent of patients [ 79 ]. The etiology is probably multifactorial. Mast cells are not found in the circulation except in those with mast cell leukemia. In this disorder, greater than 10 percent or more of circulating nucleated cells may be mast cells.

Eosinophilia is found in 25 percent of patients. In some patients, eosinophils exhibit the same phenotype as those in the hypereosinophilic syndrome or chronic eosinophilic leukemia (CEL) (ie, hypogranular and hypersegmented nuclei). Some patients with mastocytosis may have associated CEL (a clonal disorder), while others may have a reactive eosinophilia, possibly due to cytokine release [ 80 ]. (See «Clinical manifestations, pathophysiology, and diagnosis of the hypereosinophilic syndromes», section on ‘Myeloproliferative HES variants’ .)

A monocytosis can be found in patients with ASM or ASM-AHNMD, and is found in approximately one-half of patients with advanced mastocytosis [ 81 ]. This may represent a sign of marrow dysplasia [ 31 ].

Myeloproliferative or myelodysplastic diseases are most commonly associated with SM-AHNMD, although lymphoproliferative diseases such as myeloma and lymphomas and secondary acute leukemias have also been reported. Most of these patients present with activating Asp816Val KIT mutations in the peripheral blood, indicating a multipotential hematopoietic clonal nature of the SM [ 13,20 ]. Rare cases of systemic mastocytosis associated with myeloproliferative disorders exhibiting both c-kit D816V and JAK2 V617F mutations have been reported. Among the disorders that have been reported in association with systemic mastocytosis are the following [ 82 ]:

• Chronic myelomonocytic leukemia (CMML)
• Myelodysplastic syndromes (MDS)
• Unclassifiable myeloproliferative neoplasms (MPD)
• Hypereosinophilic syndrome
• Chronic eosinophilic leukemia
• Acute myeloid leukemia (especially that associated with t(8:21)(q22:q22))
• Plasma cell myeloma
• Hairy cell leukemia
• Polycythemia vera
• Hodgkin’s and non-Hodgkin lymphoma
• Primary thrombocytopenia or thrombocythemia
• Chronic myeloid leukemia (CML)

Excessive bleeding, which has been reported in some patients, may be due to the high levels of heparin released from mast cells, and a prolonged bleeding time may be observed in skin areas infiltrated by mast cells [ 83-86 ]. Another proposed mechanism involves proteolytic disruption of fibrinogen by tryptase [ 87 ]. Malabsorption of vitamin K may also contribute to a systemic bleeding diathesis. Abnormal bleeding has been observed in children with diffuse cutaneous mastocytosis, with one reported death [ 88 ]. However, in the authors’ experience, most patients with mastocytosis have normal coagulation studies.

Intestinal tract  — Peptic ulcer disease, steatorrhea, malabsorption, and hepatomegaly may occur when mast cells infiltrate the intestine or liver in aggressive systemic mastocytosis (ASM) [ 27,89 ]. Liver function tests may be elevated. Liver biopsy demonstrates an increased number of mast cells with eosinophilic infiltrates and extramedullary hematopoiesis, which is more prominent in ASM, systemic mastocytosis with an associated hematologic non-mast cell lineage disorder (SM-AHNMD), and mast cell leukemia (MCL) [ 90 ]. Portal hypertension and ascites may develop in these advanced categories of disease.

Lymphoid tissues and spleen  — The lymph nodes and spleen are commonly infiltrated in all types of systemic mastocytosis [ 91 ].

• Central and peripheral lymphadenopathy are noted in 20 to 60 percent of patients with indolent systemic mastocytosis (ISM), and in a higher proportion in those with SM-AHNMD, ASM, and MCL [ 92 ].
• Splenomegaly is observed in 50 percent of patients with ISM, but in over 70 percent of those with SM-AHNMD, ASM, and MCL. A marked increased in weight (eg, 700 grams) may be seen. Hypersplenism (ie, nonimmune hemolytic anemia and other hematologic abnormalities) may cause hematologic abnormalities. Splenic enlargement can also cause left upper quadrant discomfort or external compression of other organs. (See «Extrinsic nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and hypersplenism» .)

SUMMARY AND RECOMMENDATIONS  — Mastocytosis comprises a group of rare disorders of excessive mast cell proliferation and accumulation, which can be limited to the skin (cutaneous mastocytosis, CM) or involve bone marrow and other extracutaneous tissues (systemic mastocytosis, SM). (See ‘Introduction’ above.)

• Children are usually affected by cutaneous forms of mastocytosis. Most improve or resolve completely by adolescence. In contrast, adults more often present with systemic forms of mastocytosis and have persistent disease. (See‘Epidemiology’ above.)
• Mast cell development is dependent upon stem cell factor and its receptor, c-kit. Activating mutations of KIT (the gene for the c-kit receptor protein) are strongly associated with both cutaneous and systemic forms of mastocytosis and thus have been implicated as the major contributor to the pathogenesis of mastocytosis. (See ‘Pathogenesis’ above.)
• Cutaneous mastocytosis is further divided into three subtypes: maculopapular or urticaria pigmentosa, diffuse cutaneous mastocytosis, and solitary mastocytoma of the skin. (See ‘Cutaneous mastocytosis’ above.)
• Systemic mastocytosis is divided into four distinct disorders: indolent systemic mastocytosis, systemic mastocytosis with an associated hematologic non-mast cell lineage disorder, aggressive systemic mastocytosis, and mast cell leukemia. (See ‘Systemic mastocytosis’ above.)
• The many signs and symptoms of mastocytosis may be categorized into skin findings, symptoms due to release of mast cell mediators ( table 1 ), and symptoms arising from mast cell infiltration of organs other than the skin. (See‘Clinical features’ above.)
• Accumulations of mast cells in the skin can take various forms. Pruritus is the predominant symptom. The most common skin finding is urticaria pigmentosa ( picture 1 ), which can be present in patients with either cutaneous or systemic mastocytosis. Other specific skin findings include solitary or multiple cutaneous mastocytomas ( picture 9 ), diffuse cutaneous mastocytosis ( picture 6 ), and telangiectasia macularis eruptiva perstans (TMEP) ( picture 5 ). (See ‘Skin findings and symptoms’ above.)
• In patients with both CM and SM, a variety of triggers can precipitate mast cell mediator release ( table 2 ). Release of mediators may occur in explosive episodes, presenting as apparent allergic reactions and anaphylaxis, or on a chronic basis, giving rise to problems such as chronic gastrointestinal complaints. (See ‘Symptoms arising from mediator release’ above.)
• Extracutaneous organ involvement is only present in systemic forms of mastocytosis. Depending on the organs involved, findings include steatorrhea, malabsorption, lymphadenopathy, splenomegaly, hematologic and liver abnormalities, and skeletal lesions. (See ‘Symptoms arising from organ infiltration’ above.)