NORD gratefully acknowledges Kristina Bundra, Pharm. D, NORD Editorial Intern, and Cem Akin, MD, PhD, Associate Professor of Medicine, Harvard Medical School, Director, Mastocytosis Center, Brigham and Women's Hospital, for assistance in the preparation of this report.
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 and is known as Darier’s sign. These lesions tend to be more apparent on areas of skin exposed to pressure or rubbing. 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, mastocytoma, and diffuse cutaneous mastocytosis. Maculopapular cutaneous mastocytosis and mastocytoma are the most common forms, compared to diffuse cutaneous mastocytosis which is rarer. A mastocytoma is a single lesion 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 discolored, 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 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%), splenomegaly with or without mild abnormalities in production of other blood cells. Patients with SSM may have a higher likelihood of progressing to an advanced disease category below.
Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease
Systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease affects approximately one-fifth of all systemic mastocytosis cases. Myeloproliferative and myelodysplastic disorders are the most common diseases associated with this form and often patients do not display 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.
Mast cell leukemia
Mast cell leukemia is an aggressive hematological malignancy characterized by circulating mast cells greater than 10% or immature mast cells in bone marrow aspirates greater than 20%. This condition is rare; however, it is associated with the worst prognosis among all mastocytosis varieties.
Mast cell sarcoma
A mast cell sarcoma is a single 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. Flushing and gastric acid hypersecretion due to mast cell-associated histamine release are common symptoms. Heartburn, stomach aches, abdominal discomfort and diarrhea may occur. The liver, spleen and lymph nodes may become enlarged in some patients; 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, certain foods, insect stings, physical stress (heat, cold, mechanical irritation of the skin), emotional stress, alcohol, 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 decreased blood pressure (hypotension), increased heart rate and loss of consciousness. Recent studies have found that up to 10% of patients with severe allergic reactions to bee stings may have mastocytosis. Additional non-specific symptoms that can be seen with mastocytosis include pain, nausea, headache, and/or malaise. Patients with an associated hematologic disorder may have symptoms of that disorder such as fatigue and weight loss.
Genetic alterations (mutation) 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 adult-onset mastocytosis and approximately 80% of children in skin lesions. The most common c-kit mutation in mastocytosis is D816V and is believed to cause the abnormal proliferation and accumulation of mast cells in tissues. Approximately >90% of adults and 40% of children also express this mutation whereas another 40% of children have mutations involving other areas of KIT. Prognostic significance of the type of mutation in childhood disease is yet to be determined. The mutations are somatic in nature and therefore are not passed on to the next generation in most patients.
The release of mediators produced by mast cells, such as histamine, heparin, chemokines, cytokines, leukotrienes and prostaglandin D2, 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 two years 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 in addition to 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.
The World Health Organization (WHO) has established criteria for diagnosing systemic mastocytosis which has been summarized by The Mastocytosis 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, decreasing bone pain, treating headaches and some of the skin manifestations. Mast-cell stabilizers such as ketotifen can be used to treat some of the skin involvement. 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. Steroids may be necessary in patients unresponsive to other therapy or with more advanced disease.
Self-injectable epinephrine should be prescribed to all patients and can be administered in cases of severe anaphylactic episodes and all patients are advised to carry epinephrine self-injectors. This therapy should always be followed by evaluation of the patient in a medical facility.
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 cladribine and interferon alpha. Stem cell transplantation can be considered in selected patients with SM-AHNMD, ASM and MCL.
In 2006, the 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 imatinib mesylate (Gleevec). Gleevec is manufactured by Novartis Pharmaceuticals Corp.
In 2017, midostaurin (Rydapt) was approved by the FDA for the treatment of adults with aggressive SM, SM with associated hematological neoplasm, or mast cell leukemia. Rydapt is manufactured by Novartis Pharmaceuticals Corp.
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: prpl@cc.nih.gov
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
Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72.
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, Brockow K, Butterfield JH, Carter MC, Castells M,Escribano L, Hartmann K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sotlar K, Sperr WR, Triggiani M, Valenta R, Horny HP, Metcalfe DD. 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 cutaneousmastocytosis 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, Födinger M, Hartmann K, Brockow K, Castells M, Sperr WR, Kluin-Nelemans HC, Hamdy NA, Lortholary O, Robyn J, van Doormaal J,Sotlar K, Hauswirth AW, Arock M, Hermine O, Hellmann A, Triggiani M, Niedoszytko M, Schwartz LB, Orfao A, Horny HP, Metcalfe DD. 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.
Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000;14:537-55.
INTERNET
Mastocytosis Explained. The Mastocytosis Chronicles. The Mastocytosis Society. Available at: http://tmsforacure.org/documents/MastocytosisExplained.pdf. Accessed December 20, 2016.
Krishnan K, Jaishankar D. Systemic Mastocytosis. Medscape, Last Update April 22, 2016.. Available at: http://emedicine.medscape.com/article/203948-overview. Accessed December 20, 2016.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 154800; Available at http://omim.org/entry/154800 Last Update:01/24/2012. Accessed December 20, 2016.
Wong HK, Najib U. Urticaria. Medscape, Last Update September 13, 2016. Available at: http://emedicine.medscape.com/article/137362-overview. Accessed December 20, 2016.
Rasool HJ. Myeloproliferative Disease. Medscape, Last Update February 26, 2016 . Available at: http://emedicine.medscape.com/article/204714-overview. Accessed December 20, 2016.
Klapproth JM, Yang VW. Malabsorption. Medscape, Last Update December 16, 2014.. Available at: http://emedicine.medscape.com/article/180785-overview. Accessed December 20, 2016.
Lehrer J, Lichtenstein GR. Irritable Bowel Syndrome. Medscape, Last Update October 10, 2016. Available at: http://emedicine.medscape.com/article/180389-overview. Accessed December 20, 2016.
Rowe W, Lichtenstein GR. Irritable Bowel Disease. Medscape, Last Update June 17, 2016.. Available at: http://emedicine.medscape.com/article/179037-overview. Accessed December 20, 2016.
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