Mastocytosis is a disorder characterized by mast cell proliferation and accumulation within various organs, most commonly the skin.
Cutaneous mastocytosis – Urticaria pigmentosa, maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis, mastocytoma of skin
Indolent systemic mastocytosis
Systemic mastocytosis with an associated (clonal) hematologic non–mast cell lineage disease
Aggressive systemic mastocytosis
Mast cell leukemia
Mast cell sarcoma
This article focuses on cutaneous mastocytosis (CM). The single World Health Organization (WHO) major criterion is multifocal dense infiltrates of mast cells in bone marrow and/or other extracutaneous organs. One major and 1 minor criterion or 3 minor diagnostic criteria are needed to establish a diagnosis of systemic mastocytosis. Minor criteria include baseline total tryptase level of greater than 20 ng/mL; greater than 25% of the mast cells in bone marrow aspirate smears or tissue biopsy sections having spindle atypical morphology; mast cells in bone marrow, blood, or other lesional tissue expressing CD25 or CD2; or detection of a codon 816 c-kit point mutation in blood, bone marrow, or lesional tissue. 
Types of cutaneous mastocytosis include solitary mastocytoma, diffuse erythrodermic mastocytosis, paucicellular mastocytosis (also termed telangiectasia macularis eruptiva perstans [TMEP]), and urticaria pigmentosa (UP). Urticaria pigmentosa is the most common form and is characterized by oval or round red-brown macules, papules, or plaques ranging in number from a few to thousands (see images below).
Lesions may vesiculate in infancy (see image below).
When a urticaria pigmentosa or mastocytoma lesion is stroked, it typically urticates, becoming pruritic, edematous, and erythematous. This change is referred to as the Darier sign, which is explainable on the basis of mast cell degranulation induced by physical stimulation. Uncontrolled stroking of mastocytomas should be avoided in patients who have had a systemic reaction such as miosis and asthmalike symptoms in their past.  The Darier sign usually is not positive in patients with TMEP because the lesions are paucicellular, and, therefore, mast cells may not be present in sufficient numbers for significant degranulation to occur. See the images below.
Mastocytosis is now classified with the myeloproliferative neoplasms.  Increased local concentrations of soluble mast cell growth factor in lesions of cutaneous mastocytosis are believed to stimulate mast cell proliferation, melanocyte proliferation, and melanin pigment production. The induction of melanocytes explains the hyperpigmentation that commonly is associated with cutaneous mast cell lesions. The stimulation of pruritus seen in mastocytosis is associated with the production of interleukin (IL)–31.  Impaired mast cell apoptosis has been postulated to be involved, as evidenced by up-regulation of the apoptosis-preventing protein BCL-2 demonstrated in patients with mastocytosis.  Activating mutations of the proto-oncogene c-kit have been identified but do not explain the initiation of the disease.  IL-6 levels have been shown to be elevated and correlated with disease severity, indicating interleukin 6 is involved in the pathophysiology of mastocytosis. 
Although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with D816V and other activating c-kit mutations. 
Research from 2016 has shown that there are varied gene expressions in patients with mastocytosis and associated allergies. Those with associated food allergies have an elevated expression of the TRAF4 gene.  In the same study, patients who had an allergy to insect venom had a decreased gene expression of B3GAT1.
Associated systemic manifestations are believed to reflect the release of mast cell–derived mediators, such as histamine, prostaglandins, heparin, neutral proteases, and acid hydrolases. Symptoms and signs induced by mediators may include headache, neuropsychiatric symptoms (cognitive disorganization), flushing, dizziness, tachycardia, hypotension, syncope, anorexia, nausea, vomiting, abdominal pain, and diarrhea. The skeletal, hematopoietic, gastrointestinal (GI), cardiopulmonary, and central nervous systems may be involved either directly, via mast cell infiltration, or indirectly, via mast cell mediator release.
Of new patients visiting dermatology clinics, 0.1-0.8% have some form of mastocytosis. Maculopapular cutaneous mastocytosis is the most common subgroup found in children, at approximately 47-75% of cases. There are approximately 17-51% of mastocytoma and 1-5% of diffuse cutaneous mastocytoma in pediatric cases as well. 
