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Mastocytosis and Mast Cell Activation Syndrome

(Mast Cell Disease)

By

James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Medically Reviewed Oct 2022
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Topic Resources

Mastocytosis is mast cell proliferation with infiltration of skin or other tissues and organs. Mast cell activation syndrome is increased and inappropriate activation of mast cells without clonal proliferation. Symptoms result mainly from mediator release and include pruritus, flushing, and dyspepsia due to gastric hypersecretion. Diagnosis is by skin or bone marrow biopsy or both. Treatment is with antihistamines and control of any underlying disorder.

Mastocytosis is a group of disorders characterized by proliferation of mast cells and infiltration of the skin, other organs, or both. Pathology results mainly from release of mast cell mediators, including histamine, heparin, leukotrienes, and various inflammatory cytokines. Histamine causes many symptoms, including gastric symptoms, but other mediators also contribute. Significant organ infiltration may cause organ dysfunction. Mediator release may be triggered by physical touch, exercise, alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, insect stings, or foods.

Etiology in many cases of mastocytosis involves an activating mutation (D816V) in the gene coding for the stem cell factor receptor c-kit, which is present on mast cells. The result is autophosphorylation of the receptor, which causes uncontrolled mast cell proliferation.

Classification of Mastocytosis

Mastocytosis may be cutaneous or systemic.

Cutaneous mastocytosis

Cutaneous mastocytosis typically occurs in children. Most patients present with urticaria pigmentosa, a local or diffusely distributed salmon or brown maculopapular rash caused by multiple small mast cell collections. Nodular lesions and plaques can also develop. Less common are diffuse cutaneous mastocytosis, which is skin infiltration without discrete lesions, and mastocytoma, which is a large (1 to 5 cm) solitary collection of mast cells.

Cutaneous forms rarely progress to systemic disease in children but may do so in adults.

Images of Urticaria Pigmentosa

Systemic mastocytosis

Systemic mastocytosis most commonly occurs in adults and is characterized by multifocal bone marrow lesions; it often involves other organs, most commonly skin, lymph nodes, liver, spleen, and/or gastrointestinal (GI) tract.

Systemic mastocytosis is classified as

Mast cell activation syndrome

Mast cell activation syndrome is characterized by increased and inappropriate activation of mast cells with mediator release but without clonal proliferation or organ infiltration by mast cells (1 Classification reference Mastocytosis is mast cell proliferation with infiltration of skin or other tissues and organs. Mast cell activation syndrome is increased and inappropriate activation of mast cells without clonal... read more Classification reference ). The syndrome was originally diagnosed only when mediator release was idiopathic, but it has since been expanded to include release triggered by allergen-specific IgE, certain drugs, or physical factors. Genetic causes are suspected but not proved. Most cases do not involve clonal proliferation of mast cells but are due to a lower threshold for mast cells to degranulate. Mast cell activation syndrome has frequently been associated with postural orthostatic tachycardia syndrome (POTS) Postural orthostatic tachycardia syndrome (POTS) Orthostatic (postural) hypotension is an excessive fall in blood pressure (BP) when an upright position is assumed. The consensus definition is a drop of > 20 mm Hg systolic, > 10 mm Hg... read more and Ehlers-Danlos syndrome Ehlers-Danlos Syndrome Ehlers-Danlos syndrome is a hereditary collagen disorder characterized by articular hypermobility, dermal hyperelasticity, and widespread tissue fragility. Diagnosis is clinical. Treatment is... read more Ehlers-Danlos Syndrome , although the nature of the connection is unclear.

The manifestations of mast cell activation syndrome are frequently similar to those of patients with systemic mastocytosis; they include tachycardia, syncope, urticaria, flushing, nausea, vomiting, and brain fog.

It is unclear whether mast cell activation syndrome can progress to systemic mastocytosis or another form of mast cell disease and, if so,. how many patients are affected.

Classification reference

  • 1. Weiler CR, Austen KF, Akin C, et al: AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management. J Allergy Clin Immunol 144 (4):883–896, 2019. doi: 10.1016/j.jaci.2019.08.023

Symptoms and Signs of Mastocytosis

Skin involvement is often pruritic in mastocytosis—whether a single mastocytoma or more diffuse disease. The following may worsen itching:

  • Changes in temperature

  • Contact with clothing or other materials

  • Use of some drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Consumption of hot beverages, spicy foods, or alcohol

  • Exercising

Stroking or rubbing skin lesions causes urticaria and erythema around the lesion (Darier sign); this reaction differs from dermatographism, which involves normal skin.

