The Mastocytosis Chronicles

The Mastocytosis Society, Inc. | 2017-2018

SPECIAL EDITION
HEALTH CARE PROFESSIONALS EDITION

© 2017 The Mastocytosis Society, Inc. All rights reserved

 Our History
The Mastocytosis Society, Inc. (TMS) was founded
in 1995 by Bill Abbottsmith, Linda Buchheit, Olive
Clayson, Iris Dissinger, Bill Hingst, and Joe Palk. At
that time very little was known about Mastocytosis,
so these pioneering individuals sought to fill a massive
void with some answers to their multitude of questions
about this rare disease. They found one another
through NORD, with sheer determination and
extensive research.
The first support group meeting was held in Baltimore
at the Inner Harbor in 1994 and was attended by Linda
Buchheit and Bill Hingst. The second meeting was held
the following year at Linda Buchheit’s home in Ohio.
Fourteen members attended that year. Little did they
know how fruitful their efforts would be and what a
lifeline they would become as more and more patients
joined each year.
Until 1990 many patients diagnosed with Mastocytosis
were given a very grim prognosis. Up until that
time, Mastocytosis was not often considered when
physicians were making a differential diagnosis,
and many cases were completely missed, resulting
in patient death. At that point, signs of the disease
were then discovered on autopsy; however, because
so little was known about Mastocytosis, it was
2 tmsforacure.org | Special Edition 2017-2018
presumed that Mastocytosis was one of the causes
of death, when in fact the patient had often died of
other causes, and the Mastocytosis was an incidental
finding. On the other hand, more advanced cases of
aggressive Mastocytosis were also recognized during
post-mortem exams, leading pathologists to identify
all forms of Mastocytosis as having a high associated
mortality rate. Fortunately, that prognosis has improved
as more patients are diagnosed and treated sooner,
and more physicians research and treat this disease.
Today, we know that pediatric patients have greater
than a 75% chance of outgrowing their disease at
or before puberty, and adults with Indolent Systemic
Mastocytosis can have a near normal life expectancy if
they avoid triggers and take their medication.
Founding Members: Today’s accomplishments are built
on the foundations laid by the early volunteers, and we
are grateful for their efforts. TMS is where it is today
because of the seeds that they planted in 1994 and
in the early years. Since then there have been many
more champions who have served their fellow patients
and families affected by Mastocytosis and Mast Cell
Activation Disorders by volunteering for TMS. We
salute you!
Past Board Members: THANK YOU to all of our past
board members as they are our strong foundation for
all the wonderful and exciting things happening now
and in the future for TMS!
The Mastocytosis Chronicles
The Mastocytosis Society, Inc. | Spring 2017 - Volume 23 Issue 1
In this issue
5 Overview, Definitions, Diagnosis
and Classification
9 Cytology of Mast Cells
10 Cutaneous Mastocytosis Variants
12 Systemic Mastocytosis Variants
16 Mast Cell Activation Syndrome Variants
18 Signs, Symptoms And Triggers
21 Tests
25 Treatments For Mast Cell Disorders
27 Medications To Treat Mast Cell Disorders
29 Pediatric Mast Cell Disorders: Facts in Brief
36 Visual Guide to Diagnosing Mastocytosis
40 Medical & Research Centers that Treat Patients
with Mast Cell Diseases
43 Medical Advisory Board
45 The Mastocytosis Society Printed Materials
46 Medical Reference Highlights
49 Mast Cell Connect Patient Registry brochure
51 Support Group Contacts
Mast Cell Disorder
Challenges Meetings
and US Network Update
By Susan Jennings, PhD, and Valerie Slee, RN,
BSN - February 2017
Since 2014, The Mastocytosis Society, Inc. (TMS) has
hosted small ancillary Mast Cell Disorder Challenges
meetings during the annual gatherings of several physician
specialty associations. The objectives of these meetings
have been to bring together specialist physicians, drug
company representatives and members of the TMS
Research Committee to identify the primary challenges
facing the mast cell disorder community in the United
States and to explore possible actions that would address
those challenges. A key conclusion from our initial
Challenges meetings was that the establishment of a US
Network for Mast Cell Disorders would be extremely helpful
in overcoming many of the challenges faced by our disease
community. During these meetings, our US physicians have
received significant support from a number of international
mast cell disorder specialists, who have shared their
experiences of forming networks in their own countries and
more broadly in Europe. TMS is committed to supporting
activities that will lead to the formation of a US network
under the leadership of Cem Akin, MD, PhD, and Jason
Gotlib, MD, MS, as Co-Chairs. The American Academy
of Allergy, Asthma and Immunology (AAAAI) Mast Cell
Disorder Committee has also agreed to participate in
this effort. Challenges meetings have been held while
specialists have been gathered for American Society of
Hematology and AAAAI Annual Meetings and immediately
prior to the 2015 European Competence Network on
Mastocytosis (ECNM) Annual Meeting.
Please see www.tmsforacure.org for more
information and updates on our Mast Cell Disorder
Challenges Meetings and progress on formation of a
US Network for Mast Cell Disorders.
tmsforacure.org | Special Edition 2017-2018 3
 Committees
Board of Directors
Advanced Systemic Mastocytosis Variants
(advancedvariants@tmsforacure.org) Executive Board/Officers Stephen Rey: Treasurer
Valerie M. Slee, RN, BSN, Chair Valerie M. Slee RN, BSN: Chair treasurer@tmsforacure.org
Michele Q. Kress, Smoldering SM Liaison
Medical Advisory Board Liaison
Drug Shortage Other Board Members/Directors
(drugshortage@tmsforacure.org) Patient Referral Coordinator
Valerie M. Slee, RN, BSN, Co-Chair chairman@tmsforacure.org Patricia Beggiato: Fundraising
Emily A. Menard, Co-Chair
and Political Advocacy Chair
Education Rita Barlow: Vice Chair
(education@tmsforacure.org) fundraising@tmsforacure.org
Gail Barbera, Chair Patient Support and Advocacy
Fundraising supportgroups@tmsforacure.org Jan Hempstead, RN
(fundraising@tmsforacure.org) Patient Cair Coordination Chair
Patricia Beggiato, Chair Gail Barbera: Secretary
nurses@tmsforacure.org
Grants Education Chair
(grants@tmsforacure.org) Stacy Sheldon: Pediatrics Chair
Valerie M. Slee, RN, BSN, Co-Chair
secretary@tmsforacure.org
Patricia Beggiato, Co-Chair education@tmsforacure.o pediatrics@tmsforacure.org
Mastocytosis Chronicles
(chronicles@tmsforacure.org)
Gail Barbera, Editor/Chair Special Edition For Health Care Professionals
Judy Thompson, Copy Editor
The special edition of The Mastocytosis Chronicles has been published specifically for
Media Relations
(mediarelations@tmsforacure.org) physicians and health care professionals since 2007. This edtion contains diagnostic and
Ariella Cohen, JD, Chair treatment protocols for mastocytosis and mast cell activation disorders, locations of mast cell
Medical Conference Planning disorder treatment centers, physician contact information, documentation of research articles,
(medicalconference@tmsforacure.org)
Open and other pertinent information. For additional information visit www.tmsforacure.org.
Patient Care Coordination
(nurses@tmsforacure.org) TMS Medical Advisory Board
Jan Hempstead, RN, Chair
Pediatric Ivan Alvarez-Twose, MD Tracy I. George, MD Larry Schwartz, MD, PhD
(pediatrics@tmsforacure.org)
Stacy Rawson Sheldon, Chair K. Frank Austen, MD (Honorary) Jason Gotlib, MD, MS Theoharis Theoharides, MD, PhD
Political and Patient Advocacy Patrizia Bonadonna, MD Norton J. Greenberger, MD Megha Tollefson, MD
(advocacy@tmsforacure.org) Joseph Butterfield, MD Matthew J. Hamilton, MD Celalettin Ustun, M.D.
Patricia Beggiato, Co-Chair
Kelli Foster, Co-Chair Mariana Castells, MD, PhD Olivier Hermine, MD, PhD Peter Valent, MD
Research Madeleine Duvic, MD Nicholas Kounis, MD, PhD Srdan Verstovsek, MD, PhD
(research@tmsforacure.org) Luis Escribano, MD, PhD, Anne Maitland, MD, PhD
Susan Jennings, PhD, Chair
Special Edition Chronicles We thank each of these doctors for their time, caring, and expertise.
(education@tmsforacure.org)
Valerie M. Slee, RN, BSN, Co-Chair
Susan Jennings, PhD, Co-Chair
TMS is a long-standing National
Support Groups
(supportgroups@tmsforacure.org) Organization Member of the National
Rita Barlow, Co-Chair Organization for Rare Disorders (NORD)
Cheri Smith Co-Chair
Website Content
(education@tmsforacure.org)
TMS is proud to be a Lay Organization member of The American
Gail Barbera, Co-Chair Academy of Allergy Asthma and Immunology (AAAAI)
Susan Jennings, PhD, Co-Chair

SUPPORTING CONTRACTORS
Our Mission
Graphic Designer
John Gilligan The Mastocytosis Society, Inc. is a 501(c)3 nonprofit organization dedicated to supporting patients
Webmaster affected by Mast Cell Disease, as well as their families, caregivers, and physicians through
(webmaster@tmsforacure.org) research, education, and advocacy.
Russell Hirshon
Shannon Flynn

4 tmsforacure.org | Special Edition 2017-2018

MAST CELLS AND MAST CELL DISORDERS
Overview, Definitions, Diagnosis
and Classification
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.
Figure 1. Mast cell (electron micrograph)
Mast cell granule (sac) which contains mediators
Mast cells have within them small sacs, or granules,
surrounded by membranes (Figure 1). 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
There is a difference between someone who is healthy,
with mast cells that are functioning normally, and
someone with a mast cell disorder, 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 Disorders?
Mast cell disorders 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 two major forms of mast cell disorders
are mastocytosis and mast cell activation
syndromes (MCAS). Mast cell disorders
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
Continued on page 6
tmsforacure.org | Special Edition 2017-2018 5
 Overview, Definitions, Diagnosis and Classification
Continued from page 5
proportion of the mast cell disorder 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
disorder, as well as in patients with both mastocytosis
and MCAS.6
MASTOCYTOSIS
Definition
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
6 tmsforacure.org | Special Edition 2017-2018
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
Minorª:
•M
 ore 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
• K IT mutation at codon 816V in extracutaneous
organ(s) (in most cases bone marrow cells are
examined)
• K IT+MCs in bone marrow show aberrant expression
of CD2 and/or CD25
• S erum total tryptase > 20 ng/mL (does not count in
patients who have SM-AHN-type disease.)
Abbreviation Key:
KIT: Mast cell growth receptor/tyrosine kinase receptor
MC(s): Mast cells;
SM-AHN: Systemic mastocytosis with associatiated
hematologic neoplasm.
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
Definition
Existence of a subset of mast cell disorder patients who
experience episodes of mast cell activation without
detectable evidence of a proliferative mast cell disorder
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 disorders, 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 disorders,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. 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
Continued on page 8
tmsforacure.org | Special Edition 2017-2018 7
 Overview, Definitions, Diagnosis and Classification
Continued from page 7
References
1. Gilfillan AM, Austin SJ, Metcalfe DD. Mast cell biology:
introduction and overview. Adv Exp Med Biol. 2011;716:2-12.
2. Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and
Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72.
3. 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.
4. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome:
proposed diagnostic criteria. J Allergy Clin Immunol. 2010
Dec;126(6):1099-104 e4.
5. 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.
6. 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.
7. 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.
8. Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis.
Curr Opin Pediatr. 2012 Aug;24(4):480-6.
9. Fried AJ, Akin C. Primary mast cell disorders in children. Curr
Allergy Asthma Rep. 2013 Dec;13(6):693-701.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
8 tmsforacure.org | Special Edition 2017-2018
16. 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.
17. 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.
18. Valent P. Diagnostic evaluation and classification of mastocytosis.
Immunol Allergy Clin North Am. 2006 Aug;26(3):515-34.
19. Roberts LJ, 2nd, Oates JA. Biochemical diagnosis of systemic
mast cell disorders. J Invest Dermatol. 1991 Mar;96(3):19S-24S;
discussion S-5S.
20. Metcalfe DD. Classification and diagnosis of mastocytosis:
current status. J Invest Dermatol. 1991 Mar;96(3):2S-4S.
21. 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.
22. 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.
23. 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.
24. Horny HP. Mastocytosis: an unusual clonal disorder of bone
marrow-derived hematopoietic progenitor cells. Am J Clin Pathol.
2009 Sep;132(3):438-47.
25. 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.
26. 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.
27. 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.
28. Valent P. Mast cell activation syndromes: definition and
classification. Allergy. 2013 Apr;68(4):417-24.
29. 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.
30. Schwartz LB, Irani AM. Serum tryptase and the laboratory
diagnosis of systemic mastocytosis. Hematol Oncol Clin North
Am. 2000 Jun;14(3):641-57.
Cytology of Mast Cells1
By Tracy I. George, MD

Mast cell types Morphology Types of disease

Normal/reactive Round, well-granulated, with Normal marrow, mast
granules that fill the cytoplasm cell hyperplasia, well
and obscure the nucleus; round differentiated SM
to oval nucleus

Atypical type I Hypogranular, enlarged, with Indolent SM, ASM,

cytoplasmic projections SM-AHN
(spindle shaped)

Atypical type II Enlarged and round, hypogranular; Mast cell leukemia,

indented bilobed nuclei myelomastocytic
(promastocyte) leukemia

Metachromatic Hypogranular with a few large Mast cell leukemia,

blast metachromatic granules; high myelomastocytic
nuclear-to-cytoplasm ratio; leukemia
(immature) smooth chromatin in nuclei