Most reported cases are in whites. The cutaneous lesions of most types of mastocytosis are less visible in persons with more heavily pigmented skin.
Mastocytosis affects males and females equally (no known sex predilection).
Most patients with mastocytosis are children; 75% of cases occur during infancy or early childhood and usually resolve by puberty. Mastocytosis incidence peaks again in patients aged 30-49 years.
The prognosis depends on the age of onset. Most patients with urticaria pigmentosa (UP) exhibit onset before age 2 years, which is associated with an excellent prognosis, often with resolution by puberty. The number of lesions diminishes by approximately 10% per year. However, acute extensive degranulation rarely can cause life-threatening episodes of shock.
Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis. Serum baseline total tryptase to predict the need for daily antimediator therapy, hospitalization, and episodic management in an ICU were 6.6, 15.5, and 30.8 μg/L, respectively. 
Slight improvement of skin symptoms, reflected by decrease of SCORing MAstocytosis Index, with decline in serum tryptase levels is the typical course in patients with diffuse cutaneous mastocytosis.  Systemic mastocytosis may occur more frequently in diffuse cutaneous mastocytosis patients.  Patients with adult or adolescent-onset urticaria pigmentosa are more likely to have persistent disease and are at greater risk for systemic involvement. Juvenile-onset systemic mastocytosis has a malignant transformation rate as high as 7%, whereas adult-onset systemic mastocytosis has a malignant transformation rate as high as 30%.
Rarely, mast cell leukemia may develop in young adults with persistent maculopapular cutaneous mastocytosis. 
Primary cutaneous mast cell sarcoma due to the transformation of a benign solitary mastocytoma in an adult has been reported. 
Cutaneous mastocytosis onset after age 10 years portends a poorer prognosis, because late-onset disease tends to be persistent, is associated more often with systemic disease, and carries a higher risk of malignant transformation.
In patients with systemic mastocytosis, regression of urticaria pigmentosa is associated with a decreased frequency and severity of other symptoms. Bone marrow findings do not change with regression of urticaria pigmentosa.
One study shows that anaphylaxis is common in patients with mastocytosis (4.3-5.5% per year disease duration) and appears higher than in the healthy population. In childhood, the risk of anaphylactic episodes has been shown to be limited to those with extensive blistering skin disease, but nonexistent for children with mastocytoma or limited disease. In adults, anaphylactic episodes generally appear to be more severe in patients with extensive systemic disease. 
Instruct cutaneous mastocytosis patients about avoiding physical stimuli and substances that trigger the condition. Additionally, educate patients and/or parents about the signs and treatment of anaphylaxis, especially in patients with systemic disease or severe symptoms.
Advise mastocytosis patients with systemic disease or extensive symptoms to wear a medical alert bracelet and carry injectable epinephrine in case of an acute event causing mast cell degranulation and subsequent shock. Adults have been reported with severe anaphylaxis after insect stings, especially hymenoptera stings. 
Mastocytosis patients may present with cutaneous lesions, systemic symptoms of an acute nature, and/or chronic systemic symptoms.
Most patients have pruritic cutaneous lesions. Some patients, especially those with extensive cutaneous disease, experience acute systemic symptoms exacerbated by certain activities or ingestion of certain drugs or foods. Possible systemic symptoms include flushing, headache, dyspnea, wheezing, rhinorrhea, nausea, vomiting, diarrhea, and syncope.
Patients also may have chronic systemic symptoms involving various organ systems. Involvement of the skeletal system may be manifested as bone pain or the new onset of a fracture. Long-term exposure to heparin and stem cell factor from degranulated mast cells is believed to put patients at risk for osteoporosis.  Involvement of the central nervous system may produce neuropsychiatric symptoms, as well as nonspecific changes such as malaise and irritability. GI involvement may yield weight loss, diarrhea, nausea/vomiting, and abdominal cramps. Cardiovascular effects can include shock, syncope (resulting from vascular dilatation), or angina. Anaphylactic reactions to hymenoptera stings may be the first sign of mastocytosis.
