NORD gratefully acknowledges Kristina Bundra, Pharm. D, NORD Editorial Intern, and Cem Akin, MD, PhD, Professor of Medicine, University of Michigan, for assistance in the preparation of this report.
Mastocytosis is a rare disorder characterized by abnormal accumulation and activation of mast cells in the skin, bone marrow and internal organs (liver, spleen, gastrointestinal tract and lymph nodes). Mastocytosis can affect both children and adults. Mastocytosis can be classified to a specific type depending on the patient’s symptoms and overall presentation. Cases beginning during adulthood tend to be chronic and involve the bone marrow in addition to the skin, whereas, during childhood, the condition is often marked by skin manifestations with no internal organ involvement and can often resolve during puberty. In adult patients, mastocytosis tends to be persistent, and may progress into a more advanced category in a minority of patients.
Classification
Cutaneous mastocytosis
The skin is the only site of involvement in cutaneous mastocytosis. Urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis) lesions are small, brownish, flat or elevated spots that may be surrounded by reddened, itchy skin when scratched (Darier’s sign). These lesions tend to be more apparent on areas of skin exposed to pressure or rubbing in adult patients. When skin lesions begin during childhood, the skin tends to be the only affected organ. Blistering of the skin lesions is seen exclusively in children younger than four years of age.
Based on clinical appearance, prognosis, and disease course, cutaneous mastocytosis can be further categorized into the following: maculopapular cutaneous mastocytosis (MCPM), mastocytoma and diffuse cutaneous mastocytosis. Maculopapular cutaneous mastocytosis and mastocytoma are the most common forms, compared to diffuse cutaneous mastocytosis which is rarer. CM is most often diagnosed within the neonatal period. MCPM lesions may occur on scalp, neck, trunk and extremities. A mastocytoma is a single lesion, or up to 3 individual lesions, that is usually found early in life and resolves spontaneously with age. Diffuse cutaneous mastocytosis (DCM) is seen in children and is the most severe form of cutaneous mastocytosis. The skin is diffusely thickened and has a rough texture, generally without individual distinct lesions. Additional symptoms associated with DCM include itching, blistering, decreased blood pressure (hypotension), diarrhea, gastrointestinal bleeding, reddening of the skin (flushing) and anaphylactic shock.
Indolent systemic mastocytosis
Systemic mastocytosis is the main form of mastocytosis observed in adults whereas it is rarer in children. Systemic disease is defined by demonstration of pathologic accumulation of mast cells in a tissue other than skin (most commonly bone marrow). Indolent systemic mastocytosis is generally associated with low mast cell burden and presence of mediator-related symptoms. Most patients also have maculopapular skin lesions. Some patients may present with an enlarged liver or spleen and the gastrointestinal tract may also be affected. Life expectancy in ISM is comparable to general population with low risk of progression (approximately 3-5%) to a more advanced form.
Systemic smoldering mastocytosis
This variant of systemic mastocytosis is characterized by high mast cell burden as evidenced by high level of tryptase (>200 ng/ml) and high degree of bone marrow involvement with mast cells (>30% in biopsy tissue), splenomegaly or hepatomegaly with or without mild abnormalities in production of other blood cells, without an overt hematologic disorder. Patients with SSM may have a higher likelihood of progressing to an advanced disease category below.
The following categories are also known as advanced mastocytosis:
Systemic mastocytosis with an associated hematologic neoplasm
Systemic mastocytosis with an associated hematologic neoplasm affects approximately one-fifth of all patients with systemic mastocytosis. Myeloproliferative and myelodysplastic disorders are the most common diseases associated with this form and patients may lack urticaria pigmentosa-like skin lesions.
Aggressive systemic mastocytosis
In aggressive systemic mastocytosis, there is an impairment or loss of organ function (usually liver, gut, bone or bone marrow) due to mast cell infiltrates. Examples of organ dysfunction include low numbers of white bloods cells, anemia, low platelets, liver dysfunction, malabsorption and pathologic bone fractures associated with large osteolytic bone lesions.