SM: Systemic mastocytosis Reference

ASM: Aggressive systemic mastocytosis 1. G
 eorge TI, Horny HP. Systemic
mastocytosis. Hematol
SM-AHN: Systemic mastocytosis with an associated hematologic neoplasm [previously referred to Oncol Clin North Am. 2011
as SM-AHNMD (systemic mastocytosis with an associated (clonal) hematologic non-mast cell Oct;25(5):1067-83, vii.
lineage disease]

tmsforacure.org | Special Edition 2017 9

 Cutaneous
Mastocytosis
Variants
An international consensus task force of mast cell disorder
specialists has recently proposed updates to the diagnostic
criteria and classification for cutaneous disease.1 Typical skin
lesions found in mastocytosis, along with a positive Darier’s
sign (see below), is the major criterion for diagnosing skin
involvement in patients with mastocytosis. The two minor
criteria are identified via skin lesion biopsy: increased mast
cell numbers and the presence of an (activating) KIT mutation.1,
2
Cutaneous mastocytosis (CM) includes three variants:
maculopapular cutaneous mastocytosis (MPCM),
which includes urticaria pigmentosa (UP) and telangiectasia
macularis eruptiva perstans (TMEP), diffuse cutaneous
mastocytosis (DCM), and cutaneous mastocytoma.1 The
taskforce recommends that telangiectasia macularis eruptiva
perstans (TMEP) be removed as a separate category because,
although some adult patients may have telangiectatic lesions
on their chest, shoulders, neck and back, they may also
demonstrate maculopapular lesions in other places, therefore
fulfilling criteria for MPCM.
Most cases of pediatric mastocytosis fall into one of the
above categories and may or may not include symptoms
of systemic mast cell activation, including anaphylaxis, as
a result of mediators released from the skin.3, 4 Pediatric
CM encompasses a variety of clinical manifestations. In
children, some forms of CM will spontaneously resolve,
some will go on to be diagnosed as indolent systemic
mastocytosis (ISM), with a smaller percentage identified
as well-differentiated systemic mastocytosis (WDSM).5
In most adults with skin lesions typical for mastocytosis
(in particular, the maculopapular type), systemic disease
will ultimately be found, leading to a diagnosis of systemic
mastocytosis, usually in an indolent form (indolent
systemic mastocytosis).1, 6
Definitions1, 7
Darier’s sign is an important diagnostic finding of
10 tmsforacure.org | Special Edition 2017-2018
patients with mastocytosis. It can be elicited by stroking
an existing CM lesion with a wooden tongue depressor,
approximately 5 times with moderate pressure. Within a few
minutes, a wheal and flare reaction of the lesion will be seen.
A positive Darier’s sign is usually seen in pediatric patients,
but not always in adults. It may be decreased by treatment
with antihistamines. If the testing procedure for Darier’s sign
is not done properly, false positives or false negatives may
result. Darier’s sign is to be applied to the evaluation of fixed
cutaneous lesions except in the case of a pediatric patient
with cutaneous mastocytoma or nodular lesions. Testing for
Darier’s sign may provoke a systemic reaction and should
either be performed with the greatest of caution or avoided.
Dermatographism is a skin reaction characterized by a
wheal and flare response when normal skin, not affected by
skin lesions, is stroked with a tongue depressor, finger nails
or other instrument. The nick-name for dermatographism is
skin writing disease.
A macule is a lesion that is flat and even with the
surrounding skin, identified by a change in color compared
to the surrounding skin.
A papule is a small bump or elevated lesion, up to 1 cm in
diameter, containing no visible fluid.
A nodule is a growth of abnormal tissue just below the skin.
A bulla is a large blister filled with fluid.
Telangiectasia is a vascular lesion formed by dilatation
of a group of small blood vessels.
VARIANTS OF CUTANEOUS MASTOCYTOSIS
Maculopapular Cutaneous Mastocytosis (MPCM)/
Urticaria Pigmentosa (UP)1
• May be seen in infants, children or adults
• Adults presenting with maculopapular lesions have
a very high likelihood of systemic disease, most
frequently indolent systemic mastocytosis (ISM)
• Rarely, an adult presents with maculopapular lesions
who does not have systemic disease, and has a
diagnosis of MPCM
• Red maculopapular lesions tend to wheal when
scratched (positive Darier’s sign)
 • Blister formation can occur with rubbing or stroking
of lesion and is associated with pruritis8
• Encompasses several clinical entities with different
outcomes, including: pitted melanotic macules, reddish
brown telangiectatic macules, lightly pigmented
papules, brownish papules, and small nodules
• This group is divided into two sub-variants
° Monomorphic variant
- Mostly seen in adults and in a small subgroup
of children
- Small maculopapular lesions, similar in shape,
size and color
- Adults most typically express the KIT D816V
mutation in exon 17 of the KIT gene
- In adults, thigh, axilla, trunk, extremities and
neck may be involved
- 9 5% of adults diagnosed with ISM, 50% with
advanced systemic mastocytosis [systemic
mastocytosis with an associated hematologic
neoplasm (SM-AHN, formerly SM-AHMND) or
aggressive systemic mastocytosis (ASM)] and
less than 50 % of mast cell leukemia patients
exhibit this variant
- Children presenting with this form may have
increased serum tryptase and a tendency toward
systemic disease that persists into adulthood
- T he type of lesions can vary during the course
of the disease, i.e., nodules during infancy may
turn into plaques at age 6
° Polymorphic variant
-M  ostly seen in children
- C an be macular, plaque or nodular, with lesions
of variable shape, color and size
-A  lthough children typically express mutations
in exon 8, 9, 11 or 17 of the KIT gene, KIT
mutations may be negative
- Usually involving head, neck and extremities
- May involve blistering upon irritation until 3
years of age
- Prognosis is favorable with regression of
disease in adolescence or young adulthood
Diffuse Cutaneous Mastocytosis (DCM)1
• Skin thickened, hyperpigmented and diffusely infiltrated
• Can involve up to 100% of the skin with the trunk,
head and scalp heavily affected
• Can appear at birth or early infancy; may persist into
adulthood, possibly as well differentiated systemic
mastocytosis (WDSM)5
• Blisters, some of which are hemorrhagic, and bullae
may be present and dermatographism may be
prominent
• Flushing is a common symptom
• Tryptase may be elevated due to increased mast cell
burden in the skin and can be indicative of WDSM5
Cutaneous Mastocytoma1
• Usually present at birth
• Elevated lesion(s) (up to a total of three lesions)
which usually resolves during childhood
• Four cutaneous mastocytomas or more become a
diagnosis of MPCM
• Multiple mastocytomas may evolve into adult WDSM5
References
1. 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.
2. V alent 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.
3. M atito A, Carter M. Cutaneous and systemic mastocytosis in
children: a risk factor for anaphylaxis? Curr Allergy Asthma Rep.
2015 May;15(5):22.
4. M eni 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.
5. T orrelo A, Alvarez-Twose I, Escribano L. Childhood
mastocytosis. Curr Opin Pediatr. 2012 Aug;24(4):480-6.
6. B erezowska 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.
7. Venes D, Thomas CL. Taber’s cyclopedic medical dictionary. 19
ed. Philadelphia: F.A. Davis Co.; 2001.
8. C astells 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.
tmsforacure.org | Special Edition 2017-2018 11
 Systemic Mastocytosis Variants
Systemic mastocytosis (SM) consists of a group of
rare, heterogeneous disorders involving growth and
accumulation of abnormal mast cells (MC) in one or
multiple extracutaneous (non-skin) organ systems
(Table 1). Standard technique can be used to obtain
an iliac crest bone marrow (BM) biopsy and aspirate
smear for diagnosis. Aspirated BM should be allocated
for flow cytometry to assess for the presence of mast
cells with aberrant phenotype (i.e., co-expression
of CD25). Immunohistochemistry for KIT, mast cell
tryptase, and CD25 should be performed on sections of
the biopsy.1-5
Recent Updates in Diagnosis
A new diagnostic algorithm has been proposed by the
European Competence Network on Mastocytosis for
evaluating patients with suspected mastocytosis.6
Recommendations for KIT mutation analysis, including in
peripheral blood, have also been recently published.7

Table 1. Major Variants of Systemic Mastocytosis8

ISM (Indolent systemic mastocytosis)

WHO criteria for SM met, MC burden low, +/- skin lesions, no C findings, no evidence of AHNMD
• Bone marrow mastocytosis: ISM variant with BM involvement, but no skin lesions
SSM (Smoldering systemic mastocytosis)
WHO criteria for SM met, typically with skin lesions, with 2 or more B findings, but no C findings.
Advanced Disease Variants
SM-AHN (SM with an associated hematologic neoplasm, formerly SM-AHNMD)
Meets criteria for SM and also criteria for an AHN (MDS, MPN, MDS/MPN, AML), or other WHO-defined myeloid
hematologic neoplasm, +/- skin lesions.
ASM (Aggressive systemic mastocytosis)
Meets criteria for SM with one or more C findings. No evidence of MCL, +/- skin lesions.
MCL (Mast cell leukemia)
Meets criteria for SM. BM biopsy shows a diffuse infiltration, usually compact, by atypical, immature MCs. BM
aspirate smears show 20% or more MCs.
Typical MCL: MCs comprise 10% or more of peripheral blood white cells. Aleukemic MCL: < 10% of peripheral blood
white cells are MCs. Usually without skin lesions.

*SM-AHN is the recently updated term from the 2016 WHO classification of mastocytosis;9 a lymphoproliferative disorder or plasma cell
dyscrasia may rarely be diagnosed with SM.
WHO: World Health Organization; BM: bone marrow; MC: mast cell; MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm; MDS/
MPN: myelodysplastic syndrome/ myeloproliferative neoplasm overlap disorders; AML: acute myeloid leukemia.

12 tmsforacure.org | Special Edition 2017-2018

Table 2. B and C Findings8

B Findings
BM biopsy showing > 30% infiltration by MCs (focal, dense aggregates) and serum total tryptase level > 200 ng/mL
Myeloproliferation or signs of dysplasia in non–MC lineage(s), no prominent cytopenias; criteria for AHN not met
Hepatomegaly and/or splenomegaly on palpation without impairment of organ function and/or lymphadenopathy on
palpation/imaging (> 2 cm)
C Findings*
Cytopenia(s): ANC < 1 x 109/L, Hb < 10 g/dL, or platelets < 100 x 109/L
Hepatomegaly on palpation with impairment of liver function, ascites, and/or portal hypertension
Skeletal lesions: osteolyses and/or pathologic fractures
Palpable splenomegaly with hypersplenism
Malabsorption with weight loss from gastrointestinal tract MC infiltrates
* Must be attributable to the MC infiltrate.

INDOLENT SYSTEMIC MASTOCYTOSIS
The majority of adult patients fit into this category, fulfilling
the criteria for indolent systemic mastocytosis (ISM).2, 10-12
The bone marrow, gastrointestinal tract, skeletal system,
nervous system and skin may be affected. Some patients
may have enlarged livers and spleens and lymphadenopathy.
Mediator-related symptoms are common, but the grade of
bone marrow infiltration is low (usually less than 5 percent)
with the bone marrow fulfilling the criteria for SM and
80-90% of the patients exhibiting a positive D816V KIT
mutation. In most patients the serum tryptase concentration
exceeds 20 ng/mL, but a normal level of tryptase does not
rule out either mastocytosis or another mast cell activation
disorder. Treatment usually includes mediator-targeting
drugs, including antihistamines, but does not usually require
cytoreductive agents, although there are exceptions.
the systemic category, despite that 91% of patients
with WDSM have childhood onset of disease, with
familial involvement in 39%. There is a heterogeneous
presentation of lesions, maculopapular, nodular and
diffuse cutaneous, that may involve a large percentage of
the skin.17 Severe mast cell symptoms can occur and the
variant may persist into adulthood in a low percentage
of cases. The mast cells often do not express CD25 or
CD2 that are part of the minor World Health Organization
(WHO) criterion for SM, but may have CD30. Also, roughly
90% of WDSM patients don’t have the KIT D816V or
other exon 17 KIT mutations.17 Bone marrow analysis
identifies mast cells in WDSM patients as notably large,
round, mature-appearing mast cells with the absence
of the spindle-shaped mast cells typically seen in SM.15
Baseline serum tryptase levels
Continued on page 14