The most common physical findings in mastocytosis involve the skin, liver, spleen, and cardiovascular system.
Skin lesion types are as follows:
Macules, papules, nodules, and plaques (see image below)Lesion on the arm. Courtesy of Lee H. Grafton, MD.
Blisters and bullae in children (see image below)Blistering lesion.
Isolated nodule or tumor
Skin distribution findings are as follows:
Widespread symmetric distribution
Trunk involved more than extremities
Tendency to spare the face, scalp, palms, and soles; however, a patient with scarring alopecia has been reported 
Skin lesion color, quantity, and size findings are as follows:
Yellow-tan to red-brown
From 1 to more than 1000
From 1 mm to several centimeters
Skin special characteristics are as follows:
Darier sign: Wheal and surrounding erythema develop in a lesion after rubbing it.
Dermatographism: In approximately half the patients, stroking macroscopically uninvolved skin produces dermographia.
Flushing: Flushing may occur spontaneously following skin stroke or after ingesting a mast cell degranulating agent.
Diffuse cutaneous mastocytosis (DCM): This is rare and is characterized by mast cell infiltration of the entire skin.
Other: Large hemorrhagic bullous and infiltrative small vesicular variants occur. Blistering predominates in infancy, whereas grain-leather appearance of the skin and pseudoxanthomatous presentation develop with time. Anaphylactic shock may occur.
Liver findings include possible hepatomegaly, which is present in 40% of adult patients with systemic mastocytosis.
Spleen findings include possible splenomegaly, which is present in 50% of patients with systemic mastocytosis.
Cardiovascular findings include hypotension and tachycardia.
Gastrointestinal findings include abdominal pain, diarrhea, vomiting, and weight loss (frequency of involvement currently uncharacterized in patients with systemic mastocytosis). 
Mastocytosis probably is a hyperplastic response to an abnormal stimulus. Rare cases of familial urticaria pigmentosa have been recorded.  Rarer cases of cutaneous mastocytosis have been associated with radiotherapy fields in patients with breast cancer. 
One case report describes an apparent temporal association between the development of cutaneous mastocytosis and HIV seroconversion, proposing similarities of immunoglobulin E receptors on mast cells and basophils and the association of basophils in HIV pathophysiology. 
Autism spectrum disorders may be increased in children with mastocytosis. 
Complications may include the following:
Possible transformation into a hematologic malignancy
Death secondary to mast cell degranulation
Mast cell leukemia
Also consider the following:
Generalized eruptive histiocytoma
Non-X histiocytosis of childhood
Cafe Au Lait Spots
Congenital melanocytic nevus
Congenital smooth muscle hamartoma
Dermatologic Manifestations of Herpes Simplex
Linear IgA Dermatosis
Nodular Localized Cutaneous Amyloidosis
In many patients, urticaria pigmentosa (UP) can be diagnosed when history and physical examination findings reveal the characteristic lesions that demonstrate the Darier sign. Usually, a skin biopsy is a necessary confirmatory test, typically through a 3- or 4-mm punch biopsy. It may be helpful to complete two biopsies, one of the suspected lesion and the other of unaffected skin, in order to compare the presence of mast cells. For aid in the diagnosis, the following stains are recommended to be completed with biopsy: hematoxylin, eosin, toluidine blue, Giemsa, and monoclonal antibodies to tryptase, CD117 and KIT. 
Consider the following laboratory tests:
CBC count: In systemic mastocytosis, CBC counts may reveal anemia, thrombocytopenia, thrombocytosis, leukocytosis, and eosinophilia.
Plasma or urinary histamine level: Patients with extensive cutaneous lesions may have 24-hour urine histamine excretion at 2-3 times the normal level.