Other symptoms include epigastric pain due to peptic ulcer disease, nausea (because histamine stimulates gastric acid production), vomiting, chronic diarrhea, arthralgias, bone pain, and neuropsychiatric changes (eg, irritability, depression, mood lability). Hepatic and splenic infiltration may cause portal hypertension with resultant ascites.

Diagnosis of Mastocytosis

  • Clinical evaluation

  • Bone marrow biopsy

  • Serum tryptase levels (baseline and during symptoms if possible)

Diagnosis requires bone marrow biopsy and tryptase levels (a marker of mast cell degranulation) in most patients. Skin biopsy can be done to check for mast cells, but this test does not replace the need for a bone marrow biopsy to classify the diagnosis and staging.

Diagnosis of mastocytosis is confirmed when one major criterion and at least one minor criterion or ≥ 3 (of 4) minor criteria are met.

The major criterion is

  • The presence of multifocal, dense aggregates of > 15 mast cells in bone marrow (preferred) or other extracutaneous organs (except the GI tract, lymph nodes, liver, or spleen)

The 4 minor criteria are

  • Atypical morphology or spindle shapes in > 25% of the mast cells in bone marrow biopsy sections or aspirate

  • A kit mutation at codon 816 (commonly Asp816Val) in bone marrow, peripheral blood, or other tissue

  • Bone marrow or other extracutaneous mast cells expressing the surface markers CD2, CD25, or both

  • Baseline serum tryptase levels > 20 ng/mL (> 20 mcg/L); values > 11.4 ng/mL (11.4 mcg/L) are considered elevated in most diagnostic laboratories)

The baseline level of tryptase is elevated in systemic mastocytosis but is typically normal in cutaneous mastocytosis and mast cell activation syndrome.

Diagnostic criteria for mast cell activation syndrome include all of the following:

  • Typical clinical symptoms of mast cell mediator release

  • During symptoms, a substantial transient increase in total serum tryptase level or an increase in other mast cell–derived mediators, such as N-methyl histamine or prostaglandin D2, leukotriene E4, or their urinary metabolites

  • A clinical response to drugs that attenuate the production or activities of mast cell mediators

Patients with mast cell activation typically have a normal bone marrow biopsy if it is done.

If the diagnosis is uncertain, levels of mast cell mediators and their metabolites (eg, 24-hour N-methylhistamine, prostaglandin D2, leukotriene E4) may be measured in plasma and urine; elevated levels support the diagnosis of mast cell disease but not necessarily systemic mastocytosis.

A bone scan and GI evaluation, can also be helpful in cases where the diagnosis requires confirmation.

Diagnosis reference

  • 1. Adapted from Horny HP, Akin C, Arber DA, et al: Mastocytosis. In WHO (World Health Organization) Classification of Tumors of Hematopoietic and Lymphoid Tissues, edited by SH Swerdlow, E Campo, and NL Harris, et al, Lyon, IARC (International Agency for Research on Cancer) Press, 2017, p. 62.

Treatment of Mastocytosis

  • For cutaneous mastocytosis, H1 blockers and possibly psoralen plus ultraviolet light or topical corticosteroids

  • For systemic mastocytosis and mast cell activation syndrome, H1 and H2 blockers, cromolyn, and ketotifen, montelukast, aspirin

  • For aggressive forms, midostaurin, avapritinib, interferon alfa-2b, corticosteroids, or splenectomy

Cutaneous mastocytosis

Adults with cutaneous forms may be treated with psoralen plus ultraviolet light or with topical corticosteroids once or twice a day.

Mastocytoma usually involutes spontaneously and requires no treatment.

Systemic mastocytosis

All patients with systemic mastocytosis should be treated with H1 and H2 blockers and should carry a prefilled, self-injecting epinephrine syringe.

Aspirin controls flushing but may enhance leukotriene production, thereby contributing to other mast cell–related symptoms; it should not be given to children because Reye syndrome is a risk.

Cromolyn 200 mg orally 4 times a day (100 mg 4 times a day for children 2 to 12 years; not to exceed 40 mg/kg/day) may help by preventing mast cell degranulation. Ketotifen 2 to 4 mg orally twice a day may also be effective. No treatment can reduce the number of tissue mast cells.

Omalizumab is an anti-IgE antibody that is sometimes used for moderate to severe asthma and chronic urticaria; it has sometimes been used in patients with mastocytosis or mast cell activation syndrome to try to prevent anaphylaxis.