Isolated bone marrow mastocytosis (BMM) is a variant of

indolent SM.12 BMM is characterized by the absence of
skin lesions, lack of multi-organ involvement, and an
increased incidence of anaphylaxis.13
91% of patients
with WDSM have
Well differentiated SM (WDSM) first described
in 200414, is reported in the literature as a rare childhood onset of
variant that fulfills the major criterion for SM
and continues to be studied by researchers.15-17 disease, with familial
WDSM is distinguished from pediatric
cutaneous mastocytosis by its inclusion in
involvement in 39%
tmsforacure.org | Special Edition 2017-2018 13
 Systemic Mastocytosis Variants
Continued from page 13
in these patients are usually lower than what is frequently
detected in SM, except in a variable percentage of
children at onset. Imatinib mesylate has been used in
some patients with severe cases of WDSM, since these
patients do not usually carry the KIT D816V mutation,
which causes resistance to imatinib.18
SMOLDERING SYSTEMIC MASTOCYTOSIS
Smoldering systemic mastocytosis (SSM) was recently
moved out of the WHO ISM category and into its own
category under SM.9 In SSM, two or more B findings, but
no C findings (Table 2) are found and there is a greater
possibility that the disease will progress to a more
aggressive variant.
Advanced Systemic
Mastocytosis Variants8
SM WITH AN ASSOCIATED HEMATOLOGIC
NEOPLASM (SM-AHN)
SM-AHN is the recently updated term for SM-AHNMD
from the 2016 WHO classification of mastocytosis.9 These
patients fit the criteria for SM and they fit the WHO criteria
for myelodysplastic syndrome (MDS), myeloproliferative
neoplasm (MPN), MDS/MPN overlap disorder, or acute
myeloid leukemia (AML), with or without skin lesions.8, 19, 20
Patients are treated for both the SM component and for the
associated hematologic neoplasm.
AGGRESSIVE SYSTEMIC MASTOCYTOSIS
In this rare variant, aggressive systemic mastocytosis
(ASM) patients fit the criteria for SM, with or without skin
lesions, and also meet criteria for one or more C findings
(Table 2).8 Patients with ASM often require chemotherapy.
14 tmsforacure.org | Special Edition 2017-2018
MAST CELL LEUKEMIA21
In this rare variant, mast cell leukemia (MCL) patients fit
the criteria for SM, and a bone marrow aspirate smear
shows that 20% or more of the cells are mast cells, or
10% or more mast cells are seen in circulating blood.8,
21, 22
The mast cells have malignant features. A 2014
international consensus proposal recommends that MCL
be separated into acute and chronic23 subvariants based
on whether or not C findings (Table 2) are present.21 In
addition, it recommends a distinction between a primary
form of MCL and a secondary form that evolves from
an existing mast cell neoplasm, such as ASM or mast
cell sarcoma. There is a prognostic pre-phase identified
in patients with ASM with 5-19% mast cells in bone
marrow smears, associated with rapid progression. It
has been proposed that this condition be called “ASM
in transformation to MCL” (ASM-t). Prognosis can be
variable based on the form of disease; life expectancy
has been extended, in some cases, due to advances
in cytoreductive therapy.24 It is important to note that
myelomastocytic leukemia (MML), which is a differential
diagnosis, is not regarded by mast cell disorder specialists
as a subvariant of MCL or SM and should be considered a
secondary condition.21
References
1. 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.
2. Alvarez-Twose I, Morgado JM, Sanchez-Munoz L, Garcia-
Montero A, Mollejo M, Orfao A, et al. Current state of biology and
diagnosis of clonal mast cell diseases in adults. Int J Lab Hematol.
2012 Oct;34(5):445-60.
3. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art.
Pathobiology. 2007;74(2):121-32.
4. Horny HP, Valent P. Diagnosis of mastocytosis: general
histopathological aspects, morphological criteria, and
immunohistochemical findings. Leuk Res. 2001 Jul;25(7):543-51.
5. Escribano L, Garcia Montero AC, Nunez R, Orfao A. Flow
cytometric analysis of normal and neoplastic mast cells: role in
diagnosis and follow-up of mast cell disease. Immunol Allergy Clin
North Am. 2006 Aug;26(3):535-47.
6. 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.
7. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G,
Escribano L, et al. KIT mutation analysis in mast cell neoplasms:
recommendations of the European Competence Network on
Mastocytosis. Leukemia. 2015 Jun;29(6):1223-32.
8. Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, et
al. International Working Group-Myeloproliferative Neoplasms
Research and Treatment (IWG-MRT) & European Competence
Network on Mastocytosis (ECNM) consensus response
criteria in advanced systemic mastocytosis. Blood. 2013 Mar
28;121(13):2393-401.
9. 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.
10. Carter MC, Metcalfe DD, Komarow HD. Mastocytosis. Immunol
Allergy Clin North Am. 2014 Feb;34(1):181-96.
11. Valent P. Mastocytosis: a paradigmatic example of a rare disease with
complex biology and pathology. Am J Cancer Res. 2013;3(2):159-72.
12. Pardanani A. Systemic mastocytosis in adults: 2013 update on
diagnosis, risk stratification, and management. Am J Hematol.
2013 May 30.
13. Z anotti R, Bonadonna P, Bonifacio M, Artuso A, Schena D, Rossini
M, et al. Isolated bone marrow mastocytosis: an underestimated
subvariant of indolent systemic mastocytosis. Haematologica.
2011 Mar;96(3):482-4.
14. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD.
A novel form of mastocytosis associated with a transmembrane
c-kit mutation and response to imatinib. Blood. 2004 Apr
15;103(8):3222-5.
15. Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis.
Curr Opin Pediatr. 2012 Aug;24(4):480-6.
Mast Cell Sarcoma1, 2
Mast cell sarcoma is a rare tumor that may present in
many different anatomic locations and age groups, and
prognosis is generally poor. Mast cell sarcoma is often
misdiagnosed because the presenting cells bear little
resemblance to normal mast cells and spindle-shaped
mast cells frequently seen in systemic mastocytosis.3 The
cells of mast cell sarcoma more closely resemble “atypical
type II mast cells” or “promastocytes” that are associated
with some cases of aggressive systemic mastocytosis.1, 3
Pathological examination of the tumor has shown it to be
highly malignant with an aggressive growth pattern.3, 4
Patients with this tumor do not fulfill the criteria for SM.1
The imatinib mesylate-resistant KIT D816V mutation has
not been found in reported mast cell sarcomas, such that
use of imatinib has been attempted in some patients.3
16. Fried AJ, Akin C. Primary mast cell disorders in children. Curr
Allergy Asthma Rep. 2013 Dec;13(6):693-701.
17. Alvarez-Twose I, Jara-Acevedo M, Morgado JM, Garcia-
Montero A, Sanchez-Munoz L, Teodosio C, et al. Clinical,
immunophenotypic, and molecular characteristics of well-
differentiated systemic mastocytosis. J Allergy Clin Immunol.
2016 Jan;137(1):168-78 e1.
18. Alvarez-Twose I, Gonzalez P, Morgado JM, Jara-Acevedo M,
Sanchez-Munoz L, Matito A, et al. Complete response after
imatinib mesylate therapy in a patient with well-differentiated
systemic mastocytosis. J Clin Oncol. 2012 Apr 20;30(12):e126-9.
19. Stoecker MM, Wang E. Systemic mastocytosis with
associated clonal hematologic nonmast cell lineage disease:
a clinicopathologic review. Arch Pathol Lab Med. 2012
Jul;136(7):832-8.
20. Wang SA, Hutchinson L, Tang G, Chen SS, Miron PM, Huh
YO, et al. Systemic mastocytosis with associated clonal
hematological non-mast cell lineage disease: clinical
significance and comparison of chomosomal abnormalities
in SM and AHNMD components. Am J Hematol. 2013
Mar;88(3):219-24.
21. Valent P, Sotlar K, Sperr WR, Escribano L, Yavuz S, Reiter A, et al.
Refined diagnostic criteria and classification of mast cell leukemia
(MCL) and myelomastocytic leukemia (MML): a consensus
proposal. Ann Oncol. 2014 Sep;25(9):1691-700.
22. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO,
Hermine O, Damaj G. Mast cell leukemia. Blood. 2013 Feb
21;121(8):1285-95.
23. Valent P, Sotlar K, Sperr WR, Reiter A, Arock M, Horny HP.
Chronic mast cell leukemia: a novel leukemia-variant with distinct
morphological and clinical features. Leuk Res. 2015 Jan;39(1):1-5.
24. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K,
Hermine O, et al. Efficacy and Safety of Midostaurin in
Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun
30;374(26):2530-41.
References
1. V alent 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.
2. H
 orny 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.
3. R yan RJ, Akin C, Castells M, Wills M, Selig MK, Nielsen GP, et
al. Mast cell sarcoma: a rare and potentially under-recognized
diagnostic entity with specific therapeutic implications. Mod
Pathol. 2013 Apr;26(4):533-43.
4. Georgin-Lavialle S, Aguilar C, Guieze R, Lhermitte L, Bruneau J,
Fraitag S, et al. Mast cell sarcoma: a rare and aggressive entity-
-report of two cases and review of the literature. J Clin Oncol.
2013 Feb 20;31(6):e90-7.
tmsforacure.org | Special Edition 2017-2018 15
 Mast Cell Activation Syndrome Variants1-3
PRIMARY MCAS
Primary MCAS results from a clonal population of mast
cells, where a genetic alteration in the cells exists, and
may be due to mastocytosis or to monoclonal Mast
Cell Activation Syndrome (MMAS). Primary MCAS
with mastocytosis can be diagnosed if the patient
fulfils criteria for MCAS and fulfills the WHO criteria for
mastocytosis. MMAS is a distinct disease characterized
by the presence of abnormal mast cells and fulfillment
of criteria for MCAS, but where sufficient criteria for a
diagnosis of mastocytosis are not identified.1-10
SECONDARY MCAS
Secondary MCAS is diagnosed when mast cell activation
occurs as an indirect result of another disease or
condition.1-3, 9, 11 Physician awareness of the presence of
secondary MCAS will allow for more appropriate mast
cell activation-targeted treatments, in addition to primary
disease-related medications, to be provided. In addition
to the widespread example of IgE-dependent allergy as a
cause of secondary MCAS, other diseases that can cause
secondary MCAS have been reviewed in the literature.1-3, 11
Sometimes multiple mast
cell (or mast cell mediator)
blocking therapies must
be tried before successful
symptom resolution is
attained.
16 tmsforacure.org | Special Edition 2017-2018
IDIOPATHIC MCAS
Idiopathic MCAS is proposed as a final diagnosis
after proposed MCAS criteria have been fulfilled and
a thorough evaluation has excluded the possibility of
another known underlying cause for this activation.2,
12
Idiopathic MCAS is therefore nonclonal, with regard
to current diagnostic capabilities related to mast cell
analyses, and has been presented and discussed in the
literature by a variety of mast cell disorder specialists.1-3,
9-13
Review of other causes of MCAS to aid physicians in
evaluation for the exclusionary diagnosis of idiopathic
MCAS have also been provided.1-3, 10
Additional Considerations for MCAS
It is recognized by researchers that current diagnostic
methods for capturing a rise in mast cell mediators
after a symptomatic episode are not ideal.12, 14, 15 Some
patients who present with typical and recurrent signs
and symptoms of mast cell activation do not present
with elevated levels of mediators for which we are
currently able to test. Non-specialist physicians may
most commonly use serum tryptase levels to exclude
a mast cell disorder. However, some MCAS specialists
have indicated that tryptase rises are not seen as
often in patients with certain forms of MCAS, and
that other changes in bloodwork and urine tests can
sometimes be more reliable.13, 14 Additionally, there is a
very narrow window of time (1-2 hours after symptoms
begin) during which to obtain a serum tryptase test
to indicate mast cell activation,2 such that obtaining
laboratory evidence of the event can prove difficult in
many circumstances. Some specialists suggest that
despite lack of proof of elevated mast cell mediators,
a response to mast cell or mast cell mediator blockers
should be determined in such patients.12 If a patient
responds well to anti-mediator treatment and fulfills
the other proposed criteria,2 with the exception of
displaying a rise in mediators, then a diagnosis of
idiopathic MCAS remains open for consideration, as
long as other diagnoses continue to be considered
(please see Valent article noted below for more
information on differential diagnoses). The patient
should be periodically monitored to try to capture a rise
in any of the mediators for which commercial testing
is both available and recognized as a widely accepted
diagnostic standard.12
Even the co-criterion requiring a response to mast cell
targeted therapy can be difficult to obtain in some
patients. Sometimes multiple mast cell (or mast cell
mediator) blocking therapies must be tried before
successful symptom resolution is attained.3, 16 Also, it is
reported in another study, that only one third of MCAS
patients experience a complete resolution with treatment;
one third have a major response and another third have
a minor response, and a combination of drugs is usually
required to achieve control of symptoms.10
Please see the following article for more
information on mast cell activation syndromes,
including potential causes, symptoms, variants,
effects of comorbidities and other possible
diagnoses to exclude:
Valent P. Mast cell activation syndromes: definition and
classification. Allergy. 2013 Apr;68(4):417-24.
References
1. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome:
proposed diagnostic criteria. J Allergy Clin Immunol. 2010
Dec;126(6):1099-104 e4.
2. 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.
3. Valent P. Mast cell activation syndromes: definition and
classification. Allergy. 2013 Apr;68(4):417-24.
4. 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.
5. 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.
6. 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.
7. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi
S, Dal Fior D, et al. Clonal mast cell disorders in patients with
systemic reactions to hymenoptera stings and increased
serum tryptase levels. J Allergy Clin Immunol Pract. 2009
Mar;123(3):680-6.
8. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, Matito
A, Esteban-Lopez MI, Vega A, et al. Clinical, biological, and
molecular characteristics of clonal mast cell disorders presenting
with systemic mast cell activation symptoms. J Allergy Clin
Immunol. 2010 Jun;125(6):1269-78 e2.
9. Akin C, Metcalfe DD. Mastocytosis and mast cell activation
syndromes presenting as anaphylaxis. In: Castells MC, editor.
Anaphylaxis and hypersensitivity reactions. New York: Humana
Press; 2011. p. 245-56.
10. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding
spectrum of mast cell activation disorders: monoclonal and
idiopathic mast cell activation syndromes. Clin Ther. 2013
May;35(5):548-62.
11. Valent P, Horny HP, Triggiani M, Arock M. Clinical and laboratory
parameters of mast cell activation as basis for the formulation of
diagnostic criteria. Int Arch Allergy Immunol. 2011;156(2):119-27.
12. C ardet JC, Castells MC, Hamilton MJ. Immunology and clinical
manifestations of non-clonal mast cell activation syndrome. Curr
Allergy Asthma Rep. 2013 Feb;13(1):10-8.
13. Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ.
Mast cell activation syndrome: a newly recognized disorder with
systemic clinical manifestations. J Allergy Clin Immunol. 2011
Jul;128(1):147-52 e2.
14. Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell
activation disease: a concise practical guide for diagnostic
workup and therapeutic options. J Hematol Oncol. 2011;4:10.
15. Afrin LB. Polycythemia from mast cell activation syndrome:
lessons learned. Am J Med Sci. 2011 Jul;342(1):44-9.
16. 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.
tmsforacure.org | Special Edition 2017-2018 17
 Signs, Symptoms And Triggers

Mast cells can be activated through both IgE and
non-IgE-related mechanisms, resulting in the release
of mediators, such as tryptase, histamine, heparin,
leukotrienes and prostaglandins.1 This activation can
occur in a healthy person, for example in response
to a mosquito bite, and in patients with both
mastocytosis and mast cell activation syndrome
(MCAS). Patients with mastocytosis have extra mast
cells that can activate and release their mediators,
in addition to the possibility of mast cells that may
more readily release mediators, resulting in increased
mediator-induced symptoms. Patients with MCAS
may also have mast cells that are signaled to release
their mediators more easily; this may depend on
genetics, tissue location of the reacting mast cells,
the trigger that initiates the response, or even
coexisting conditions.2, 3 Symptomatology can arise
from both mediator release and/or from mast cell
proliferation, accumulation and infiltration in tissues,
depending on the form of mast cell disease. Triggers
can be common to both patients with mastocytosis
and MCAS, but may be different for each patient.
SYMPTOMS AND TRIGGERS OF MAST
CELL ACTIVATION (MASTOCYTOSIS
AND MCAS)
Mast Cell Activation and Triggers
Mast cells can be activated to release mediators by
multiple triggers. Possible triggers of mediator release
are shown below in Figure 1. Please note that any patient
with a mast cell disorder can potentially react to any
trigger, and triggers can change over the course of the
disease. In addition, patients may experience reactions to
virtually any medications, including medications that they
have tolerated previously. Common medication reactions
in mast cell disorder patients include, but are not limited
to: opioids, antibiotics, NSAIDs, alcohol-containing
medicines and intravenous vancomycin. Use with caution.
More information related to drug hypersensitivity in mast
cell disorders is available in a position paper by European
specialists (http://onlinelibrary.wiley.com/doi/10.1111/
all.12617/full).4

Figure 1. Some Potential Mast Cell Triggers5-8

Exercise Fatigue Food or beverages, Mechanical irritation, Infections (viral,

including alcohol friction, vibration bacterial or fungal)

Heat, cold or sudden Stress: emotional, Drugs (opioids, NSAIDs, Natural odors, Venoms (bee, wasp, mixed
temperature changes, physical, including pain, antibiotics and some chemical odors, vespids, spiders, fire ants,
Sun/sunlight or environmental local anesthetics) and perfumes and scents jelly fish, snakes, biting
(i.e., weather changes, contrast dyes insects, such as flies,
pollution, pollen, pet mosquitos and fleas, etc.)
dander, etc.)