Total tryptase level: Tryptase is a marker of mast cell degranulation released in parallel with histamine. Total tryptase levels in plasma correlate with the density of mast cells in urticaria pigmentosa lesions in adults with systemic mastocytosis. Patients with only cutaneous mastocytosis typically have normal levels of total tryptase. Total tryptase values are recommended by the WHO as a minor criterion for use in the diagnostic evaluation of systemic mastocytosis. [1, 2, 29] The total tryptase level in serum or plasma seems to be a more discriminating biomarker than urinary methylhistamine for the diagnosis of systemic mastocytosis.  Most patients with systemic anaphylaxis of sufficient severity to result in hypotension have elevated serum or plasma beta-tryptase levels. During insect sting–induced anaphylactic hypotension, beta-tryptase levels in the circulation are maximal 15-120 minutes after the sting. 
WHO major criteria for the diagnosis of systemic mast cell disease include the following  :
Multifocal dense infiltrates of mast cells (>15 close to each other) observed in bone marrow biopsy specimens and/or mast cells stained for tryptase in biopsy specimens from other extracutaneous organs.
WHO minor major criteria for the diagnosis of systemic mast cell disease include the following  :
Mast cells in bone marrow, or other extracutaneous organs show abnormal (spindling) morphology (>25%) or the presence of greater than 25% atypical mast cells in bone marrow aspirates
Demonstration of c- kit point mutation on codon 816 in bone marrow, blood, or other extracutaneous organs
CD117 (c-kit receptor)–positive cells, also positive for CD2 and/or CD25
Serum tryptase values greater than 20 ng/mL 
Bone scan and radiologic survey
Obtain a bone scan and radiologic survey in nonpediatric patients or if the CBC count is abnormal in a young child. If a patient has skeletal system symptoms, perform a bone scan and radiologic survey to identify lytic bone lesions, osteoporosis, or osteosclerosis.
GI workup (upper GI series, small bowel radiography, CT scanning, endoscopy)
If a patient has GI symptoms, order a GI workup to identify peptic ulcers, abnormal mucosal patterns, or motility disturbances.
If a diagnosis of mastocytosis is uncertain, tests for elevated mast cell mediators and degradation products may help establish the diagnosis.
Serum tryptase level
Tryptase levels are elevated in patients with mastocytosis. Tryptase levels may be more useful than histamine levels, because histamine can be elevated in hypereosinophilic states.
Urinary N-methylhistamine (NMH) and N-methylimidazoleacetic acid levels
Urinary NMH and N-methylimidazoleacetic acid levels [30, 31] may be more specific and sensitive than urinary histamine levels. NMH levels correlate directly with the extent of skin lesions. NMH levels decrease with age; therefore, consider the patient’s age when interpreting results.
Urinary prostaglandin D2 metabolite level
Even during asymptomatic periods, urinary prostaglandin D2 metabolites levels may range from 1.5-150 times higher than normal levels. This test is not widely available.
Bone marrow biopsy and aspirate
Perform bone marrow biopsy and aspirate in patients with urticaria pigmentosa if they have peripheral blood test abnormalities, hepatomegaly, splenomegaly, or lymphadenopathy to determine if they have an associated hematologic disorder.
Inject an anesthetic agent without epinephrine adjacent to, not directly into, the lesion chosen as the biopsy specimen to avoid mast cell degranulation, which makes histologic examination difficult.
Examination reveals dermal mast cell infiltrates, especially in the papillary dermis around blood vessels (see image below).Hematoxylin and eosin stain revealing mast cells in the papillary dermis.
Diagnosis of urticaria pigmentosa may require demonstration of mast cell granules using Giemsa stain (see image below) or toluidine blue stain. The Leder stain is not dependent on intact mast cell granules.Giemsa stain revealing mast cells.
Mast cell nuclei are round with surrounding ample cytoplasm producing a “fried egg” appearance. The typical presentation of mast cells is a single nuclei, yet there have also been atypical histological findings reported in four patients with uriticaria pigmentosa that showed mast cells with bilobed and multilobed morphology.  In telangiectasia macularis eruptiva perstans (TMEP), mast cells are brick shaped or spindle shaped. In nodular urticaria pigmentosa, mast cells are observed in dense aggregates and may extend through the entire dermis and into subcutaneous tissue. If the lesion from which the biopsy specimen was taken was traumatized during harvest, edema and eosinophil infiltrates may be present. The hyperpigmentation of cutaneous mastocytosis is secondary to increased melanin in the basal cell layer and melanophages in the upper dermis.
