Overview & Diagnosis
OVERVIEW, DIAGNOSIS, DEFINITIONS AND CLASSIFICATION
Please see the Mast Cell Disease Primer.
What are Mast Cells?
Mast cells (MC) are immune system cells that live in the bone marrow and in body tissues, internal and external, such as the gastrointestinal tract, the lining of the airway, and the skin. Everyone has mast cells in their body, and they play many complex and critical roles in keeping us healthy. The positive roles that they play include protecting us from infection, and helping our body by participating in the inflammatory process. However, mast cells are also involved in allergic reactions, from the tiny swelling that appears after a mosquito bite to a life threatening, full-blown anaphylaxis.
Mast cells have within them small sacs, or granules, surrounded by membranes. The sacs contain many different kinds of substances called mediators, which participate in all of the roles above, including allergic response and anaphylaxis.
The mediators are selectively released when there is an allergic or mast cell based reaction.1
Figure 1. Mast cell (electron micrograph)
There is a difference between someone who is healthy, with mast cells that are functioning normally, and someone with a mast cell disease, whose mast cells may be activating inappropriately in response to triggers, or may also be proliferating and accumulating in organ tissues.
What are Mast Cell Diseases?
MCD, MCAD, MCAS… there are so many acronyms in the mast cell disease community, and they can be confusing. Let’s clarify so we can all understand each other. Mast cell disease(s) (MCD) is the term used by mast cell specialists in the U.S. and internationally for all mast cell diseases. This covers each variant: systemic mastocytosis (SM), cutaneous mastocytosis (CM), smoldering mastocytosis (SSM), advanced disease variants, mast cell activation syndrome (MCAS) and hereditary alpha tryptasemia (HaT). Since MCD covers all variants of mast cell disease, it is inclusive of every patient suffering from any type of mast cell disease. The American Initiative in Mast Cell Diseases (AIM) also chose their name to represent all mast cell diseases. MCAD is an older term used by some that meant mast cell activation disorder. Some physicians and patients still use the term disorder as we all slowly transition to disease. MCAS is a specific syndrome with diagnostic criteria to define it and is not interchangeable with MCAD. We can all work and learn together.
Mast cell diseases are caused by the proliferation and accumulation of genetically altered mast cells and/or the inappropriate release of mast cell mediators, creating symptoms in multiple organ systems.2 The three major forms of mast cell diseases are mastocytosis, mast cell activation syndrome (MCAS), and Hereditary Alpha tryptasemia (HAT). Mast cell diseases can cause tremendous suffering and disability due to symptomatology from daily mast cell mediator release, and/or symptoms arising from infiltration and accumulation of mast cells in major organ systems. Although systemic mastocytosis is a rare disease,3 those suffering with MCAS have recently been increasingly recognized and diagnosed. As a result, patients with MCAS appear to represent a growing proportion of the mast cell disease patient population.4, 5 It is important to note that the process of mast cell activation can occur in anyone, even without a mast cell disease, as well as in patients with both mastocytosis and MCAS.6
Mastocytosis has been defined in the literature as an abnormal accumulation of mast cells in one or more organ systems. Previously classified by the World Health Organization (WHO) as a myeloproliferative neoplasm, mastocytosis is now classified in its own category under myeloid neoplasms.7 Broadly separated into three categories, cutaneous mastocytosis (CM), systemic mastocytosis (SM) and mast cell sarcoma these diseases occur in both children and adults. CM is considered a benign skin disease representing the majority of pediatric cases. In 67-80% of pediatric cases seen, resolution will occur before or in early adulthood.8-10 In pediatric mastocytosis, symptoms of mast cell mediator release may occur systemically as a result of mast cell mediators released from skin lesions.10 This, however, does not necessarily indicate systemic disease. The incidence of systemic pediatric disease was previously unknown, but systemic forms have now been proven to exist in some children.8-10 The majority of adult patients are diagnosed with systemic disease. Skin involvement, typically maculopapular cutaneous mastocytosis/urticaria pigmentosa, is common in adult patients and can provide an important clue to accurate diagnosis.11, 12
Diagnosis and Classification13-17
CM is diagnosed by the presence of typical skin lesions and a positive skin biopsy demonstrating characteristic clusters of mast cells. The preferred method of diagnosing SM is via bone marrow (BM) biopsy. The WHO has established criteria for diagnosing SM, summarized18 as follows:
Major ª: Multifocal dense infiltrates of mast cells (MCs) (> 15 MCs in aggregate) in tryptase stained biopsy sections of the bone marrow or other extracutaneous organ
- More than 25% of MCs in bone marrow or other extracutaneous organ(s) show abnormal morphology (i.e. are atypical MC type 1 or are spindle–shaped MCs) in multifocal lesions in histologic examination
- KIT mutation at codon 816b in extracutaneous organ(s) (in most cases bone marrow cells are examined)
- KIT+MCs in bone marrow show aberrant expression of CD2 and/or CD25
- Serum total tryptase > 20 ng/mL (does not count in patients who have AHN-type disease.)