18 tmsforacure.org | Special Edition 2017-2018

Mast Cell Mediator Symptoms
The myriad symptoms patients with mast cell disorders
experience during mast cell activation can wreak havoc
on patients on a daily basis, and multiple organ systems,
including pulmonary, cardiovascular, dermatologic,
gastrointestinal, musculoskeletal, and neurologic can be
involved. Table 1 lists some potential effects linked to
specific mediators.1, 8-15 Symptoms (Table 2) may include,
but are not limited to: flushing of the face, neck, and
chest; headache; tachycardia and chest pain; abdominal
pain, bloating, gastroesophageal reflux disease (GERD),
diarrhea, vomiting; uterine cramps or bleeding; rashes,
including maculopapular cutaneous mastocytosis
(MPCM)/urticaria pigmentosa (UP), telangiectatic
lesions; bone/muscle pain, osteosclerosis, osteopenia,
osteoporosis; itching, +/- rash; blood pressure instability;
brain fog, cognitive dysfunction; anxiety/depression;
lightheadedness, syncope; and the most life-threatening
symptom, anaphylaxis. These symptoms may appear
as acute (as in anaphylaxis, see Table 3) or as chronic
conditions. It should be noted that the manifestation
of anaphylaxis or similar symptoms among infants and
preschoolers may be more difficult to identify.
Table 1. Possible Effects of Some
Mast Cell Mediators15, 16
MEDIATOR POSSIBLE EFFECTS
Histamine Flushing, itching, diarrhea, hypotension
Leukotrienes Shortness of breath
Prostaglandins Flushing, bone pain, brain fog, cramping
Tryptase Osteoporosis, skin lesions
Interleukins Fatigue, weight loss, enlarged lymph
nodes
Heparin Osteoporosis, problems with clotting/
bleeding
Tumor Necrosis Fatigue, headaches, body aches
Factor-α
This mediator list is by no means complete and serves as an example.
Mast cells secrete many mediators responsible for numerous
symptoms within different organ systems.
Table 2. Mast Cell Mediator Symptoms14, 15
MAST CELL MEDIATOR SYMPTOMS
ANAPHYLAXIS
Flushing of the face, neck, and chest
Itching, +/- rash
Hives, skin rashes
Angioedema (swelling)
Nasal itching and congestion
Wheezing and shortness of breath
Throat itching and swelling
Headache and/or brain fog, cognitive dysfunction, anxiety, depression
Diarrhea, nausea, vomiting, abdominal pain, bloating,
gastroesophageal reflux disease (GERD)
Bone/muscle pain, osteosclerosis, osteopenia, osteoporosis
Light-headedness, syncope/fainting
Tachycardia (rapid heart rate), chest pain
Low blood pressure, high blood pressure at the start
of a reaction, blood pressure instability
Uterine cramps or bleeding
Table 3. When Does this Become Anaphylaxis?
Anaphylaxis is an acute life-threatening systemic
reaction that results from the sudden, rapid, systemic
release of mediators.
MOUTH Itching, swelling of lips and/or tongue
THROAT* Itching, tightness/closure, hoarseness
SKIN Itching, hives, redness, swelling
GUT Vomiting, diarrhea, cramps
LUNG* Shortness of breath, cough, wheeze
HEART* Weak pulse, dizziness, passing out
Only a few symptoms may be present. Severity of symptoms
can change quickly. *Some symptoms can be life-threatening.
ACT FAST! Use your anaphylaxis action plan!17
Information from Table 3 taken from the American Academy of
Allergy, Asthma and Immunology (AAAAI) Anaphylaxis Emergency
Action Plan17 and the Anaphylaxis Guidelines Pocketcard.18
An AAAAI Anaphylaxis Card (http://www.aaaai.org/
Aaaai/media/MediaLibrary/PDF%20Documents/Libraries/
Anaphylaxis-Card.pdf) in English and Spanish is also available.
Continued on page 20
tmsforacure.org | Special Edition 2017-2018 19
 Signs, Symptoms And Triggers
Continued from page 19
SIGNS AND SYMPTOMS OF MAST CELL
PROLIFERATION, ACCUMULATION AND
INFILTRATION (MASTOCYTOSIS)
Advanced disease symptoms may include the following
signs of mast cell proliferation, accumulation and infiltration:
anemia, thrombocytopenia, ascites, bone fractures,
gastrointestinal abnormalities, and enlargement of the
liver, spleen, and lymph nodes.19, 20 Mast cell proliferation,
accumulation and infiltration can occur in systemic
mastocytosis (SM), smoldering SM (SSM), aggressive SM
(ASM), SM with an associated hematologic neoplasm
(SM-AHN) [previously called “SM with associated clonal
hematologic non mast cell lineage disease” (SM-AHNMD)],21
or mast cell leukemia (MCL). B and C findings (see Systemic
Mastocytosis Variants section), in addition to meeting the
criteria for SM (see Overview section), clearly define these
signs and assist physicians with the diagnosis.
References
1. Castells M. Mast cell mediators in allergic inflammation
and mastocytosis. Immunol Allergy Clin North Am. 2006
Aug;26(3):465-85.
2. Akin C. Mast cell activation disorders. J Allergy Clin Immunol
Pract. 2014 May-Jun;2(3):252-7 e1; quiz 8.
3. Valent P. Mast cell activation syndromes: definition and
classification. Allergy. 2013 Apr;68(4):417-24.
4. Bonadonna P, Pagani M, Aberer W, Bilo MB, Brockow K, Oude
Elberink H, et al. Drug hypersensitivity in clonal mast cell disorders:
ENDA/EAACI position paper. Allergy. 2015 Jul;70(7):755-63.
5. Silva I, Carvalho S, Pinto PL, Machado S, Rosado Pinto J.
Mastocytosis: a rare case of anaphylaxis in paediatric age and
literature review. Allergol Immunopathol (Madr). 2008 May-
Jun;36(3):154-63.
6. Jennings S, Russell N, Jennings B, Slee V, Sterling L, Castells M,
et al. The Mastocytosis Society survey on mast cell disorders:
patient experiences and perceptions. J Allergy Clin Immunol
Pract. 2014 Jan-Feb;2(1):70-6.
7. Boyden SE, Desai A, Cruse G, Young ML, Bolan HC, Scott LM,
et al. Vibratory Urticaria Associated with a Missense Variant in
ADGRE2. N Engl J Med. 2016 Feb 18;374(7):656-63.
8. Akin C, Metcalfe DD. Mastocytosis and mast cell activation
syndromes presenting as anaphylaxis. In: Castells MC, editor.
Anaphylaxis and hypersensitivity reactions. New York: Humana
Press; 2011. p. 245-56.
9. Escribano L, Akin C, Castells M, Orfao A, Metcalfe DD.
20 tmsforacure.org | Special Edition 2017-2018
Mastocytosis: current concepts in diagnosis and treatment. Ann
Hematol. 2002 Dec;81(12):677-90.
10. Castells M, Austen KF. Mastocytosis: mediator-related signs and
symptoms. Int Arch Allergy Immunol. 2002 Feb;127(2):147-52.
11. Butterfield JH, Weiler CR. Prevention of mast cell activation
disorder-associated clinical sequelae of excessive prostaglandin
D(2) production. Int Arch Allergy Immunol. 2008;147(4):338-43.
12. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome:
proposed diagnostic criteria. J Allergy Clin Immunol. 2010
Dec;126(6):1099-104 e4.
13. 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.
14. 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.
15. Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and
Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72.
16. Carter MC, Metcalfe DD, Komarow HD. Mastocytosis. Immunol
Allergy Clin North Am. 2014 Feb;34(1):181-96.
17. A merican Academy of Allergy Asthma and Immunology
Anaphylaxis Emergency Action Plan. 2016 [9/9/16]; Available
from: https://www.aaaai.org/aaaai/media/medialibrary/pdf%20
documents/libraries/anaphylaxis-emergency-action-plan.pdf.
18. Lieberman P, American College of Allergy, Asthma and
Immunology and American Academy of Allergy, Asthma and
Immunology. Anaphylaxis Guidelines Pocketcard. Baltimore,
MD: International Guidelines Center; 2011; Available from:
http://eguideline.guidelinecentral.com/i/55265-anaphylaxis.
19. Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, et
al. International Working Group-Myeloproliferative Neoplasms
Research and Treatment (IWG-MRT) & European Competence
Network on Mastocytosis (ECNM) consensus response
criteria in advanced systemic mastocytosis. Blood. 2013 Mar
28;121(13):2393-401.
20. Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH,
et al. Systemic mastocytosis in 342 consecutive adults: survival
studies and prognostic factors. Blood. 2009 Jun 4;113(23):5727-36.
21. 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.

Tests
First and foremost, a careful examination of the skin
should be undertaken, looking for characteristic lesions
of mastocytosis. If lesions are found, the physician should
stroke the lesion firmly with a tongue depressor 5 or 6 times
to see if it urticates (Darier’s sign). However, flushing and
systemic low blood pressure can result from attempts to
identify Darier’s sign in young children who have cutaneous
mastocytoma or a polymorphic variant of maculopapular
cutaneous mastocytosis with nodular lesions, such that
this test should be avoided in these patients.1, 2 Darier’s
sign is positive in almost all children and most of the
adults who have skin involvement in mastocytosis. An
international consensus task force of mast cell disorder
specialists has recently proposed that Darier’s sign be
included as part of the major criterion for diagnosing skin
involvement in mastocytosis patients.2 Clear areas of skin
can be stroked in the same way noted above to check for
dermatographism, or skin writing, in which the area stroked
becomes inflamed. Darier’s sign and dermatographism are
characteristic cutaneous symptoms in mast cell disorders.
Tests for Mast Cell Activation and/or Mast Cell
Activation Syndrome (MCAS) Diagnostic Workup
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.3-5 An international consensus
article provides a method for calculating the required
minimum rise in serum tryptase:5
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 for a mast
cell activation event. For example, if a patient had a basal
(baseline level, at least 24 hours after a reaction) serum
tryptase level of 8 ng/ml, a 20% rise, plus 2 ng/ml, would
be 11.6 ng/ml. To meet the above criterion for serum
tryptase, the patient would need a post-reaction serum
tryptase level above 11.6 ng/ml. The calculation would be
conducted as follows:
TMS strongly supports and
currently funds research to
identify better markers for
mast cell activation.
(basal level, plus 20%) + additional 2 ng/ml =
the serum tryptase level, after a reaction,
that must be met or exceeded in order to meet a
rise in serum tryptase considered a mast
cell activation event
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.5, 6 Some practitioners currently utilize
other tests to make a diagnosis of mast cell activation.
While we strongly recognize that we are limited in that
there are many mast cell mediators, and yet we have
commercial tests available for less than five of them here
in the US, The Mastocytosis Society, Inc. (TMS) cannot
endorse the use of other mediator markers as diagnostic
tools until they have been adequately evaluated and proven
as valid for mast cell disorders in sound, scientific research.
TMS strongly supports and currently funds research to
identify better markers for mast cell activation.
TMS does recognize, however, that capturing a mediator
rise is not always easy, and depends on many factors,
internal and environmental. We have seen 24-hour urine
samples test negative simply because the lab technician
did not refrigerate the sample in a timely manner (when
the test was repeated and handled properly, the result
was positive). Therefore, we support the use of a clinical
diagnosis and advise that the patient continues to be
treated when the following criteria have been met:7
Continued on page 22
tmsforacure.org | Special Edition 2017-2018 21
 Tests
Continued from page 21
• An exhaustive work-up has ruled out other medical
conditions with similar symptoms and presentations
• The patient has exhibited consistent symptoms of
mast cell activation in 2 or more organ systems
during the same period of time, such as skin,
gastrointestinal tract, central nervous system, etc.
• The patient responds to antimediator therapy
• The patient is monitored on a regular basis, with
testing for mediator rises performed periodically, by
a mast cell or other specialist and/or in conjunction
with an established local allergist or other physician
• The patient is evaluated for other disease processes
on an ongoing basis in order to be inclusive of any
new changes in the patient’s condition
Routine and Follow-up Testing for MCAS
In patients who demonstrate a mediator rise, mediator
testing should be repeated periodically. In addition,
a complete blood count (CBC) with differential, blood
chemistries, immunoglobulin levels, liver function tests,
DEXA scans for bone density, and other testing may all
be done as part of the routine exam, depending on the
patient’s age, presenting symptoms, coexisting conditions
and medication profile.8
In patients who
demonstrate a mediator
rise, mediator testing
should be repeated
periodically.
22 tmsforacure.org | Special Edition 2017-2018
Tests for Clonal Mast Cell Disorders Such as
Systemic Mastocytosis or Monoclonal MCAS
Bone Marrow Biopsy
Standard technique can be used to obtain an iliac crest
bone marrow biopsy and aspirate smear for diagnosis.
Aspirated bone marrow should be allocated for flow
cytometry to assess for the presence of mast cells with
aberrant phenotype (i.e., co-expression of CD25). KIT
mutation testing (see below) can also be performed on
bone marrow aspirate. Immunohistochemistry for KIT,
mast cell tryptase, and CD25 should be performed on
sections of the biopsy.1, 9-12
KIT Mutation Testing13
To understand why KIT testing is necessary, one must first
understand the difference between clonal and non-clonal
mast cell disorders. Clonal means that there is a defect
in a person’s mast cell DNA, which results in their mast
cells having abnormal characteristics. Although the most
common defect seen in mast cell disease is KIT D816V, it
is not the only one that can result in an abnormal disease
process. Numerous other mutations in KIT have been
associated with mastocytosis, and in the absence of a
KIT D816V mutation, other testing can be performed to
identify them, including KIT sequencing. If there is no
change (no mutation, such as a KIT mutation) identified
in the mast cell DNA, but the patient experiences mast
cell activation, this may be non-clonal disease, such as
idiopathic mast cell activation syndrome.
There has been a peptide nucleic acid mediated PCR
based test available for years that can identify the KIT
D816V mutation in peripheral blood, and it has been able
to detect the mutation in 44% of systemic mastocytosis
patients tested.14 A newer test, an allele-specific
oligonucleotide qPCR test, has proven to be much more
sensitive and reliable. Patients with indolent systemic
mastocytosis with skin involvement, for example, were
found to have the KIT D816V mutation 92% of the time • Serum tryptase and 24-hour urines for
using the newer allele-specific qPCR blood test.14 N-methyl histamine, prostaglandin D2 (PGD2),
11β-prostaglandin F2α
Although the more sensitive test for the KIT D816V • Liver function tests, serum albumin, serum LDH, and
mutation (the allele-specific qPCR, with a sensitivity of serum alkaline phosphatase
0.01%) that can be performed in peripheral blood samples • Blood chemistries
has been developed, is not yet widely available here in the • Total immunoglobulins or total IgE, if indicated by
US. However, Mayo Clinic in Rochester, MN can perform previous testing
the allele-specific oligonucleotide PCR (ASO-PCR) test for • Serum β2-microglobulin
KIT D816V and the test may be available through several • DEXA scans for bone density; nuclear medicine bone
other labs in the US. Currently in the US, the result is scan, if indicated
often reported as either positive or negative, although • Bone marrow biopsy with flow cytometry and
in a research setting, results can be presented in more cytology, when indicated
detail as an “allelic frequency”, which is essentially a • Allele-specific qPCR for KIT D816V mutation in
measure of the extent to which the mutation is present peripheral blood/bone marrow, if not already
versus KIT without that mutation (the allelic frequency can performed; KIT sequencing, if indicated13
help in determining disease prognosis). It is important to • CT scan/ultrasound, if indicated
note that receiving a negative test does not rule out a mast • Other tests may be performed, as indicated, if there
cell disorder.13, 15 If an adult with systemic mastocytosis does is a suspected hematologic disorder or to evaluate
not test positive for the KIT D816V mutation using sensitive the individual patient’s symptoms.
testing methods, then sequencing of KIT might be considered.
Diagnostic Workup for Advanced Systemic
Knowing the KIT mutation status can be very important
Mastocytosis Variants or Associated
when considering therapeutic options such as new
Hematological Disorders1, 13, 16, 17
medications and chemotherapy. The development of the
allele-specific qPCR test will make peripheral blood KIT
When advanced disease or an associated hematological
testing more widely available in the near future. More
disorder is suspected, further evaluation of the patient
information on the use of KIT mutation testing in mast cell
beyond a bone marrow biopsy and aspirate with flow
disorders (including potential use in prognosis) is available
cytometry may include:
in published recommendations from the European
Competence Network on Mastocytosis.
• Comprehensive bloodwork
• X-ray or CT scan of the chest, looking for evidence
Routine and Follow-up Testing for Systemic
of significantly enlarged lymph nodes (greater than 2
Mastocytosis (SM) and Smoldering SM
cm in diameter)
• X-ray, nuclear medicine bone scan of the
Examinations should occur periodically and include:13
skeletal system, or bone density scan looking for
osteoporosis, osteosclerosis, or areas where calcium
• Dermatological exam (with stroking for Darier’s sign)
has been completely lost from bone
• Careful palpation of the liver, spleen and lymph nodes
• CT scan or ultrasound of the abdomen, looking for
• A full neuropsychological evaluation
enlarged liver or spleen, enlarged lymph nodes, or
• CBC with differential
the collection of fluid
Continued on page 24

tmsforacure.org | Special Edition 2017-2018 23

 Tests
Continued from page 23
• Endoscopy/colonoscopy and biopsy of the
gastrointestinal tract, looking for evidence of mast
cell infiltration, ulcers, or areas of bleeding. Mast
cell infiltration can be identified by aggregates of
15 or more abnormal mast cells, or sheets of mast
cells. Abnormal mast cells can be identified by the
presence of CD25 on these cells.18
• Other tests may include next-generation sequencing
and myeloid gene panels for additional genetic lesions.
References
1. 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.
2. 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.
3. 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.
4. Schwartz LB, Irani AM. Serum tryptase and the laboratory
diagnosis of systemic mastocytosis. Hematol Oncol Clin North
Am. 2000 Jun;14(3):641-57.
5. 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.
6. Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ.
Mast cell activation syndrome: a newly recognized disorder with
systemic clinical manifestations. J Allergy Clin Immunol. 2011
Jul;128(1):147-52 e2.
7. Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical
manifestations of non-clonal mast cell activation syndrome. Curr
Allergy Asthma Rep. 2013 Feb;13(1):10-8.
24 tmsforacure.org | Special Edition 2017-2018
8. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding
spectrum of mast cell activation disorders: monoclonal and
idiopathic mast cell activation syndromes. Clin Ther. 2013
May;35(5):548-62.
9. Alvarez-Twose I, Morgado JM, Sanchez-Munoz L, Garcia-
Montero A, Mollejo M, Orfao A, et al. Current state of biology and
diagnosis of clonal mast cell diseases in adults. Int J Lab Hematol.
2012 Oct;34(5):445-60.
10. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art.
Pathobiology. 2007;74(2):121-32.
11. Horny HP, Valent P. Diagnosis of mastocytosis: general
histopathological aspects, morphological criteria, and
immunohistochemical findings. Leuk Res. 2001 Jul;25(7):543-51.
12. Escribano L, Garcia Montero AC, Nunez R, Orfao A. Flow
cytometric analysis of normal and neoplastic mast cells: role in
diagnosis and follow-up of mast cell disease. Immunol Allergy Clin
North Am. 2006 Aug;26(3):535-47.
13. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G,
Escribano L, et al. KIT mutation analysis in mast cell neoplasms:
recommendations of the European Competence Network on
Mastocytosis. Leukemia. 2015 Jun;29(6):1223-32.
14. Jara-Acevedo M, Teodosio C, Sanchez-Munoz L, Alvarez-
Twose I, Mayado A, Caldas C, et al. Detection of the KIT D816V
mutation in peripheral blood of systemic mastocytosis: diagnostic
implications. Mod Pathol. 2015 Aug;28(8):1138-49.
15. Kristensen T, Vestergaard H, Bindslev-Jensen C, Moller MB,
Broesby-Olsen S, Mastocytosis Centre OUH. Sensitive KIT D816V
mutation analysis of blood as a diagnostic test in mastocytosis.
Am J Hematol. 2014 May;89(5):493-8.
16. Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, et
al. International Working Group-Myeloproliferative Neoplasms
Research and Treatment (IWG-MRT) & European Competence
Network on Mastocytosis (ECNM) consensus response
criteria in advanced systemic mastocytosis. Blood. 2013 Mar
28;121(13):2393-401.
17. Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH,
et al. Systemic mastocytosis in 342 consecutive adults: survival
studies and prognostic factors. Blood. 2009 Jun 4;113(23):5727-
36.
18. Hahn HP, Hornick JL. Immunoreactivity for CD25 in
gastrointestinal mucosal mast cells is specific for systemic
mastocytosis. Am J Surg Pathol. 2007 Nov;31(11):1669-76.
Treatments For Mast Cell Disorders