In patients with an aggressive form of mastocytosis, characterized by increasing mast cell accumulation in different organs, leading to dysfunction, the multikinase inhibitors midostaurin or avapritinib (1 Treatment references Mastocytosis is mast cell proliferation with infiltration of skin or other tissues and organs. Mast cell activation syndrome is increased and inappropriate activation of mast cells without clonal... read more Treatment references ) can be used to help control end-organ damage, cytopenias, and mast cell accumulation in bone marrow (2 Treatment references Mastocytosis is mast cell proliferation with infiltration of skin or other tissues and organs. Mast cell activation syndrome is increased and inappropriate activation of mast cells without clonal... read more Treatment references ). Dosages are

  • Midostaurin 100 mg orally twice a day

  • Avapritinib 200 mg orally once a day

Interferon alfa-2b 4 million units subcutaneously once a week to a maximum of 3 million units a day induces regression of bone lesions. Corticosteroids (eg, prednisone 40 to 60 mg orally once a day for 2 to 3 weeks) may be required as adjunctive treatment for severe cases. Some limited evidence suggests that splenectomy may improve survival in patients with aggressive disease.

Cytotoxic drugs (eg, daunomycin, etoposide, 6-mercaptopurine) may be indicated for treatment of mast cell leukemia, but efficacy is unproved. Imatinib (a tyrosine kinase receptor inhibitor) may be useful when treating adults with aggressive systemic mastocytosis but is ineffective in patients with the D816V c-kit mutation.

Mast cell activation syndrome

Treatment is directed at preventing mediator release (eg, with cromolyn and/or ketotifen) and blocking mediator effects with some regimen of H1 and H2 blockers to block histamine, aspirin to block prostaglandins and montelukast to block leukotrienes.

Known triggers should be avoided.

Treatment references

  • 1. Radia D, Deininger M, Gotlib J, et al: Avapritinib, a potent and selective inhibitor of KIT D816V, induces complete and durable responses in patients (pts) with advanced systemic mastocytosis (AdvSM). EHA Library. 2019;267413:S830.

  • 2. Gotlib J, Kluin-Nelemans HC, George TI, et al: Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med 374 (26):2530–2541, 2016. doi: 10.1056/NEJMoa1513098

Key Points

  • Patients with cutaneous mastocytosis, usually children, typically present with a diffuse salmon or brown, often pruritic maculopapular rash.

  • Systemic mastocytosis causes multifocal bone marrow lesions, usually in adults, but often affects other organs.

  • All types can cause systemic symptoms (most commonly, flushing but sometimes anaphylactoid reactions).

  • For cutaneous mastocytosis, use H1 blockers to relieve symptoms, and in adults, consider treatment with psoralen plus ultraviolet light or topical corticosteroids.

  • For systemic mastocytosis, use H1 and H2 blockers and sometimes cromolyn, and for aggressive mastocytosis, consider midostaurin, avapritinib, interferon alfa-2b, systemic corticosteroids, or splenectomy.

  • For mast cell activation syndrome, target mediators released during activation with antihistamines, leukotriene inhibitors, and mast cell stabilizers.

  • Make sure all patients with mastocytosis carry a prefilled, self-injecting epinephrine syringe.

Drugs Mentioned In This Article

Drug Name Select Trade
Hepflush-10 , Hep-Lock, Hep-Lock U/P, Monoject Prefill Advanced Heparin Lock Flush, SASH Normal Saline and Heparin
Alaway, Children's Alaway, Claritin Eye, Eye Itch Relief, Itchy Eye, Zaditor, Zyrtec Itchy Eye
Singulair
Anacin Adult Low Strength, Aspergum, Aspir-Low, Aspirtab , Aspir-Trin , Bayer Advanced Aspirin, Bayer Aspirin, Bayer Aspirin Extra Strength, Bayer Aspirin Plus, Bayer Aspirin Regimen, Bayer Children's Aspirin, Bayer Extra Strength, Bayer Extra Strength Plus, Bayer Genuine Aspirin, Bayer Low Dose Aspirin Regimen, Bayer Womens Aspirin , BeneHealth Aspirin, Bufferin, Bufferin Extra Strength, Bufferin Low Dose, DURLAZA, Easprin , Ecotrin, Ecotrin Low Strength, Genacote, Halfprin, MiniPrin, St. Joseph Adult Low Strength, St. Joseph Aspirin, VAZALORE, Zero Order Release Aspirin, ZORprin
Rydapt
AYVAKIT
Intron A, Intron A Multidose Pen
Adrenaclick, Adrenalin, Auvi-Q, Epifrin, EpiPen, Epipen Jr , Primatene Mist, SYMJEPI, Twinject
Xolair, Xolair Prefilled
Deltasone, Predone, RAYOS, Sterapred, Sterapred DS
Etopophos, Toposar, VePesid
Purinethol, PURIXAN
Gleevec
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