ª If at least one major criterion and one minor criterion OR at least three minor criteria are fulfilled, the diagnosis of systemic mastocytosis can be established.
b Activating mutations at codon 816, in most cases, KIT D816V
MAST CELL ACTIVATION SYNDROMES
Existence of a subset of mast cell disease patients who experience episodes of mast cell activation without detectable evidence of a proliferative mast cell disease was postulated over 20 years ago.19, 20 Over the last two decades, with development of improved methodology for identification of abnormal mast cells,21-24 it became apparent that there were patients who exhibited symptoms of mast cell mediator release who did not fulfill the criteria for SM.25, 26 Thus began the evolution of discussions about other forms of mast cell diseases, both clonal and nonclonal, which became known as Mast Cell Activation Syndromes (MCAS).6, 27, 28
Diagnosis and Proposed Classification
Recognition by specialist physicians of the importance of mast cell activation in disease led to an international Mast Cell Disorders Working Conference emphasizing this topic in September of 2010. Consensus statements were published regarding classification of and diagnostic criteria for mast cell diseases,6 where mast cell activation plays a prominent role.
Mediators produced by mast cells have a considerable effect on specific symptomatology. Symptoms, including, but not limited to flushing, pruritis (itching), urticaria (hives), headache, gastrointestinal symptoms (including diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux), and hypotension (low blood pressure), allow a patient to meet the first of three required co-criterion for systemic mast cell activation when the patient exhibits symptoms involving two or more organ systems in parallel, which recur, or are chronic, are found not to be caused by any other condition or disorder other than mast cell activation, and require treatment or therapy.6, 28
The second required co-criterion for systemic mast cell activation depends on documentation that mast cells are directly involved in the symptomatology. An increase in the serum level of tryptase, above baseline and within a narrow (generally accepted as one to two hour) window of time after a symptomatic episode, is proposed as the preferred method for providing evidence of mast cell involvement according to these criteria.6, 28-30 The consensus article provides a method for calculating the required minimum rise in serum tryptase.6 After a reaction, a level of serum tryptase that is a minimum of 20% above the basal serum tryptase level, plus 2 ng/ml, will meet the second criterion listed above for a mast cell activation event (see Tests for further information). Consensus members also agreed that when serum tryptase evaluation is not available or when the tryptase level does not rise sufficiently to meet the required increase for the co-criterion, other mediator tests could suffice. A rise in urinary n-methyl histamine, prostaglandin-D2, or its metabolite, 11β-prostaglandin-F2α (24-hour urine test for any of the three), is considered an alternative for the co-criterion related to a requirement for a mast cell mediator level rise during a systemic mast cell activation event.6
Finally, the third co-criterion requires a response (based on response criteria15) to medications that inhibit the action of histamine.6 In addition, in those with typical mast cell activation symptoms, a “complete or major” response to drugs that inhibit other mediators produced by mast cells or block mast cell mediator release can be regarded as fulfillment of the third co-criterion for MCAS.6, 28
- Gilfillan AM, Austin SJ, Metcalfe DD. Mast cell biology: introduction and overview. Adv Exp Med Biol. 2011;716:2-12. http://www.ncbi.nlm.nih.gov/pubmed/21713648
- Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72. http://www.ncbi.nlm.nih.gov/pubmed/26154789
- Horny HP, Sotlar K, Valent P, Hartmann K. Mastocytosis: a disease of the hematopoietic stem cell. Dtsch Arztebl Int. 2008 Oct;105(40):686-92. http://www.ncbi.nlm.nih.gov/pubmed/19623287
- Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol. 2010 Dec;126(6):1099-104 e4. http://www.ncbi.nlm.nih.gov/pubmed/21035176
- Afrin LB. Presentation, diagnosis and management of mast cell activation syndrome. In: Murray DB, editor. Mast cells: phenotypic features, biological functions and role in immunity. Hauppauge: Nova Science Publishers, Inc.; 2013. p. 155-232.
- Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, 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. http://www.ncbi.nlm.nih.gov/pubmed/22041891
- Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. http://www.ncbi.nlm.nih.gov/pubmed/27069254
- Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis. Curr Opin Pediatr. 2012 Aug;24(4):480-6. http://www.ncbi.nlm.nih.gov/pubmed/22790101
- Fried AJ, Akin C. Primary mast cell disorders in children. Curr Allergy Asthma Rep. 2013 Dec;13(6):693-701. http://www.ncbi.nlm.nih.gov/pubmed/24150753
- Meni C, Bruneau J, Georgin-Lavialle S, Le Sache de Peufeilhoux L, Damaj G, Hadj-Rabia S, et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015 Mar;172(3):642-51. http://www.ncbi.nlm.nih.gov/pubmed/25662299
- Berezowska S, Flaig MJ, Rueff F, Walz C, Haferlach T, Krokowski M, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol. 2014 Jan;27(1):19-29. http://www.ncbi.nlm.nih.gov/pubmed/23807778
- Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, 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. http://www.ncbi.nlm.nih.gov/pubmed/26476479
- Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001 Jul;25(7):603-25. http://www.ncbi.nlm.nih.gov/pubmed/11377686
- Valent P, Horny H-P, Li CY, Longley JB, Metcalfe DD, Parwaresch RM, et al. Mastocytosis. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization (WHO) Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.
- Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, 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. http://www.ncbi.nlm.nih.gov/pubmed/17537151
- Horny HP, Akin C, Metcalfe DD, Escribano L, Bennett JM, Valent P, et al. Mastocytosis (mast cell disease) Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization (WHO) Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.
- Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K, et al. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74. http://www.ncbi.nlm.nih.gov/pubmed/24836395
- Valent P. Diagnostic evaluation and classification of mastocytosis. Immunol Allergy Clin North Am. 2006 Aug;26(3):515-34. http://www.ncbi.nlm.nih.gov/pubmed/16931291
- Roberts LJ, 2nd, Oates JA. Biochemical diagnosis of systemic mast cell disorders. J Invest Dermatol. 1991 Mar;96(3):19S-24S; discussion S-5S. http://www.ncbi.nlm.nih.gov/pubmed/2002247
- Metcalfe DD. Classification and diagnosis of mastocytosis: current status. J Invest Dermatol. 1991 Mar;96(3):2S-4S. http://www.ncbi.nlm.nih.gov/pubmed/2002248
- Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10560-4. http://www.ncbi.nlm.nih.gov/pubmed/7479840
- Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet. 1996 Mar;12(3):312-4. http://www.ncbi.nlm.nih.gov/pubmed/8589724
- Escribano L, Orfao A, Diaz-Agustin B, Villarrubia J, Cervero C, Lopez A, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood. 1998 Apr 15;91(8):2731-6. http://www.ncbi.nlm.nih.gov/pubmed/9531582
- Horny HP. Mastocytosis: an unusual clonal disorder of bone marrow-derived hematopoietic progenitor cells. Am J Clin Pathol. 2009 Sep;132(3):438-47. http://www.ncbi.nlm.nih.gov/pubmed/19687320
- Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M, Sperr WR, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Arch Allergy Immunol. 2007;142(2):158-64. http://www.ncbi.nlm.nih.gov/pubmed/17057414
- Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007 Oct 1;110(7):2331-3. http://www.ncbi.nlm.nih.gov/pubmed/17638853
- Horny HP, Sotlar K, Valent P. Evaluation of mast cell activation syndromes: impact of pathology and immunohistology. Int Arch Allergy Immunol. 2012;159(1):1-5. http://www.ncbi.nlm.nih.gov/pubmed/22555026
- Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013 Apr;68(4):417-24. http://www.ncbi.nlm.nih.gov/pubmed/23409940
- Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest. 1995 Dec;96(6):2702-10. http://www.ncbi.nlm.nih.gov/pubmed/8675637
- Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am. 2000 Jun;14(3):641-57. http://www.ncbi.nlm.nih.gov/pubmed/10909044