Mast Cell Activation/Mediator

Release Symptoms

Controlling symptoms of mast cell activation/mediator

release starts with avoiding the triggers which will
initiate mast cell activation, and the triggers can be
very individual. Avoiding heat, cold, abrupt changes
in temperature, sunlight, strong odors/perfumes and
chemical smells can help many patients. Caution must be
taken around venomous creatures such as bees, wasps,
hornets, spiders, jellyfish and snakes, etc. Stress and
fatigue can be major triggers for many patients, as can
viruses, bacterial and fungal infections. Sometimes a
simple change in routine can be a trigger.
Many foods can trigger mast cells to activate and release
their mediators; shellfish, peanuts, nuts, citrus, and high
histamine foods are high on the list of potential triggers
known to bother some people, but not others. Medications
to be taken with caution include NSAIDs such as ibuprofen,
toradol, aspirin (this can be confusing, because aspirin
can also be used as a treatment for those with high
prostaglandin levels; when used as a treatment it must
be started under the supervision of a physician!), opioid
narcotics, alcohol, the intravenous form of vancomycin
(the oral form is usually fine), some anesthetics, some
antibiotics, and topical agents, like benzocaine. However,
everyone is different. Anyone can react to anything, and
a patient can even react to something that he or she has
never reacted to before. Encourage your patients to always
have someone with them when taking a new medication,
starting a new treatment, or traveling to a new place.
Patients are often frustrated by their inability to determine
what trigger activated their mast cells. In that situation,
treat the symptoms, advise rest, tell the patient to be
watchful for any recurrence of symptoms (bi-phasic
reaction) and advise the patient to keep a diary of foods,
medications, symptoms and possible triggers.
TMS recommends keeping
a food, medicine and
symptom diary to help the
physician and patient to
connect the dots!
In addition to avoiding triggers, futher treatment
of mastocytosis depends on the symptoms and the
classification of disease.1-3 Symptoms of mast cell
activation/mediator release are treated with H1 and
H2 antihistamines, mast cell stabilizers, leukotriene
inhibitors, and possibly aspirin (under direct supervision of
a physician). All mast cell disease patients should carry
two doses of self-injectable epinephrine, unless otherwise
contraindicated (glucagon may need to be administered
for patients on beta-blockers). Patients should also be
instructed on how to self-administer the epinephrine while
lying down, to maximize rapid absorption of the drug.
Every patient should carry a physician-signed American
Academy of Allergy, Asthma and Immunology Anaphylaxis
Action Plan at all times.
Treatment of MCAS is similar to that listed above for
mastocytosis symptoms related to mast cell activation and
mediator release.4-6

Continued on page 26

tmsforacure.org | Special Edition 2017-2018 25

 Treatments For Mast Cell Disorders
Continued from page 25
There has been growing recognition of the detrimental
effects on cognition (mental clouding and other
cognitive impairments) caused by long term use of
antihistamines.7 A high risk group of patients 65 years
and older (defined as patients taking 50 mg per day
for 3 years diphenhydramine or doxepin or 25 mg for
6 years), were found to have a significant association
between diphenhydramine use and cognitive impairment.8
Similarly, high doses of sedating antihistamines such as
diphenhydramine can cause increased seizure activity,
seen mostly in children. In addition, a tolerance to or a
dependence upon diphenhydramine may result in a need
for even higher doses.7 Caution and restraint must be
used when taking antihistamines long term in order to
help preserve neurological function. While these drugs
are crucial for their antimediator effects, they should be
titrated to the lowest dose necessary to achieve control
of mast cell activation symptoms.
Additional Symptoms of Indolent
Systemic Mastocytosis
A suggested order of treatment options for adult
patients with indolent systemic mastocytosis, aimed at
symptom control, and including suggested therapies for
osteoporosis, can be found in table 3 of this article: http://
onlinelibrary.wiley.com/doi/10.1002/ajh.23931/full from
the American Journal of Hematology.9
Advanced Disease
Therapies exist for smoldering systemic mastocytosis
(SSM) and advanced systemic mastocytosis, and
promising new treatments are being developed.
Prominent among these newer treatments are tyrosine
kinase inhibitors (TKIs) targeting the KIT kinase10, 11 (e.g.,
midostaurin10, 12). Imatinib is approved therapy for adult
aggressive systemic mastocytosis (ASM) patients lacking
the KIT D816V mutation or if mutation status is unknown.
Additional standard therapies for advanced variants are
interferon, the chemotherapeutic agent cladribine, and
tyrosine kinase inhibitors such as midostaurin.9, 12 These
26 tmsforacure.org | Special Edition 2017-2018
chemotherapeutic agents are used in combination with
antimediator therapy to control symptoms and reduce
the overall mast cell burden. In patients with systemic
mastocytosis with associated clonal hematologic
non-mast cell lineage disease (SM-AHNMD)/systemic
mastocytosis with an associated hematologic neoplasm
(SM-AHN), therapy selection usually depends on the
associated disease, which is commonly more aggressive
than the SM part. Mast cell leukemia and sarcoma require
a polychemotherapy approach.
References
1. Carter MC, Metcalfe DD, Komarow HD. Mastocytosis. Immunol
Allergy Clin North Am. 2014 Feb;34(1):181-96.
2. Fried AJ, Akin C. Primary mast cell disorders in children. Curr
Allergy Asthma Rep. 2013 Dec;13(6):693-701.
3. Cardet JC, Akin C, Lee MJ. Mastocytosis: update on
pharmacotherapy and future directions. Expert Opin
Pharmacother. 2013 Oct;14(15):2033-45.
4. Lee MJ, Akin C. Mast cell activation syndromes. Ann Allergy
Asthma Immunol. 2013 Jul;111(1):5-8.
5. Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical
manifestations of non-clonal mast cell activation syndrome. Curr
Allergy Asthma Rep. 2013 Feb;13(1):10-8.
6. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding
spectrum of mast cell activation disorders: monoclonal and
idiopathic mast cell activation syndromes. Clin Ther. 2013
May;35(5):548-62.
7. Theoharides TC, Stewart JM. Antihistamines and Mental Status.
J Clin Psychopharmacol. 2016 Jun;36(3):195-7.
8. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker
R, et al. Cumulative use of strong anticholinergics and incident
dementia: a prospective cohort study. JAMA Intern Med. 2015
Mar;175(3):401-7.
9. Pardanani A. Systemic mastocytosis in adults: 2015 update on
diagnosis, risk stratification, and management. Am J Hematol.
2015 Mar;90(3):250-62.
10. Verstovsek S. Advanced systemic mastocytosis: the impact of
KIT mutations in diagnosis, treatment, and progression. Eur J
Haematol. 2013 Feb;90(2):89-98.
11. Ustun C, DeRemer DL, Akin C. Tyrosine kinase inhibitors in
the treatment of systemic mastocytosis. Leuk Res. 2011
Sep;35(9):1143-52.
12. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine
O, et al. Efficacy and Safety of Midostaurin in Advanced Systemic
Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41.
mastocytosis. Am J Surg Pathol. 2007 Nov;31(11):1669-76.
Medications To Treat Mast Cell Disorders

ALL PATIENTS: Please see Table 7 for a list of some specific drugs for
advanced systemic mastocytosis.
Self-Injectable Epinephrine (two doses; e.g.,
EpiPen®/EpiPen Jr®) should be carried by all Table 1. Some First Generation H1 Antihistamines
patients with a mast cell disorder at all times, even
if previous anaphylaxis has not occurred. Both the Brand Name Generic Name
patient and family members/caregivers should be
Atarax® Hydroxyzine hydrochloride
trained on administering the epinephrine!
Benadryl® Diphenhydramine
Please visit the American Academy of Allergy, Asthma Chlor-trimeton® Chlorpheniramine
and Immunology (AAAAI) website for more information on Doxepin®, Sinequan® Doxepin hydrochloride
anaphylaxis. Tavist® Clemastine

http://www.aaaai.org/conditions-and-treatments/allergies/
Table 2. Some Second Generation H1
anaphylaxis
Antihistamines (may tend to cause less
Basic Medications for Symptomatic Patients with drowsiness)
Mast Cell Disorders1-4
Brand Name Generic Name
• H1 antihistamines: help with itching, abdominal
Allegra® Fexofenadine
pain, flushing, headaches, brain fog
• H2 antihistamines: help with gastrointestinal
Claritin® Loratidine
symptoms and overall mast cell stability (all mast cell Clarinex® Desloratidine
activation symptoms) Zaditor®/Zaditen® Ketotifen
• Mast cell stabilizers: help with stomach and (in Europe)*
intestinal symptoms and brain fog Xyzal® Levocetirizine
• Leukotriene inhibitors: help with respiratory Zyrtec® Cetirizine
symptoms and overall mast cell stability (all mast cell
activation symptoms) *Zaditor® is only available in the US as eye drops;
• Aspirin therapy (under direct supervision of a Zaditen® is available by prescription, but it must be
physician): if tolerated and if prostaglandins are obtained from a compounding pharmacy or from abroad.
elevated, helps with flushing, brain fog and bone pain
Note: The H1 and H2 antihistamines are necessary to Table 3. Some H2 Antihistamines
stabilize receptors on the mast cell. Therefore, if additional
medication is required for control of gastroesophageal Brand Name Generic Name
reflux (GERD), a proton pump inhibitor may be added to this Axid® Nizatidine
protocol, but it cannot replace the H2 antihistamine.
Pepcid® Famotidine
Tagamet® Cimetidine
Please see Table 1- Table 6 for lists of some specific
drugs in these different categories.
Zantac® Ranitidine

Continued on page 28

tmsforacure.org | Special Edition 2017-2018 27

 Medications To Treat Mast Cell Disorders
Continued from page 27

Table 4. Mast Cell Stabilizers Table 7. Some Chemotherapy Drugs for Selected
Patients with Smoldering and Advanced
Brand Name Generic Name Variants of Systemic Mastocytosis1, 5
Gastrocrom ®
Oral cromolyn sodium
Zaditor®/Zaditen® Ketotifen Brand Name Generic Name
(in Europe)* Gleevec® Imatinib
Algonot, Neuroprotect, Food supplements containing Masivet® Masitinib
etc. bioflavonoids such as Sprycel® Dasatinib
quercetin and luteolin Tasigna® Nilotinib
Aspirin; ASA Aspirin, acetylsalicylic Midostaurin® PKC 412
acid (for those with high
Hydrea® Hydroxyurea
prostaglandin levels;
Leustatin®, Leustat®, Cladribine, 2-CDA
aspirin therapy must
Litak®
be initiated under the
direct supervision of a Intron® Interferon Alfa-2b
physician!) There are several more therapies in the pipeline, including
®
* Zaditor is only available in the US as eye drops; Zaditen® additional tyrosine kinase inhibitors and other targeted
is available by prescription, but it must be obtained from a therapies.
compounding pharmacy or from abroad.

Sometimes symptoms change, and it becomes necessary

Table 5. Some Leukotriene Inhibitors to increase or decrease doses of medications, or to add
additional medications to a patient’s prescribed protocol.
Sometimes a simple adjustment made by a mast cell
Brand Name Generic Name
specialist can make a significant difference in a patient’s
Singulair® Montelukast symptoms. Please reinforce with your patients that while
Accolate® Zafirlukast it is tempting to change dosing regimins on their own, it
Zyflo®/Zyflo CR® Zileuton is important that they work closely with their physician to
achieive the safest most effective outcome.
Table 6. Proton Pump Inhibitors to Help
with GERD (Gastroesophageal Reflux) References

Brand Name Generic Name 1. P ardanani A. Systemic mastocytosis in adults: 2015 update on
diagnosis, risk stratification, and management. Am J Hematol. 2015
Mar;90(3):250-62.
Aciphex® Rabeprazole
2. T heoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and
Dexilant® Dexlansoprazole Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72.
Nexium® Esomeprazole 3. Akin C. Mast cell activation disorders. J Allergy Clin Immunol Pract.
Prevacid® Lansoprazole 2014 May-Jun;2(3):252-7 e1; quiz 8.

Prilosec® Omeprazole 4. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding

spectrum of mast cell activation disorders: monoclonal and
Protonix® Pantoprazole idiopathic mast cell activation syndromes. Clin Ther. 2013
May;35(5):548-62.
5. C , DeRemer DL, Akin C. Tyrosine kinase inhibitors in the treatment
of systemic mastocytosis. Leuk Res. 2011 Sep;35(9):1143-52.

