Mastocytosis

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  • Author: Jacquiline Habashy, DO, MSc; Chief Editor: Dirk M Elston, MD  more…

Background

Mastocytosis is a disorder characterized by mast cell proliferation and accumulation within various organs, most commonly the skin.

The World Health Organization (WHO) classification of mastocytosis includes the following [1, 2] :

  • 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
  • Extracutaneous mastocytoma [1, 2]

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. [3]

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).

Urticaria pigmentosa lesions on the face of a chil Urticaria pigmentosa lesions on the face of a child. Courtesy of Lee H. Grafton, MD.

Urticaria pigmentosa lesions on the back of a chil Urticaria pigmentosa lesions on the back of a child. Courtesy of Lee H. Grafton, MD.

Lesions may vesiculate in infancy (see image below).

Lesion on the scalp of an infant. Lesion on the scalp of an infant.

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. [4] 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.

Positive Darier sign on a child's back. Positive Darier sign on a child’s back.

Urticaria pigmentosa on a child. Urticaria pigmentosa on a child.

Pathophysiology

Mastocytosis is now classified with the myeloproliferative neoplasms. [5] 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. [6] 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. [7] Activating mutations of the proto-oncogene c-kit have been identified but do not explain the initiation of the disease. [8] IL-6 levels have been shown to be elevated and correlated with disease severity, indicating interleukin 6 is involved in the pathophysiology of mastocytosis. [9]

Although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with D816V and other activating c-kit mutations. [10]

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. [11] 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.

Epidemiology

Frequency

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. [12]

Race

Most reported cases are in whites. The cutaneous lesions of most types of mastocytosis are less visible in persons with more heavily pigmented skin.

Sex

Mastocytosis affects males and females equally (no known sex predilection).

Age

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.

Prognosis

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. [13]

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. [14] Systemic mastocytosis may occur more frequently in diffuse cutaneous mastocytosis patients. [15] 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. [16]

Primary cutaneous mast cell sarcoma due to the transformation of a benign solitary mastocytoma in an adult has been reported. [17]

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. [18]

Patient Education

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. [19]

History

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. [20]  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.

Physical Examination

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. Lesion on the arm. Courtesy of Lee H. Grafton, MD.

  • Blisters and bullae in children (see image below)

    Blistering lesion. Blistering lesion.

  • Diffuse induration
  • 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 [25]

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). [26]

Causes

Mastocytosis probably is a hyperplastic response to an abnormal stimulus. Rare cases of familial urticaria pigmentosa have been recorded. [21] Rarer cases of cutaneous mastocytosis have been associated with radiotherapy fields in patients with breast cancer. [22]

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. [23]

Autism spectrum disorders may be increased in children with mastocytosis. [24]

Complications

Complications may include the following:

  • Possible transformation into a hematologic malignancy
  • Death secondary to mast cell degranulation
  • Mast cell leukemia

    Diagnostic Considerations

    Also consider the following:

    • Generalized eruptive histiocytoma
    • Histiocytosis X
    • Non-X histiocytosis of childhood
    • Secondary syphilis
    • Xanthogranuloma [27]
    • Carcinoid [28]
    • Leiomyoma [12]

    Differential Diagnoses

    • Achlorhydria

    • Cafe Au Lait Spots

    • Carcinoid

    • Congenital melanocytic nevus

    • Congenital smooth muscle hamartoma

    • Cutaneous Pseudolymphoma

    • Dermatologic Manifestations of Herpes Simplex

    • Epidermolysis Bullosa

    • Juvenile Xanthogranuloma

    • Leiomyoma

    • Lentigo

    • Linear IgA Dermatosis

    • Lymphocytoma Cutis

    • Nodular Localized Cutaneous Amyloidosis

    • Postinflammatory Hyperpigmentation

      Laboratory Studies

      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. [12]

      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. [29] 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. [29]

      WHO major criteria for the diagnosis of systemic mast cell disease include the following [19] :

      • 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 [19] :

      • 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 [2]

      Imaging Studies

      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.

      Other Tests

      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.

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