Mast cell leukemia
Mast cell leukemia is an aggressive hematological malignancy characterized by presence of circulating mast cells greater than 10%, or immature mast cells in bone marrow aspirates greater than 20%. This subtype is very rare; however, it is associated with the worst prognosis among all mastocytosis varieties.
Mast cell sarcoma
A mast cell sarcoma is a solid tumor composed of abnormal mast cells invading the tissue. This condition is very rare and often is not associated with additional skin involvement. More aggressive forms of mastocytosis, mast cell leukemias and mast cell sarcomas are very rarely encountered.
The severity of the symptoms associated with mastocytosis may vary from mild to life-threatening. In general, symptoms occurring in mastocytosis are mainly due to the release of chemicals from the mast cells and thus produce symptoms associated with an allergic reaction, although a true allergic trigger may not be identified. Flushing and gastric acid hypersecretion due to mast cell-associated histamine release are common symptoms. Heartburn, stomach aches, abdominal discomfort, bloating and diarrhea may occur. The liver, spleen and lymph nodes may become enlarged in advanced disease varieties; therefore regular follow-up is necessary. Bones affected by mastocytosis may become softened (osteoporosis) and deteriorate, although some new bone growth may occur with thickening of the outer portions or spongy inner areas of the bones. In aggressive systemic mastocytosis, a decrease in blood cells (cytopenia), break-down of bones (osteolysis), swelling of the lymph nodes (lymphadenopathy), swelling of the liver (hepatomegaly), impaired liver function, ascites or portal hypertension and malabsorption, may also occur.
Massive chemical release from the mast cells (degranulation) may lead to life-threatening episodes of anaphylaxis (anaphylactic shock). The most common triggers include, but are not limited to, insect stings, physical stress (heat, cold, mechanical irritation of the skin, exercise), emotional stress, alcohol, spicy foods and medications, including aspirin and non-steroidal anti-inflammatory drugs (NSAIDS), narcotics, muscle relaxants, radiocontrast material, among others. These are similar in nature to severe allergic reactions and may involve flushing, decreased blood pressure (hypotension), increased heart rate and loss of consciousness along with abdominal cramps. Recent studies have found that some patients with severe allergic reactions to bee stings, and some previously diagnosed with idiopathic anaphylaxis may have mastocytosis. Additional non-specific symptoms that can be seen with mastocytosis include pain, nausea, headache, memory and concentration difficulties, and/or malaise. Patients with an associated hematologic disorder may have symptoms of that disorder such as fatigue, left upper quadrant pain due to enlarged spleen, brusing/bleeding and weight loss.
Genetic alterations (mutations) resulting in the over-activation of the receptor for mast cell growth factor (KIT) have been identified in the abnormal mast cells in almost all patients with adult-onset mastocytosis and in skin lesions of approximately 80% of affected children. The most common KIT mutation in mastocytosis is D816V and is believed to cause the abnormal proliferation and accumulation of mast cells in tissues. Over 90% of adults and 40% of children also express this mutation whereas another 40% of children have mutations involving other areas of the KIT gene. It is not yet clear if the type of KIT mutation in children has value in predicting disease severity. The mutations are present in the body cells (somatic) of affected individuals, but not in egg and sperm cells (germline) in the majority of patients and, therefore, are not passed on to the next generation.
The release of mediators produced by mast cells, such as histamine, leukotriene C4, prostaglandin D2, chemokines, cytokines and heparin, among other cellular mediators, results in symptomatic episodes. Histamine is a natural chemical released during an allergic event that causes itching, wheezing, dilation of blood vessels and hypersecretion of stomach acid.
Mastocytosis affects males and females in equal numbers. It can begin during childhood or adulthood. Childhood-onset disease most commonly presents within the first year of life.