28 tmsforacure.org | Special Edition 2017-2018

Pediatric Mast Cell Disorders: Facts in Brief
By Valerie M. Slee, RN, BSN, Mishele Cunningham, RN, BSN, PHN, and Susan Jennings, PhD
Pediatric mast cell disorders, a group of rare diseases, are
characterized by either the presence of too many mast
cells in the skin or other tissues (pediatric mastocytosis),1
or recurrent symptoms arising from release of mast cell
mediators in two or more organ systems, in parallel (mast cell
activation syndrome, MCAS). Mast cells are instrumental in
mediating anaphylaxis, and children with mast cell disorders
are at higher risk to develop both provoked and unprovoked
episodes of anaphylaxis. A child whose disease appears to
be confined to the skin may still exhibit systemic symptoms
due to mast cell activation and mediator release.2
Symptoms common to pediatric mastocytosis and MCAS
include flushing of the face and neck, dermatographism,
gastrointestinal complaints [such as diarrhea, abdominal
pain, nausea, gastroesophageal reflux (GERD)], pruritis,
dyspnea, headache, lethargy, fatigue, and neuropsychiatric
symptoms. Many children with these disorders may complain
of generally feeling unwell, may have difficulty identifying or
localizing specific symptoms, or may seem to present with
several symptoms of mast cell activation, while others may
seem to have very few or none.
Pediatric cutaneous mastocytosis (CM) encompasses a
variety of clinical manifestations. In children, some of
these varieties will spontaneously resolve, some will go
on to be diagnosed as indolent systemic mastocytosis
(ISM) and some will evolve into well-differentiated
systemic mastocytosis (WDSM).2
DEFINITIONS1, 3
Darier’s sign is an important diagnostic finding of
patients with mastocytosis. It can be elicited by stroking
an existing CM lesion with a wooden tongue depressor,
approximately 5 times with moderate pressure. Within a
few minutes, a wheal and flare reaction of the lesion will
be seen.
A positive Darier’s sign is usually seen in pediatric
patients, but not always in adults. It may be decreased by
treatment with antihistamines. If the testing procedure
for Darier’s sign is not done properly, false positives or
false negatives may result. Darier’s sign is to be applied
to the evaluation of fixed cutaneous lesions except in the
case of a pediatric patient with cutaneous mastocytoma
or nodular lesions. Testing for Darier’s sign may provoke
a systemic reaction and should either be performed with
the greatest of caution or avoided.
Dermatographism is a skin
reaction characterized
by a wheal and flare
response when
normal skin, not
affected by skin
lesions, is stroked with
a tongue depressor,
finger nails or other
instrument. The nick-name
for dermatographism is skin
writing disease.
A macule is a lesion that is flat and even with the
surrounding skin, identified by a change in color compared
to the surrounding skin.
A papule is a small bump or elevated lesion, up to 1 cm
in diameter, containing no visible fluid.
A nodule is a growth of abnormal tissue just below the skin.
A bulla is a large blister filled with fluid.
Telangiectasia is a vascular lesion formed by dilatation
of a group of small blood vessels.
Continued on page 30
tmsforacure.org | Special Edition 2017-2018 29
 Pediatric Mast Cell Disorders
Continued from page 29

AGE OF ONSET - Small maculopapular lesions, similar in shape,

• Pediatric CM is commonly diagnosed prior to age two.
-Pediatric disease is seen at a ratio of 1.4 males:1
female.4
- No race has been found to be predominant.5
• Pediatric mast cell activation syndrome (MCAS) can
be diagnosed at any age.
PEDIATRIC CUTANEOUS
MASTOCYTOSIS VARIANTS
Presentation:
In 90% of the cases, the typical presentation involves
cutaneous manifestations (skin lesions). These may include:
Cutaneous Mastocytoma1
• Usually present at birth
• Elevated lesion(s) (up to a total of three lesions)
which usually resolves during childhood
• Four cutaneous mastocytomas or more become a
diagnosis of MPCM
• Multiple mastocytomas may evolve into adult WDSM2
size and color
- Children presenting with this form may have
increased serum tryptase and a tendency toward
systemic disease that persists into adulthood
- The type of lesions can vary during the course of
the disease, i.e., nodules during infancy may turn
into plaques at age 6
■ Polymorphic
 variant (Polymorphic means
different shapes/sizes)
- Mostly seen in children
- Can be macular, plaque or nodular, with lesions
of variable shape, color and size
- Although children typically express mutations in
exon 8, 9, 11 or 17 of the KIT gene, KIT mutations
may be negative
- Usually involving head, neck and extremities
- May involve blistering upon irritation until 3
years of age
- Prognosis is favorable with regression of
disease in adolescence or young adulthood

Maculopapular Cutaneous Mastocytosis (MPCM)/

Urticaria Pigmentosa (UP)1
• Red maculopapular lesions tend to wheal when
scratched (positive Darier’s sign)
• Blister formation can occur with rubbing or stroking
of lesion and is associated with pruritis5
• Encompasses several clinical entities with different
outcomes, including: pitted melanotic macules, reddish
brown telangiectatic macules, lightly pigmented
papules, brownish papules, and small nodules
• This group is divided into two sub-variants
■ Monomorphic variant (Monomorphic means one

basic shape/size)
- Mostly seen in adults and in a small
subgroup of children

30 tmsforacure.org | Special Edition 2017-2018

Diffuse Cutaneous Mastocytosis (DCM)1
• Skin thickened, hyperpigmented and diffusely
infiltrated
• Can involve up to 100% of the skin with the trunk,
head and scalp heavily affected
• Can appear at birth or early infancy; may persist into
adulthood, possibly as well differentiated systemic
mastocytosis (WDSM)2
• Blisters, some of which are hemorrhagic; bullae may
be present and dermatographism may be prominent
• Flushing is a common symptom
• Tryptase may be elevated due to increased mast
cell burden in the skin, as most patients do not have
systemic organ involvement, and can be indicative
of WDSM2
Pediatric MCAS
SYMPTOMS OF MAST CELL ACTIVATION Which
May be Seen in Both Pediatric CM and MCAS6
• Itching
• Flushing
• Darier’s sign and dermatographism
• Abdominal pain, nausea, diarrhea, bloating, colic in
infants, GERD
• Bone and muscle pain
• Headache
• Fatigue
• Neuropsychiatric symptoms, such as: brain fog,
ADD/ADHD, irritability, behavioral issues, seizures
• Anaphylaxis
GUIDELINES FOR DIAGNOSIS
Pediatric CM
• Completion of a thorough patient history
• Careful skin examination and biopsy of lesions with
mast cell stains (hematoxylin, eosin, giemsa stains)
and immunohistochemistry for tryptase and KIT
(CD117)
• Acquisition of labs, including complete blood count,
peripheral smear, serum chemistry, serum tryptase
and liver function tests
• E xam of liver and spleen for hepatosplenomegaly by
ultrasound or scan
• Any other exam relevant to individual symptoms
(endoscopy, colonoscopy, bone scan, etc.)
• Bone marrow biopsy and aspirate with flow
cytometry only if clinical suspicion of systemic
or progressive disease, as indicated by abnormal
peripheral blood counts, organomegaly, significant
lymphadenopathy, severe recurrent systemic mast
cell mediator-related symptoms, persistent high
tryptase, persistence of disease into adulthood5, 7
• Although specific guidelines do not exist for
diagnosing pediatric MCAS, proposed consensus
criteria for diagnosing MCAS have been utilized by
specialists.8
• Three criteria must be met:
■ T he patient exhibits symptoms of mast cell
activation involving two or more organ systems at
the same time, which recur or are always present,
cannot be attributed to any other disease or
condition and require treatment.8
■ T he patient demonstrates a rise in either total
serum tryptase (above baseline and within one
to two hours of a symptomatic episode; see
below for calculation method to determine if the
rise indicates mast cell activation has occurred)
or one of the three urinary mediators, n-methyl
histamine, prostaglandin-D2, or its metabolite,
11β-prostaglandin-F2α (24-hour urine test for
any of the three, also best captured after a
symptomatic episode).8 Additionally, Mayo Clinic
(Rochester) has a test available to measure urinary
levels of leukotrienes that is not yet incorporated
into this criteria, as it is not yet widely available.
Continued on page 32
tmsforacure.org | Special Edition 2017-2018 31
 Pediatric Mast Cell Disorders
Continued from page 31
“It requires further study to determine if all
patients with MCAS will demonstrate a rise in one
of the known mast cell mediators for which tests
are available.”6
- The consensus article provides a method for
calculating the required minimum rise in serum
tryptase.8 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. For example, if a patient
had a basal (baseline level, at least 24 hours
after a reaction) serum tryptase level of 8 ng/ml,
a 20% rise, plus 2 ng/ml, would be 11.6 ng/ml.
To meet the above criterion for serum tryptase,
the patient would need a post-reaction serum
tryptase level above 11.6 ng/ml. The calculation
would be conducted as follows:
(8 ng/ml x 1.2) + 2 ng/ml = 11.6 ng/ml
(basal level plus 20%) + additional 2 ng/ml = the
serum tryptase level, after a reaction, that must be
exceeded in order to meet a rise in serum tryptase
considered a mast cell activation event
o The patient must display a response (based on
response criteria9) to antimediator therapy.8
SOME POTENTIAL TRIGGERS TO AVOID
(VARIES BY PATIENT)
• Heat and/or cold; abrupt changes in temperature;
sun/sunlight
• Friction or pressure on the skin; vibration
• Specific foods: very individualized but may include
shellfish, high histamine foods such as left-overs,
salicylate-containing foods, nuts, peanuts and other
potential allergens
• Contrast dyes and medications, including: opioid
narcotics, alcohol as an additive or in any form, IV
vancomycin, neomycin, benzocaine, and certain
32 tmsforacure.org | Special Edition 2017-2018
anesthetics.10 See TMS Emergency Protocol: https://
tmsforacure.org/wp-content/uploads/2016-TMS-
ER-Protocol-Pages-2.pdf
• Venoms (bee, wasp, mixed vespids, spiders, fire
ants, jelly fish, snakes, biting insects, such as flies,
mosquitos and fleas, etc.)Bacterial, viral and fungal
infections
• Stress: physical, including pain, emotional or
environmental
• Fatigue
• Exercise
• Perfumes, odors, natural odors and chemical
exposures
TREATMENT GUIDELINES FOR PEDIATRIC
CM AND MCAS
• Identification and avoidance of triggers
• H1 and H2 antihistamines
- H1: loratadine, cetirizine, desloratadine,
diphenhydramine, hydroxyzine, fexofenadine,
chlorpheniramine maleate, doxepin
- H2: ranitidine, cimetidine, famotidine
• Leukotriene inhibitors
- Montelukast, zileuton, zafirlukast
• UVA/UVB Photolight therapy (treatment option
for pediatric CM only)
• Mast cell stabilizers
- Oral cromolyn sodium
- Ketotifen
• Injectable epinephrine
- EpiPen®/EpiPen Jr ® auto injector
• Topical treatments
- Steroid creams
- Cromolyn sodium cream 1%-5%
• No chemotherapy is indicated in cutaneous or
indolent systemic mastocytosis in children, unless
evidence of progression to aggressive disease is
identified
PROGNOSIS
Pediatric CM
• Benign course will be seen in approximately 70% of
patients.2
• Approximately 30% of pediatric mastocytosis cases
persist into adulthood.2
• Children with extensive bullous lesions appear to
be at increased risk of shock or sudden death from
anaphylaxis.11
• Children with widespread skin lesions (MPCM/UP
& DCM) are at increased risk for severe systemic
reaction due to potential mast cell mediator release
from affected skin.11
Pediatric MCAS
• There is no data on prognosis for pediatric patients
with MCAS; however all patients with MCAS are
at increased risk for anaphylaxis and a potentially
poor outcome. Therefore, these children need to
be followed by an allergist familiar with pediatric
MCAS and be treated with antimediator therapy,
when indicated and always carry two doses of
injectable epinephrine.
SUPPORT SERVICES
• The Mastocytosis Society, Inc. is a 501(c)3, nonprofit
organization dedicated to supporting patients
affected by Mastocytosis or Mast Cell Activation
Disorders, as well as their families, caregivers,
and physicians through research, education and
advocacy.
• The Mastocytosis Society, Inc. coordinates support
groups in nearly every state.
• Mastokids.org is a site where parents and caregivers
of children with mastocytosis or mast cell disease
can come to learn, find support, and discover a safe
environment to interact with other families.
References:
1. 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.
2. Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis.
Curr Opin Pediatr. 2012 Aug;24(4):480-6.
3. Venes D, Thomas CL. Taber’s Cyclopedic Medical Dictionary. 19
ed. Philadelphia: F.A. Davis Co.; 2001.
4. 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.
5. 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.
6. Butterfield J, et al., American Academy of Allergy, Asthma and
Immunology Mast Cell Disorder Committee and The Mastocytosis
Society, Inc. Mastocytosis and Mast Cell Activation Syndrome
(MCAS). Laminated sheet, 2012.
7.  Fried AJ, Akin C. Primary mast cell disorders in children. Curr
Allergy Asthma Rep. 2013 Dec;13(6):693-701.
8.  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.
9. 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.
10.  Bonadonna P, Pagani M, Aberer W, Bilo MB, Brockow K,
Oude Elberink H, et al. Drug hypersensitivity in clonal mast
cell disorders: ENDA/EAACI position paper. Allergy. 2015
Jul;70(7):755-63.
11.  Alvarez-Twose I, Vano-Galvan S, Sanchez-Munoz L, Morgado
JM, Matito A, Torrelo A, et al. Increased serum baseline
tryptase levels and extensive skin involvement are predictors
for the severity of mast cell activation episodes in children with
mastocytosis. Allergy. 2012 Jun;67(6):813-21.
Pediatric Mast Cell Disorders: Facts in Brief
Copyright © 2016 The Mastocytosis Society, Inc.
All rights reserved.
tmsforacure.org | Special Edition 2017-2018 33
 Visual Guide to Diagnosing Mastocytosis
The following pages are a photo journal of examples of how mast
cell disorders can present. A majority of the pictures are of skin
manifestations of mastocytosis. While cutaneous mastocytosis
can include maculopapular cutaneous mastocytosis (MPCM),
including urticaria pigmentosa (UP) and telangiectasia macularis
eruptiva perstans (TMEP), diffuse cutaneous mastocytosis
(DCM), and cutaneous mastocytoma, skin manifestations can
also occur in systemic mastocytosis (SM), mast cell activation
syndrome (MCAS) and idiopathic anaphylaxis patients.
Pic. 1- Female adult athlete with maculopapular cutaneous
lesions, monomorphic type (formerly known as urticaria
pigmentosa or UP), during a flare when the lesions are swelling
Pic. 3- Female child with cutaneous mastocytosis and
characteristic maculopapular, polymorphic skin lesions (formerly
known as urticaria pigmentosa or UP)
34 tmsforacure.org | Special Edition 2017-2018
Most cases of childhood-onset mastocytosis fall into one of the
cutaneous mastocytosis categories listed above and may or may
not include symptoms of systemic mast cell activation as a result
of mediators released from the skin. It should be noted that
the formerly used term “UP” encompasses a variety of clinical
manifestations. In children, some of these varieties will fade
away, some will develop into indolent systemic mastocytosis
and some will evolve into a newly described entity called well-
differentiated systemic mastocytosis.
Pic.2- Female adult with smoldering systemic
mastocytosis (SSM), and typical maculopapular,
cutaneous lesions, monomorphic type (formerly called
urticaria pigmentosa or UP) during a flare
Pic. 4- Female child with cutaneous mastocytoma on shoulder,
which can present with an elevated lesion which is red or
tannish brown
 Pic. 5- Male child with cutaneous
mastocytosis, characterized by
maculopapular cutaneous lesions,
polymorphic type (formerly known as
urticaria pigmentosa or UP). Note that in
some children, during a flare in response
to a trigger, lesions may become bullous or
blistered.

