Presentation, Diagnosis, and Management of Mast Cell Activation Syndrome (pp. 155-232)
Authors: (Lawrence B. Afrin, Division of Hematology/Oncology, Medical University of South Carolina, Charleston, SC, USA)
Abstract: First recognized in 1991 and finally termed such in 2007, “mast cell activation
syndrome” (MCAS) is a large, likely quite prevalent collection of illnesses resulting from
MCs which have been inappropriately activated but which, in contrast to the rare
“mastocytosis,” are not proliferating, or otherwise accumulating, to any significant
extent. Due to the marked diversity of direct and indirect, local and remote biological
effects caused by the plethora of mediators released by MCs, MCAS typically presents as
chronic, persistent or recurrent, waxing and waning or slowly progressive multisystem
polymorbidity generally, but not necessarily, of an inflammatory theme. Suspected to be
of clonal origin in most cases, MCAS usually is acquired relatively early in life via
unknown mechanisms; interaction of environmental factors with inheritable risk factors is
one possibility. Initial manifestations often occur in childhood or adolescence but are
non-specific; in fact, virtually all of the syndrome’s manifestations are non-specific,
leading to decades of mysterious illness (and incorrect diagnoses often poorly responsive
to empiric therapies) prior to diagnosis. A large menagerie of mutations in MC regulatory
elements has been found in MCAS patients; most patients appear to have multiple such
mutations, with no clear patterns, or genotype-phenotype correlations, yet apparent. Such
mutational heterogeneity likely drives the heterogeneity of aberrant MC mediator
expression, in turn causing the extreme heterogeneity of clinical presentation. Different
MCAS patients can present with polar opposite clinical aberrancies. All of the body’s
systems can be affected by MCAS. In addition to clinical heterogeneity, diagnosis is
confounded by difficulty not only in detecting sensitive and specific biomarkers of
primary MC disease but also in finding histologic evidence of a non-proliferative disease
wrought by cells capable of great pleomorphism. For example, in contrast to proliferative
mastocytosis which usually drives significantly elevated tryptase levels, relatively non-
proliferative MCAS usually presents with normal tryptase levels; instead, histamine, MCspecific
prostaglandins, and other mediators need to be assessed in evaluations for
MCAS. Although the World Health Organization 2008 classification scheme for
myeloproliferative neoplasms does not recognize MCAS, proposals for diagnostic criteria
have been published recently and generally require presence of symptoms consistent with
chronic/recurrent aberrant MC mediator release, laboratory evidence of such release (or
of mast cell proliferation not meeting WHO criteria for systemic mastocytosis), absence
of any other evident disease which could better explain the full range of findings in the
patient, and, ideally but not necessarily, at least partial response to therapy targeted
against MCs or MC mediators. Systemic MC disease of any form is not presently curable.
Therapies for MCAS generally aim to control and ameliorate the disease by inhibiting
aberrant mediator production and release, blocking released mediators, and/or managing
the consequences of aberrantly released mediators. Many such therapies are available.
Although there presently is no method to predict which set of therapies will best control
the individual patient’s disease, a methodical, persistent, trial-and-error approach usually
succeeds in finding significantly helpful therapy. Lifespan for most MCAS patients
appears normal, but quality of life can be mildly to severely impaired absent correct
diagnosis and effective treatment.
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