Planar xanthoma has been described in association with mastocytomas.
Therapy is conservative and aimed at symptom relief because the prognosis for most patients with cutaneous mastocytosis (CM) is excellent. None of the currently available therapeutic measures induces permanent involution of cutaneous or visceral lesions. Advise patients to avoid agents that precipitate mediator release, such as aspirin, nonsteroidal anti-inflammatory drugs, codeine, morphine, alcohol, thiamine, quinine, opiates, gallamine, decamethonium, procaine, radiographic dyes, dextran, polymyxin B, scopolamine, and D-tubocurarine.
H1 and H2 antihistamines decrease pruritus, flushing, and GI symptoms. Oral disodium cromoglycate may ameliorate cutaneous symptoms, such as pruritus, whealing, and flushing, as well as systemic symptoms, such as diarrhea, abdominal pain, bone pain, and disorders of cognitive function.
Cautious administration of aspirin to inhibit prostaglandin synthesis and maintain mast cell degranulation may be beneficial for patients with disease resistant to H1 and H2 antagonist therapy alone. The patient, premedicated with H1 and H2 antihistamines, may be started on small doses of aspirin, slowly titrated to reach a plasma level of 20-30 mg/100 mL. Initiate this treatment regimen in a controlled environment, because aspirin can induce mast cell mediator release and subsequent cardiovascular collapse.
Cutaneous lesions that involve a limited body area may be treated with a potent class 1 topical corticosteroid, with occlusion if required. Intralesional injections of small amounts of dilute corticosteroids may resolve skin lesions temporarily or indefinitely. The risk of skin atrophy and adrenocortical suppression resulting from the treatment is minimized by treating limited body areas during a single treatment session. Systemic corticosteroids are useful only in specific situations, such as ascites, malabsorption, and severe skin disease. Case reports have described complete remission of bullous mastocytosis with oral corticosteroids,  but systemic therapy is often disappointing because the primary mode of action of corticosteroids is redistribution rather than death of mast cells.
Oral psoralen plus UV-A (PUVA) therapy results in general and cosmetic benefits in the treatment of cutaneous mastocytosis,  particularly telangiectasia macularis eruptiva perstans (TMEP); however, risks are involved, such as skin cancer if more than 200 treatments are required. The manifestations of the disease usually recur several months after discontinuation of PUVA, but recurrences respond as well as the original lesions. PUVA rarely is required in children. Currently, PUVA is reserved for severe, unresponsive cases in adults. In a 2003 study, medium-dose UV-A1 therapy was shown to be as effective as high-dose UV-A1 in reducing symptoms and the number of mast cells in affected skin.  Narrowband UV-B has also been used. 
Medical alert bracelets should be made available, and an epinephrine self-injector demonstration should be performed and self-injector prescribed for patients with systemic mastocytosis or patients with episodes of vascular collapse. Patients with recurrent episodes of vascular collapse may be prophylactically placed on H1 and H2 antihistamines to lessen the severity of attacks. Episodes of vascular collapse may be spontaneous but have also occurred after stings from insects or after administration of iodinated contrast media for imaging studies. Premedication with antihistamines and corticosteroids is recommended before such procedures in patients at risk.
General anesthesia may be problematic in patients with systemic mastocytosis and perioperative modalities of these patients need to be considered.  The treatment algorithm for systemic mastocytosis is complex, and the condition is primarily managed by a hematologist. [37, 38]
Patients with aggressive systemic mastocytosis have disease-related organ dysfunction; interferon-alfa (with or without corticosteroids) can control dermatological, hematological, GI, skeletal, and mediator-release symptoms, but may be poorly tolerated. Cladribine has broad therapeutic activity, particularly when rapid debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in patients with unmutated KITD816. 