Pic. 6- Male child with cutaneous

mastocytosis with polymorphic lesions
and other rashes

tmsforacure.org | Special Edition 2017-2018 35

 Pic. 7- Male child with cutaneous mastocytosis during flare Pic. 8- Male child with mast cell activation syndrome, during
causing blisters in his maculopapular cutaneous lesions flushing episode

Pic. 9- Male child with the maculopapular cutaneous lesions, polymorphic type, consistent with cutaneous mastocytosis
(formerly called urticaria pigmentosa or UP)

36 tmsforacure.org | Special Edition 2017-2018

 Pic. 12- Cutaneous mastocytoma, normal and inflamed

Pic. 10- Adult female with maculopapular, cutaneous lesions,

monomorphic type during a flare

Pic. 13- Female with idiopathic anaphylaxis, hives (urticaria) and

dermatographism

For more information on skin manifestations in mastocytosis

(including a large selection of photos) and to review the
source of our publication’s descriptions of cutaneous
mastocytosis variants, please see the following Full-text
article, which is freely available online:

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
Pic. 11- Female child with maculopapular, polymorphic lesions of
cutaneous mastocytosis

tmsforacure.org | Special Edition 2017-2018 37

 Medical & Research Specialty Centers
for Mast Cell Disease
Please note carefully what each center specializes in. For example, some centers only treat patients with biopsy-confirmed systemic
mastocytosis, while others only treat advanced variants. It is indicated below if a center will treat patients for mast cell activation
syndrome and whether or not they will treat adults and/or children. Comprehensive centers can do the entire work-up, including
evaluation, physical exam, KIT mutation analysis, mediator testing and bone marrow biopsy with flow cytometry, using appropriate
stains for tryptase and expression of CD2 and CD25.
Abbreviations used below:
MCAS: Mast Cell Activation Syndrome
CM: Cutaneous Mastocytosis
SM: Systemic Mastocytosis
ISM: Indolent Systemic Mastocytosis
SSM: Smoldering Systemic Mastocytosis
SM-AHN: Systemic Mastocytosis with
an Associated Hematologic Neoplasm
ASM: Aggressive Systemic
Mastocytosis
MCL: Mast Cell Leukemia
MCS: Mast Cell Sarcoma
MPN: Myeloproliferative Neoplasm
UNITED STATES OF AMERICA
California
Stanford Cancer Center
875 Blake Wilbur Drive, Room 2327B
Stanford, CA 94305-5821
Contact: Jason Gotlib, MD, MS
Professor of Medicine (Hematology)
Stanford University Medical Center
Email: jason.gotlib@stanford.edu
Phone: 650-498-6000
Fax: 650-724-5203
Specialization: Adults. Biopsy-proven,
advanced variants of SM only, including
SSM, SM-AHN, ASM and MCL.
Diagnosis, treatment, and research.
Colorado
University of Colorado Hospital
Blood Cancer/Bone Marrow
Transplant Program
1665 Aurora Ct, Rm 2257
Aurora, CO 80045
Contact: William A. Robinson, MD, PhD
Professor, Division of Medical Oncology
Email: William.Robinson@ucdenver.edu
Phone: 720-848-2869
Fax: 720-848-0704
38 tmsforacure.org | Special Edition 2017-2018
Specialization: Adults. ISM, SSM, 60 Fenwood Rd., Brookline, MA 02115
SM-AHN, ASM and MCL. Diagnosis Phone: 617-732-9850
(bone marrow biopsy can be arranged), Fax: 617-525-1310
treatment, and research.
Contact: Mariana Castells, MD, PhD
Maryland Director, Center of Excellence for
Mastocytosis
National Institutes of Health/National
Professor of Medicine
Institute of Allergy and
Harvard Medical School
Infectious Diseases (NIH/NIAID)
Email: mcastells@partners.org
Building 10, Room 11C207
Phone: 617-732-9850
10 Center Drive - MSC1881
Fax: 617-525-1310
Bethesda, MD 20892-1881
Contact: Richard Horan, MD
Contact: Dean D. Metcalfe, MD
Assistant Professor of Medicine
Chief, Mast Cell Biology Section
Harvard Medical School
Email: dmetcalfe@niaid.nih.gov
Phone: 301-496-2165
Email: rhoran@partners.org
Phone: 617-732-9850
Fax: 301-480-8384
Fax: 617-525-1310
Contact: Melody Carter, MD
Contact: Matthew P. Giannetti, MD
Pediatrics
Phone: 617-525-1272
Email: mcarter@niaid.nih.gov
Fax: 617-732-5766
Phone: 301-496-8772
Brigham and Women’s Hospital
Contact: Joshua Milner, MD
Division of Gastroenterology
Chief, Laboratory of Allergic Diseases
75 Francis St., Boston, MA 02115
Chief, Genetics and Pathogenesis of
Allergy Section
Contact: Norton J. Greenberger, MD
Email:Joshua.milner@nih.gov
Senior Physician
Phone: 301-827-3662
Clinical Professor of Medicine,
Fax: 301-480-8384
Harvard Medical School
Email: ngreenberger@partners.org
Specialization: Adults and pediatric.
Phone: 617-732-6389
Physician referrals only for CM,
Fax: 617-264-5277
biopsy-proven SM, and adult idiopathic
anaphylaxis. Diagnosis (bone marrow
Contact: Matthew J. Hamilton, MD
biopsies), treatment, and research.
Instructor of Medicine
Harvard Medical School
Massachusetts Email: mjhamilton@partners.org
Brigham and Women’s Hospital (BWH) Phone: 617-732-6389
and Dana Farber Cancer Institute Fax: 617-264-5277
(DFCI): Boston Center of Excellence for
Mastocytosis Dana Farber Cancer Institute
Hematologic Oncology Program
Brigham and Women’s Hospital 450 Brookline Ave., Dana D1B30
Division of Rheumatology, Immunology Boston, MA 02215
and Allergy
Contact: Daniel DeAngelo, MD, PhD
Associate Professor of Medicine
Harvard Medical School
Email: daniel_deangelo@dfci.harvard.edu
Phone: 617-632-6028
Fax: 617-632-6771
Specialization: Adults. Pediatric
(outpatient only at BWH; more complex
pediatric cases may be seen in
conjunction with Children’s Hospital
Boston). Physician referral required. All
mastocytosis and MCAS; only SM and
variants for DFCI. Diagnosis (can arrange
bone marrow biopsies), treatment, and
research.
Tufts University School of Medicine
136 Harrison Avenue
Boston, MA 02111
Contact: Theoharis Theoharides, MD, PhD
Professor of Pharm. and Internal Medicine
Email: theoharis.theoharides@Tufts.edu
Phone: 617-636-6866
Fax: 617-636-2456
Does not see patients in clinic. Available
for consultation.
Michigan
University of Michigan
Comprehensive Cancer Center
Myeloproliferative Neoplasms and
Systemic Mastocytosis Clinic
1500 East Medical Center Drive, Ann
Arbor, MI 48109
Contact: Cem Akin, MD, PhD
Professor of Medicine
Department of Internal Medicine
Division of Allergy and Clinical
Immunology
24 Frank Lloyd Wright Drive
PO Box 442, Suite H-2100, Ann Arbor, MI
48106-0422
Email: cemakin@med.umich.edu
Phone: 734-936-5634
Phone (new patient coordinator): 734-
232-2071
Fax: 734-647-6263
Specialization: Adults. Biopsy-proven
only. ISM, SSM, ASM, SM-AHN,
and MCL. Will perform diagnostic
bone marrow biopsies for patients
with elevated tryptase or biopsy-
proven cutaneous disease. Diagnosis,
treatment, and research.
Minnesota
Mayo Clinic Program for Mast Cell and
Eosinophil Disorders
200 First St. SW, Rochester, MN 55905
Mayo Clinic – Allergy Department
Contact: Joseph Butterfield, MD,
Co-Director
Email: butterfield.joseph@mayo.edu
Contact: Catherine Weiler, MD, PhD,
Co-Director
Email: weiler.catherine@mayo.edu
Contact: Anupama Ravi, MD
Email: ravi.anupama@mayo.edu
Pediatrics
Contact: Thanai Pongdee, MD
Email: pongdee.thanai@mayo.edu
Phone: 507-284-9077
Fax: 507-284-0902
Specialization: Adults and pediatric.
All mast cell related diseases including
MCAS. Diagnosis, bone marrow biopsy,
treatment, and research.
Mayo Clinic – Hematology Department
Contact: Animesh Pardanani, MBBS, PhD
Email: pardanani.animesh@mayo.edu
Contact: Ayalew Tefferi, MD
Email: tefferi.ayalew@mayo.edu
Phone: (507) 284-3417
Fax: (507) 266-4972
Specialization: Adults. ISM, SSM,
ASM, SM-AHN, and MCL. Will perform
diagnostic bone marrow biopsies for
patients with elevated tryptase or
biopsy-proven cutaneous disease.
Diagnosis, treatment, and research.
University of Minnesota
Division of Hematology, Oncology &
Transplantation
420 Delaware St. SE, MMC 480,
Minneapolis, MN 55455
Contact: Celalettin Ustun, MD
Email: custun@umn.edu
Phone: 612-624-0123
Fax: 612-625-6919
Specialization: Adults with advanced
variants: SSM, ASM, SM-AHN, and
MCL. Diagnosis, treatment, and
research. Stem cell transplant program.
New York
Columbia University Medical Center
New York Presbyterian Hospital
Herbert Irving Pavilion
161 Fort Washington Avenue Garden
Level
New York, NY 10032
Contact: Mark Heaney, MD, PhD
Director, Hematology and Medical
Oncology
Fellowship Program
Email: mlh2192@cumc.columbia.edu
Phone: 202-305-0566
Fax: (212) 305-8112
Specialization: Adults with advanced
variants: SSM, ASM, SM-AHN, and
MCL. Diagnosis, treatment, and
research. Specialty area-MPNs.
Ohio
University of Cincinnati College of
Medicine
231 Albert Sabin Way, ML#563
Cincinnati, Ohio 45267-0563
Contact: Jonathan Bernstein, MD
Professor of Clinical Medicine
Department of Internal Medicine
Division of Immunology/Allergy
Email: Jonathan.Bernstein@uc.edu
Phone: 513-558-5533
Fax: 513-558-3799
Specialization: All mast cell related
diseases including mastocytosis and
MCAS. Adults and pediatric. Diagnosis,
treatment, and research. Can arrange
bone marrow biopsies. Private family
practice.
Texas
MD Anderson Cancer Center
1515 Holcombe Blvd, Unit 428 Houston,
TX 77030
Contact: Srdan Verstovsek, MD, PhD
Associate Professor, Leukemia
Department
Email: sverstov@mdanderson.org
Phone: 713-792-7305
Fax: 713-794-4297
Specialization: Adults. Advanced
variants of SM only: SSM, SM-AHN,
ASM and MCL. Diagnosis, treatment,
and research.
Continued on page 40
tmsforacure.org | Special Edition 2017-2018 39
 Medical & Research Centers that Treat Patients with Mast Cell Diseases
Continued from page 39

Utah INTERNATIONAL
The University of Utah School of Medicine (Active Centers)
Department of Internal Medicine, Hematology Division
30 N 1900 E, Room 5C402, Salt Lake City, UT 84132 Europe
For medical and research centers in Europe, please visit the
Contact: Michael Deininger, MD, PhD European Competence Network on Mastocytosis website:
Professor of Internal Medicine www.ecnm.net
Adjunct Professor of Oncological Sciences
Email: michael.deininger@hsc.utah.edu Brazil
Phone: 801-585-3229 University of Sao Paulo, Sao Paulo

Specialization: Adults. Advanced variants of systemic

mastocytosis (SM) only: SSM, SM-AHN, ASM and MCL.
Israel
Diagnosis, treatment, and research. Technion - Israel Institute of Technology, Haifa
Emek Medical Center, Afula
Virginia Contact: Menachem Rottem, MD, PhD
Virginia Commonwealth University Head of the Allergy, Asthma and Immunology Service
P.O. Box 980263 Clinical Associate Professor
1250 East Marshall St., Richmond, VA 23298 Email: menachem@rottem.net
Phone: 972-52-8617823
Contact: Dr. Larry Schwartz, MD, PhD
Professor of Medicine Meir Medical Center, Kfar Saba
Chair, Division of Rheumatology, Allergy, and Immunology Contact: Alon Hershko, MD, PhD
Email: lbschwar@vcu.edu Email: alon.hershko@clalit.org.il
Phone: 804-828-9685
Fax: 804-828-0283 Other international centers are being developed. For
information, please contact TMS at info@tmsforacure.org.
Specialization: All mast cell related diseases including
mastocytosis and MCAS. Adults and pediatric. Diagnosis,
treatment, and research. Can arrange bone marrow biopsies

Please note that the names of these centers and specialists are listed for informational purposes only. The Mastocytosis Society, Inc. is not responsible for any
diagnostic evaluations, treatment or information provided as a result of visits or interactions with these medical professionals.

40 tmsforacure.org | Special Edition 2017-2018

Medical Advisory Board
Contact Information: The Mastocytosis Society, Inc. is a nonprofit volunteer organization guided by a board of medical advisors who
donate their time and expertise in support of the TMS mission. They have graciously agreed to act as a point of contact for other
physicians and health care providers needing additional information about mastocytosis and mast cell activation disorders. We thank
them for their dedication and volunteerism.

Ivan Alvarez-Twose, MD Joseph Butterfield, MD Tracy I. George, MD

Staff Physician and Clinical Coordinator,
Instituto de Estudios de Mastocitosis de
Castilla La Mancha (CLMast)
Toledo, Spain
Email: ivana@sescam.jccm.es
Phone: 0034-615-653-157
K. Frank Austen, MD (Honorary)
Astra Zeneca Professor of Respiratory and
Inflammatory Diseases
Department of Medicine Brigham and
Women’s Hospital
Smith Building, Room 638
One Jimmy Fund Way
Boston, MA 02115
Email: fausten@rics.bwh.harvard.edu
Phone: 617-525-1300
Fax: 617-525-1310
Patrizia Bonadonna, MD
Allergy and Immunology Clinic
Multidisciplinary Outpatient
Clinic of Mastocytosis (also hymenoptera
venom allergy,drug allergy and other
allergic diseases)
Verona General and University Hospital
Piazzale Stefani 1
Verona, Italy
Email: patrizia.bonadonna@
ospedaleuniverona.it
Phone: +390458122556
Fax: +390458122048
Co-Director, Mayo Clinic Program for Mast
Cell and Eosinophil Disorders
W15-B Mayo Clinic 200 SW 1st Street
Rochester, MN 55905
Email: butterfield.joseph@mayo.edu
Phone: 507-284-9077
Fax: 507-284-0902
Mariana Castells, MD, PhD
Professor of Medicine
Harvard Medical School
Director, Mastocytosis
Center of Excellence
Brigham and Women’s Hospital
Allergy and Clinical Immunology
60 Fenwood Rd., Brookline, MA 02115
Email: mcastells@partners.org
Phone: 617-732-9850
Fax: 617-525-1310
Madeleine Duvic, MD
Professor and Deputy Chair, Dermatology,
Univ. of Texas MD Anderson
Cancer Center
1515 Holcombe Blvd, Unit 1452
Houston, TX 77030
Email: mduvic@mdanderson.org
Phone: 713 745-4615
Fax: 713 745-3597
Luis Escribano, MD, PhD
Coordinator, Spanish Network on
Mastocytosis (REMA) Associated
Research, Servicio de Citometría, Centro
de Investigación del Cáncer, Universidad
de Salamanca
Salamanca, Spain
Professor of Medicine
University of New Mexico
Division Chief, Hematopathology
Director, Hematopathology Fellowship
Program
Email: TracyGeorge@salud.umn.edu
Phone: 505-272-4814
Fax: 505-272-8084
Jason Gotlib, MD, MS
Associate Professor of Medicine
(Hematology), Director, Stanford
Hematology Fellowship Program Director,
MPN Center
Stanford Cancer Institute
875 Blake Wilbur Drive, Room 2324
Stanford, CA 94305-5821
Email: jason.gotlib@stanford.edu
Phone: 650-725-0744
Fax: 650-724-520
Norton J. Greenberger, MD
Clinical Professor of Medicine/
Gastroenterology
Harvard Medical School
Senior Physician
Brigham and Women’s Hospital
75 Francis Street
Boston, MA 02115
Email: ngreenberger@partners.org
Phone: 617-732-6389
Fax: 617-264-5277