Other disorders associated with mast cell activation cannot be clinically distinguished from mastocytosis and diagnostic testing for mastocytosis should be performed. In cutaneous mastocytosis, a diagnosis can be made based on the appearance of the skin and can be confirmed by a skin biopsy revealing high numbers of mast cells. Diagnosis of systemic mastocytosis should be established by a bone marrow biopsy, which would reveal an abnormally high number of mast cells with abnormal appearance.
Tryptase is a protease associated with mast cells. Measurable serum tryptase is made up of alpha and beta tryptases and the median serum tryptase level is approximately 5 ng/ml. Alpha tryptase is a protryptase that is secreted constitutively by mast cells and its serum levels correlate with mast cell numbers and is often found elevated in systemic mastocytosis. A baseline serum tryptase level of greater than 20 ng/ml is a minor diagnostic criterion for systemic mastocytosis. Beta tryptase is stored in mast cell granules and is detectable in circulation after anaphylaxis usually returns to baseline after 4 hours.
The World Health Organization (WHO) has established criteria for diagnosing systemic mastocytosis which has been summarized by The Mast Cell Disease Society here:
http://tmsforacure.org/patients/mastocytosis_explained_2.php
Treatment
Currently, there is no curative treatment for mastocytosis. Treatment of mastocytosis is primarily directed at controlling the symptoms caused by the release of mast cell mediators. H1 and H2 antihistamines are therefore cornerstones of the treatment to relieve symptoms. Cromolyn sodium can be especially effective for the treatment of some gastrointestinal symptoms. Mast-cell stabilizers such as ketotifen can be used to treat some mast cell activation symptoms. Leukotriene antagonists can also be used to improve symptoms in patients. Proton-pump inhibitors can be used to treat the increased acid production in the stomach. Bisphosphonates can be used if osteoporosis or significant osteopenia is present. PUVA (psoralen plus ultraviolet A radiation) treatment may cause temporary attenuation of the urticaria pigmentosa lesions. Glucocorticoids may be necessary in patients unresponsive to other therapy or with more advanced disease.
Self-injectable epinephrine should be prescribed to all patients with systemic mastocytosis and can be administered in cases of severe anaphylactic episodes and all patients are advised to carry epinephrine self-injectors. Xolair (omalizumab), an IgE antibody, currently indicated for allergic asthma, chronic spontaneous urticaria and nasal polyposis, has been shown to be effective in preventing anaphylactic mast cell activation episodes in case reports.
Associated hematologic disorders should be treated by a blood specialist (hematologist). In patients with advanced systemic mastocytosis, therapies to reduce mast cell numbers are considered. These include tyrosine kinase inhibitors (TKIs), cladribine and interferon alpha. Safety and tolerability of TKIs have made them the first line of therapy in most patients with advanced disease. TKIs include midostaurin, imatinib and some investigational drugs. Stem cell transplantation can be considered in selected patients with SM-AHNMD, ASM and MCL.
In 2006, the U.S. Food and Drug Administration (FDA) granted expanded approval to treat aggressive systemic mastocytosis (SM) not associated with the genetic mutation D816V c-KIT or with an unknown mutation status with the cancer drug Gleevec (imatinib mesylate). Response to imatinib is rare in mastocytosis as most cases are associated with D816V KIT mutation.
In 2017, the FDA approved Rydapt (midostaurin) for the treatment of adults with aggressive SM, SM with associated hematological neoplasm or mast cell leukemia. Most recently, in 2021, the FDA approved Ayvakit (avapritinib) for the treatment of adults with aggressive SM, SM with associated hematological neoplasm or mast cell leukemia.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com.
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
REVIEW ARTICLES
Jendoubi F, Gaudenzio N, Gallini A, Negretto M, Paul C, Bulai Livideanu C. Omalizumab in the treatment of adult patients with mastocytosis: A systematic review. Clin Exp Allergy. 2020 Jun;50(6):654-661. doi: 10.1111/cea.13592. Epub 2020 Mar 25. PMID: 32107810.
Hartmann K, Escribano L, Grattan C, et al. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016 Jan;137(1):35-45. doi: 10.1016/j.jaci.2015.08.034. Epub 2015 Oct 21. PMID: 26476479.
Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72.
Niedoszytko M, Bonadonna P, Oude Elberink JN, Golden DB. Epidemiology, diagnosis, and treatment of Hymenoptera venom allergy in mastocytosis patients. Immunol Allergy Clin North Am. 2014 May;34(2):365-81. doi: 10.1016/j.iac.2014.02.004. Epub 2014 Mar 15. PMID: 24745680.
Cardet JC, Akin C, Lee MJ. Mastocytosis: update on pharmacotherapy and futuredirections. Expert Opin Pharmacother. 2013 Oct;14(15):2033-45. doi:10.1517/14656566.2013.824424. PubMed PMID: 24044484.
Fried AJ, Akin C. Primary mast cell disorders in children. Curr Allergy AsthmaRep. 2013 Dec;13(6):693-701. doi: 10.1007/s11882-013-0392-6. Review. PubMed PMID: 24150753.
Lange M, Nedoszytko B, Gorska A, Zawrocki A, Sobjanek M, Kozlowski D. Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci.Jul 4 2012;8(3):533-541.
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(3):215-25. doi: 10.1159/000328760. Epub 2011 Oct 27. PubMed PMID: 22041891; PubMed Central PMCID: PMC3224511.
Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol. 2011 Aug 1;12(4):259-70. doi: 10.2165/11588890-000000000-00000. Review. PubMed PMID:21668033.
Valent P, Sperr WR, Akin C. How I treat patients with advanced systemicmastocytosis. Blood. 2010 Dec 23;116(26):5812-7. doi: 10.1182/blood-2010-08-292144. Epub 2010 Sep 20. PubMed PMID: 20855864.
Metcalfe DD. Mast cells and mastocytosis. Blood. 2008 Aug 15;112(4):946-56.doi: 10.1182/blood-2007-11-078097. Review. PubMed PMID: 18684881; PubMed Central PMCID: PMC2515131.
Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53. Review. PubMed PMID: 17537151.
Tharp MD, Longley BJ Jr. Mastocytosis. Dermatol Clin. 2001;19:679-96, viii-ix.
Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-25.
Marone G, Spadaro G, Granata F, et al. Treatment of mastocytosis: pharmacologic basis and current concepts. Leuk Res. 2001;25:583-94.
Longley BJ, Reguera MJ, Ma Y. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. Leuk Res. 2001;25:571-76.
Austen KF, Boyce JA. Mast cell lineage development and phenotypic regulation. Leuk Res. 2001;25:511-18.
Hartmann K, Henz BM. Mastocytosis: recent advances in defining the disease. Br J Dermatol. 2001;144:682-95.
Valent P, Schernthaner GH, Sperr WR, et al. Variable expression of activation-linked surface antigens on human mast cells in health and disease. Immunol Rev. 2001;179:74-84.
Hartmann K, Metcalfe DD. Pediatric mastocytosis. Hematol Oncol Clin North Am. 2000;14:579-623, vii.
Parker RI. Hematologic aspects of systemic mastocytosis. Hematol Oncol Clin North Am. 2000;14:557-68.
CLINICAL STUDIES
Gotlib J, Kluin-Nelemans HC, George TI, Akin C, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098. PMID: 27355533.
INTERNET
Castells MC and Akin C. Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations. Updated: Apr 05, 2021. Available at https://www.uptodate.com/contents/mastocytosis-cutaneous-and-systemic-epidemiology-pathogenesis-and-clinical-manifestations?search=mastocytosis&source=search_result&selectedTitle=1~99&usage_type=default&display_rank=1. Accessed April 26, 2021.
Jaishankar D and Manthri S. Systemic Mastocytosis. Medscape, Last Update: June 29, 2020. Available at: https://emedicine.medscape.com/article/203948-overview Accessed April 26, 2021.
Mastocytosis,Cutaneous. McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 154800; Last Update: 06/06/2019. Available at https://omim.org/entry/154800 Accessed April 26, 2021.
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