Future novel therapy for cutaneous mastocytosis includes immune modulators. One successful case report from 2008 described treatment of progressive c-kit mutation cutaneous mastocytosis with imatinib, halting disease symptoms and progression and improving the length of disease course.  Imatinib is approved by the Food and Drug Administration for use in patients with aggressive systemic mastocytosis with organ dysfunction due to progressive infiltration of various organs by mast cells without D816V c-kit mutation or unknown c-kit mutation status. 
Masitinib may be superior to sunitinib as second-line therapy for patients who are imatinib resistant with systemic or severe cutaneous mastocytosis. 
Pimecrolimus and other calcineurin inhibitors may be another potential therapy for mastocytosis and other mast cell-associated diseases. 
Emergency resuscitation or hospitalization may be required for severe syncope or hypotensive shock resulting from the sudden severe degranulation of many mast cells.
Consultation with a hematologist may be necessary for a bone marrow biopsy and staging. The WHO classification of systemic mastocytosis mandates a number of staging investigations to define the exact subtype of disease. Identification of “B” findings alone, such as the following, is indicative of a high systemic mastocytosis burden:
Greater than 30% bone marrow mastocytosis burden
Serum tryptase level greater than 200 ng/mL
The additional presence of “C” findings, such as the following, is diagnostic for the presence of aggressive disease. 
Absolute neutrophil count less than 1000/µL (see the Absolute Neutrophil Count calculator)
Hemoglobin value less than 10 g/µL
Platelet count less than 100 000/µL
Hepatomegaly with ascites and impaired liver function
Palpable splenomegaly with hypersplenism
Malabsorption with hypoalbuminemia and weight loss
Large-sized osteolysis or severe osteoporosis causing pathologic fractures or life-threatening organopathy in other organ systems definitively caused by an infiltration of the tissue by neoplastic mast cells
Traditionally, physicians have advised cutaneous mastocytosis patients to avoid substances that induce mast cell mediator release, such as salicylates, crawfish, lobster, alcohol, spicy foods, hot beverages, and cheese. While evidence indicates that alcohol can cause adverse reactions, the role of the other foods mentioned above is hypothetical at this point and merits further investigation. 
Advise cutaneous mastocytosis patients to avoid certain physical stimuli, including emotional stress, temperature extremes, physical exertion, bacterial toxins, envenomation by insects to which the patient is allergic, and rubbing, scratching, or traumatizing the lesions of cutaneous mastocytosis.
Tailor therapy according to the patient’s specific needs for symptomatic relief. Patients may be started on oral H1 antihistamine and/or oral disodium cromoglycate with or without the use of a potent topical steroid for selected cutaneous lesions. In patients with a limited number of lesions, intralesional corticosteroid injections are an additional therapeutic option. Oral histamine H2 antagonists may be administered in addition to an oral H1 antihistamine.
Antihistamines relieve pruritus and flushing.
Hydroxyzine (Atarax, Atozine, Vistaril)
Hydroxyzine antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the CNS.
Mast cell stabilizers
Cromolyn is a mast cell stabilizer that improves diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching in some patients.
Cromolyn sodium (Gastrocrom)
Cromolyn sodium inhibits degranulation of sensitized mast cells following exposure to specific antigens. It is available as an oral concentrate solution in 5-mL ampules to mix with water and is administered at least 30 minutes before eating. Each 5-mL ampule contains 100 mg of cromolyn sodium, USP, in purified water. Each foil pouch contains 8 ampules.
Histamine H2 antagonists
The addition of H2 antagonist to H1 antagonist helps control pruritus and whealing. In addition, GI symptoms associated with hyperchlorhydria, such as peptic ulcer disease and gastritis, respond well to this medication.
Cimetidine is an H2 antagonist that when combined with an H1 type may be useful in treating itching and flushing in urticaria and contact dermatitis that do not respond to H1 antagonists alone. Use cimetidine in addition to H1 antihistamines.
Vasopressors are for patients with systemic disease or extensive symptoms.
Epinephrine is the drug of choice for treating anaphylactoid reactions. It has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Its beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.