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Progression of mast cell diseases (Part 4)

If ISM is life threatening, why is not considered as dangerous as ASM or MCL?

ISM is not life threatening. Anaphylaxis is life threatening. They are not the same. Many people with ISM never experience anaphylaxis. ISM can make anaphylaxis more dangerous, but ISM is not the same as anaphylaxis. Outside of anaphylaxis, ISM is not life threatening.

“Indolent systemic mastocytosis (SM) patients have a varied clinical presentation, ranging from predominantly cutaneous symptoms to recurrent systemic symptoms (eg, flushing, palpitations, dyspepsia, diarrhea, bone pain) that can be severe and potentially life threatening (anaphylaxis.)” (Pardanini 2013)


Is MCAS more or less dangerous than ISM?

“From a clinical standpoint, MMAS and MCAS share many similarities with systemic mastocytosis (SM), a primary disorder of mast cells in which patients experience symptoms ranging from pruritus and flushing to anaphylaxis.” (Picard 2013)

Again, the real danger here is anaphylaxis rather than these entities themselves. Statistically, the numbers don’t have a lot of uniformity regarding frequency of anaphylaxis in SM, what constitutes a severe reaction, and so on. Additionally, there are multiple definitions of MCAS and how that is distinguished from IA, which is really important to understanding the true frequency of anaphylaxis in MCAS. However, the data currently shows a trend of anaphylaxis being less common in MCAS than in SM. Still, it is important to realize that this may be due to less research being available on MCAS than mastocytosis.

“In our cohort 3 [MCAS] patients (17%) had a history of anaphylaxis. These patients were included in our cohort because they had primary symptoms characteristic of MCAS that responded to medications and had other laboratory evidence of MC mediator release…There likely exists a spectrum of disease for MCAS in which the more severe form includes anaphylaxis and a spectrum of IA in which a form includes MCAS symptoms.” (Hamilton 2011)

It is well known that people with mastocytosis are more likely to experience anaphylaxis than the general public. In adults with any type of mastocytosis, 49% experience anaphylaxis. Patients with systemic mastocytosis were more likely to anaphylax than those with cutaneous mastocytosis. In adults, 48% of the anaphylactic reactions were severe, with 38% causing unconsciousness. 60% of those reactions were Grade III anaphylaxis. (Brockow 2008)

“In 4 of the 137 [SM] patients (3%), severe life-threatening anaphylaxis resulting in a severe handicap with or without transient or permanent disability occurred.” (Wimazal 2012)

“Prolonged hypotension following anaphylaxis and cerebral hypoxia were identified as major factors leading to a substantial handicap, clinical deterioration or even death in these patients.” (Wimazal 2012)

“However, in both patients in whom recurrent life-threatening anaphylaxis was recorded, the smoldering subtype of SM with a huge burden of MCs was diagnosed, whereas most patients in whom only one documented severe life-threatening event had occurred were found to have low-grade SM with a low burden of MCs.” (Wimazal 2012)

“Thirty-six [SM] patients (43%) had had at least one episode of an anaphylactic reaction. The clinical courses of the reactions were usually severe and patients often presented with syncope attacks (72%). Most patients reacted after hymenoptera venom stings (19/36; 53%). In 39% (14/36), a clear etiology could not be determined. While males and females were equally frequent among the patients with SM, anaphylaxis patients showed a male predominance (61%). Anaphylactic reactions occurred more frequently in patients without cutaneous engagement. The rate of allergy sensitization was significantly higher in SM patients with anaphylaxis as compared with non-anaphylaxis SM patients, 70% vs. 23%, respectively.” (Gulen 2014)


Does an elevated GI mast cell count tract (in the absence of aberrant receptors, clustering or spindled mast cells) indicate MCAS or SM?

“Our immunohistochemical analysis led us to the conclusion that there was no significant difference between the numbers of intestinal mucosal MCs in our patients with MCAS and our reference standard. We recognize that there is currently no consensus for what constitutes a normal number of MCs in the various intestinal tissues. We therefore chose data from a recently published study by one of the authors to be the reference standard. In this study normal numbers of MCs were tabulated for each tissue site. Although we did not find appreciably increased numbers of MCs or abnormal morphology, it is possible that patients with MCAS have a different threshold for MC activation and differentially release MC mediators on activation or that peripheral tissues have an abnormal response to these mediators. We also recognize that a population of patients with chronic diarrhea has been described and labeled as having mastocytic enterocolitis. These patients had a greater number of MCs per hpf in duodenal and colon biopsy specimens compared with the control population (>20 vs 13 MCs/hpf). We were not able to verify this observation in our cohort because many of our control population biopsy specimens had more than 20 MCs/hpf.” (Hamilton 2011)


What is the relationship between CM and MCAD (including SM and MCAS)?

“[M]ost patients with adult-onset MIS [mastocytosis in the skin (commonly called cutaneous mastocytosis,CM)] have demonstrable bone marrow (BM) involvement with clonal mast cells when modern-era diagnostic tools are used, in most instances, satisfying WHO diagnostic criteria for SM. While historical series of patients with MIS revealed an 18% to 50% prevalence of systemic involvement based on conventional histologic criteria, more modern series suggest that only a minority of adult patients have skin-limited disease. Further, approximately 50% of adults with apparent skin-limited mastocytosis may have a clonal BM mast cell infiltrate that falls short of the diagnostic threshold for SM (satisfies major criterion only or only 1 or 2 minor criteria), suggesting prediagnostic or early stage of ISM.” (Pardanini 2013)

“The relationship between systemic MCAD and cutaneous mastocytosis (CM, synonyms: paediatric or childhood onset mastocytosis) remains unclear. Early studies suggested that CM and systemic MCAD were separate disease entities, because the majority of CM patients were found to lack mutations of the tyrosine kinase KITgene. However, subsequent studies have demonstrated that the frequency of clonal KIT mutations is similar in patients with CM, SM and MCAS, and that they are present in up to 86% of patients from each diagnostic group.” (Haenisch 2012)

“Interestingly, in contrast to adult-onset systemic MCAD, more than 50% of paediatric cases of cutaneous mastocytosis appear to enter long-term remission spontaneously, though whether such remissions are permanent or relapse in adulthood as systemic MCAD is unknown.” (Haenisch 2012)

“In contrast, most adults with CM have an underlying SM and should undergo a bone marrow biopsy regardless of the presence of associated systemic symptoms of mediator release. Conversely, 80% of SM patients have cutaneous disease that manifests as urticaria pigmentosa. In contrast, patients with MMAS and MCAS never have CM, and patients with ASM or MCL frequently lack CM.” (Picard 2013)



Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Animesh Pardanani. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) April 18, 2013; Blood: 121 (16).

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.

Brockow, C. Jofer, H. Behrendt and J. Ring. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy, Volume 63, Issue 2, pages 226–232, February 2008.

Wimazal F., Geissler P., Shnawa P., Sperr W.R., Valent P. Severe Life-Threatening or Disabling Anaphylaxis in Patients with Systemic Mastocytosis: A Single-Center Experience. Int Arch Allergy Immunol 2012; 157: 399–405.

Gülen, H. Hägglund, B. Dahlén and G. Nilsson. High prevalence of anaphylaxis in patients with systemic mastocytosis – a single-centre experience. Clinical & Experimental Allergy, Volume 44, Issue 1, pages 121–129, January 2014.