E-mail: escribanomoraluis@gmail.com
Continued on page 42

tmsforacure.org | Special Edition 2017-2018 41

 Medical Advisory Board
Continued from page 41

Matthew J. Hamilton, MD Anne Maitland, MD, PhD Megha M. Tollefson, MD

Assistant Professor of Medicine Asst. Professor, Dept. of Medicine and Assistant Professor of Dermatology
Harvard Medical School Dept. of Otolaryngology and Pediatrics
Division of Gastroenterology Icahn School of Medicine at Mount Sinai Mayo Clinic
Brigham and Women’s Hospital New York, NY 10029 200 First Street SW
75 Francis St. Medical Director, Rochester, MN 55905
Boston, MA 02115 Comprehensive Allergy & Asthma
Email: Tollefson.Megha@mayo.edu
Care, PLLC
Email: mjhamilton@partners.org Phone: (507) 284-3579
Department of Otolaryngology
Phone: 617-732-6389 Fax: (507) 284-2072
5 East 98th Street, 8th Floor
Fax: 617-566-0338
New York, NY 10029 Celalettin Ustun, MD
Olivier Hermine, MD, PhD 55 South Broadway, 2nd floor Associate Professor of Medicine
Université Sorbonne Paris Cité Tarrytown, NY 10591 Division of Hematology, Oncology &
Department of Clinical Hematology Transplantation
Email: am.mdphd@gmail.com
National Center of Mastocytosis University of Minnesota
Phone: 914-631-3283
Hôpital Necker 420 Delaware St. SE, MMC 480
Fax: 914-631-3284
149-161 Rue de Sèvres, Minneapolis, MN 55455
75015 Paris, France Larry Schwartz, MD, PhD
Email: custun@umn.edu
Professor of Medicine
Email: ohermine@gmail.com Phone: 612-624-0123
Chair, Division of Rheumatology, Allergy,
Tel: 33-1-44-49-52-82 (office) Fax: 612-625-6919
and Immunology
Nicholas Kounis, MD, PhD Virginia Commonwealth University Peter Valent, MD
Patras Highest Institute of Education P.O. Box 980263 Department of Internal Medicine I
and Technology 1250 East Marshall St., Division of Hematology and
Professor of Medicine in Cardiology Richmond, VA 23298 Hemostaseology
Department of Medical Sciences University of Vienna
Email: lbschwar@vcu.edu
7 Aratou St. Währinger Gürtel 18-20
Phone: 804-828-9685
Queen Olgas Square A-1090 Vienna, Austria
Fax: 804-828-0283
Patras 26221, Greece
Email: peter.valent@meduniwien.ac.at
Theoharis Theoharides, MD, PhD
Email: ngkounis@otenet.gr Phone: +43-1 40400-5488 or -6086
Professor of Pharmacology and
Phone: +302610279579 Fax: +43 1 40400 4030
Internal Medicine
Fax: +302610279579
Tufts University School of Medicine Srdan Verstovsek, MD, PhD
136 Harrison Avenue Associate Professor
Boston, MA 02111 Leukemia Department
MD Anderson Cancer Center
Email: Theoharis.Theoharides@Tufts.edu
1515 Holcombe Blvd, Unit 428
Phone: 617-636-6866
Houston, TX 77030
Fax: 617-636-2456
Email: sverstov@mdanderson.org
Phone: 713-792-7305
Fax: 713-794-4297

42 tmsforacure.org | Special Edition 2017-2018

The Mastocytosis Society Printed Materials
Mastocytosis and mast cell activation disorders are complicated and not well-known diseases. To help educate and spread awareness,
The Mastocytosis Society, Inc. (TMS) is pleased to offer informational material to physicians and patients.

Tri-fold Informational Brochures

Symptoms, diagnosis and treatment of mast cell disorders.

Infant Card

Card and Brochure Dimensions:

Spot Card, Generic Business 2" x 3.5"
Informational Brochure, Tri-fold 8.5" x 11" Images not to scale

Ordering Information
TMS printed material is available for free on our website. If your medical office would like printed copies, please fill out the form or
email us at education@tmsforacure.org

Name_____________________________________________ Please indicate a quantity next to each item

Address____________________________________________
City ______________________________________________
State ___________________Zip________________________
Tri-fold Informational Brochures
____ Emergency Care For Patients with Mast Cell Disorder
____ S ystemic Mastocytosis Including Indolent &
Aggressive Variants
____ Mastocytosis and Mast Cell Activation Disorders

Phone _____________________________________________ Cards

____ Infant Card
Email______________________________________________

The Mastocytosis Society, Inc., P.O. Box 416 Sterling, MA 01564 | education@tmsforacure.org

tmsforacure.org | Special Edition 2017-2018 43

 MASTOCYTOSIS AND MAST CELL ACTIVATION SYNDROMES
Medical Reference Highlights
The following are selected references, listed by topic, that
might be of interest to mast cell disorder patients, their
caregivers, physicians or others. This is NOT a complete
list of all articles available on this subject. All references
were obtained through searches of the PubMed database
(http://www.ncbi.nlm.nih.gov/pubmed). Additional
individually relevant references can be obtained by
searching the PubMed database. Selected additional
references may also be found at www.tmsforacure.org/
research/research-resources.
DISCLAIMER: Listing of an article in this file does not
imply TMS support of its authors or contents and an
article that is not listed does not imply a lack of support of
its authors or contents. Patients should consult with
their doctors, or, if necessary, mast cell specialists,
regarding any questions or concerns related to
applicability, accuracy and individual usefulness of
information presented in these articles.
TOPICS INCLUDED IN THIS FILE:
• International Consensus Statements, Position Papers
and WHO Criteria 1-13
• Reviews and Expert Opinions 14-44
• Laboratory Tests, Pathology, Immunohistology and Flow
Cytometry 5, 15, 38, 40, 42, 43, 45-51
• Perioperative Care/Pre-Medication for Dental Work,
Diagnostic Testing or Surgical Procedures 4, 37, 52-54
• Therapy 15, 19, 20, 36, 37, 40, 55-59
• The Mastocytosis Society Survey on Mast Cell
Disorders 60
44 tmsforacure.org | Special Edition 2017-2018
1. 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
2. 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
3. Ustun C, Gotlib J, Popat U, Artz A, Litzow M, Reiter
A, et al. Consensus Opinion on Allogeneic
Hematopoietic Cell Transplantation in Advanced
Systemic Mastocytosis. Biol Blood Marrow
Transplant. 2016 Aug;22(8):1348-56. http://www.ncbi.
nlm.nih.gov/pubmed/27131865
4. Bonadonna P, Pagani M, Aberer W, Bilo MB, Brockow
K, Oude Elberink H, et al. Drug hypersensitivity
in clonal mast cell disorders: ENDA/EAACI
position paper. Allergy. 2015 Jul;70(7):755-63.
http://www.ncbi.nlm.nih.gov/pubmed/25824492
5. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann
G, Escribano L, et al. KIT mutation analysis in
mast cell neoplasms: recommendations
of the European Competence Network on
Mastocytosis. Leukemia. 2015 Jun;29(6):1223-32.
http://www.ncbi.nlm.nih.gov/pubmed/25650093
6. 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
7. Valent P, Sotlar K, Sperr WR, Escribano L, Yavuz S,
Reiter A, et al. Refined diagnostic criteria and
classification of mast cell leukemia (MCL) and
myelomastocytic leukemia (MML): a consensus
proposal. Ann Oncol. 2014 Sep;25(9):1691-700.
http://www.ncbi.nlm.nih.gov/pubmed/24675021
8. Gotlib J, Pardanani A, Akin C, Reiter A, George T,
Hermine O, et al. International Working Group-
Myeloproliferative Neoplasms Research and
Treatment (IWG-MRT) & European Competence
Network on Mastocytosis (ECNM) consensus
response criteria in advanced systemic
mastocytosis. Blood. 2013 Mar 28;121(13):2393-401.
http://www.ncbi.nlm.nih.gov/pubmed/23325841
9. 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
10. 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.
11. 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
12. 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.
13. 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
14. Monnier J, Georgin-Lavialle S, Canioni D, Lhermitte
L, Soussan M, Arock M, et al. Mast cell sarcoma:
new cases and literature review. Oncotarget.
2016 Oct 04;7(40):66299-309. http://www.ncbi.nlm.
nih.gov/pubmed/27602777
15. Azana JM, Torrelo A, Matito A. Update on
Mastocytosis (Part 2): Categories, Prognosis,
and Treatment. Actas Dermosifiliogr. 2016 Jan-
Feb;107(1):15-22. http://www.ncbi.nlm.nih.gov/
pubmed/26525106
16. Azana JM, Torrelo A, Matito A. Update on
Mastocytosis (Part 1): Pathophysiology, Clinical
Features, and Diagnosis. Actas Dermosifiliogr.
2016 Jan-Feb;107(1):5-14. http://www.ncbi.nlm.nih.
gov/pubmed/26546030
17. Bonadonna P, Bonifacio M, Lombardo C, Zanotti
R. Hymenoptera Allergy and Mast Cell
Activation Syndromes. Curr Allergy Asthma Rep.
2016 Jan;16(1):5. http://www.ncbi.nlm.nih.gov/
pubmed/26714690
18. Pieri L, Bonadonna P, Elena C, Papayannidis C,
Grifoni FI, Rondoni M, et al. Clinical presentation
and management practice of systemic
mastocytosis. A survey on 460 Italian patients.
Am J Hematol. 2016 Jul;91(7):692-9.
http://www.ncbi.nlm.nih.gov/pubmed/27060898
Continued on page 46
tmsforacure.org | Special Edition 2017-2018 45
 Medical Reference Highlights
Continued from page 45
19. Valent P, Akin C, Metcalfe DD. Mastocytosis
2016: Updated WHO Classification and Novel
Emerging Treatment Concepts. Blood. 2016 Dec
28. http://www.ncbi.nlm.nih.gov/pubmed/28031180
20. Gonzalez de Olano D, Matito A, Orfao A, Escribano
L. Advances in the understanding and clinical
management of mastocytosis and clonal mast
cell activation syndromes. F1000Res. 2016
Nov 14;5:2666. https://www.ncbi.nlm.nih.gov/
pubmed/27909577
21. Alvarez-Twose I, Jara-Acevedo M, Morgado JM,
Garcia-Montero A, Sanchez-Munoz L, Teodosio C, et
al. Clinical, immunophenotypic, and molecular
characteristics of well-differentiated systemic
mastocytosis. J Allergy Clin Immunol. 2016
Jan;137(1):168-78 e1. http://www.ncbi.nlm.nih.gov/
pubmed/26100086
22. Carter MC, Clayton ST, Komarow HD, Brittain EH,
Scott LM, Cantave D, et al. Assessment of clinical
findings, tryptase levels, and bone marrow
histopathology in the management of pediatric
mastocytosis. J Allergy Clin Immunol. 2015
Dec;136(6):1673-9 e3. http://www.ncbi.nlm.nih.gov/
pubmed/26044856
23. Valent P. Diagnosis and management of
mastocytosis: an emerging challenge in applied
hematology. Hematology Am Soc Hematol Educ
Program. 2015 Dec 5;2015(1):98-105. http://www.
ncbi.nlm.nih.gov/pubmed/26637707
46 tmsforacure.org | Special Edition 2017-2018
24. Bonadonna P, Bonifacio M, Lombardo C, Zanotti R.
Hymenoptera Anaphylaxis and C-kit Mutations:
An Unexpected Association. Curr Allergy Asthma
Rep. 2015 Aug;15(8):49. http://www.ncbi.nlm.nih.gov/
pubmed/26149588
25. 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
26. Matito A, Carter M. Cutaneous and systemic
mastocytosis in children: a risk factor for
anaphylaxis? Curr Allergy Asthma Rep. 2015
May;15(5):22. http://www.ncbi.nlm.nih.gov/
pubmed/26139333
27. 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
28. Valent P, Sotlar K, Sperr WR, Reiter A, Arock M,
Horny HP. Chronic mast cell leukemia: a novel
leukemia-variant with distinct morphological
and clinical features. Leuk Res. 2015 Jan;39(1):1-5.
http://www.ncbi.nlm.nih.gov/pubmed/25443885
29. Akin C. Mast cell activation disorders. J Allergy
Clin Immunol Pract. 2014 May-Jun;2(3):252-7 e1; quiz
8. http://www.ncbi.nlm.nih.gov/pubmed/24811013
30. Akin C, Valent P. Diagnostic criteria and
classification of mastocytosis in 2014. Immunol
Allergy Clin North Am. 2014 May;34(2):207-18. http://
www.ncbi.nlm.nih.gov/pubmed/24745670
31. 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. http://www.ncbi.nlm.
nih.gov/pubmed/24745680
32. Weiler CR, Butterfield J. Mast cell sarcoma:
clinical management. Immunol Allergy Clin North
Am. 2014 May;34(2):423-32. http://www.ncbi.nlm.
nih.gov/pubmed/24745684
33. Rossini M, Zanotti R, Viapiana O, Tripi G, Orsolini
G, Idolazzi L, et al. Bone involvement and
osteoporosis in mastocytosis. Immunol Allergy
Clin North Am. 2014 May;34(2):383-96. http://www.
ncbi.nlm.nih.gov/pubmed/24745681
34. Brockow K. Epidemiology, prognosis, and risk
factors in mastocytosis. Immunol Allergy Clin
North Am. 2014 May;34(2):283-95. http://www.ncbi.
nlm.nih.gov/pubmed/24745674
35. Moura DS, Georgin-Lavialle S, Gaillard R, Hermine
O. Neuropsychological features of adult
mastocytosis. Immunol Allergy Clin North Am. 2014
May;34(2):407-22. http://www.ncbi.nlm.nih.gov/
pubmed/24745683
36. C arter MC, Metcalfe DD, Komarow HD.
Mastocytosis. Immunol Allergy Clin North Am.
2014 Feb;34(1):181-96. http://www.ncbi.nlm.nih.gov/
pubmed/24262698
37. 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
38. Valent P. Mast cell activation syndromes:
definition and classification. Allergy. 2013
Apr;68(4):417-24. http://www.ncbi.nlm.nih.gov/
pubmed/23409940
39. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris
MO, Hermine O, Damaj G. Mast cell leukemia.
Blood. 2013 Feb 21;121(8):1285-95. http://www.ncbi.
nlm.nih.gov/pubmed/23243287
40. Cardet JC, Castells MC, Hamilton MJ. Immunology
and clinical manifestations of non-clonal mast
cell activation syndrome. Curr Allergy Asthma
Rep. 2013 Feb;13(1):10-8. http://www.ncbi.nlm.nih.
gov/pubmed/23212667
41. 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.
42. Alvarez-Twose I, Morgado JM, Sanchez-Munoz L, Garcia-
Montero A, Mollejo M, Orfao A, et al. Current state of
biology and diagnosis of clonal mast cell diseases
in adults. Int J Lab Hematol. 2012 Oct;34(5):445-60. http://
www.ncbi.nlm.nih.gov/pubmed/22551157
43. 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
44. 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
45. Teodosio C, Mayado A, Sanchez-Munoz L, Morgado
JM, Jara-Acevedo M, Alvarez-Twose I, et al.
The immunophenotype of mast cells and its
utility in the diagnostic work-up of systemic
mastocytosis. J Leukoc Biol. 2015 Jan;97(1):49-59.
http://www.ncbi.nlm.nih.gov/pubmed/25381388
46. Horny HP, Sotlar K, Valent P. Mastocytosis:
immunophenotypical features of the
transformed mast cells are unique among
hematopoietic cells. Immunol Allergy Clin North
Am. 2014 May;34(2):315-21. http://www.ncbi.nlm.nih.
gov/pubmed/24745676
47. Doyle LA, Hornick JL. Pathology of extramedullary
mastocytosis. Immunol Allergy Clin North Am. 2014
May;34(2):323-39. http://www.ncbi.nlm.nih.gov/
pubmed/24745677
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tmsforacure.org | Special Edition 2017-2018 47
 Medical Reference Highlights
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48. Horny HP, Sotlar K, Valent P. Evaluation of mast ncbi.nlm.nih.gov/pubmed/18633019

cell activation syndromes: impact of pathology
55. Arock M, Akin C, Hermine O, Valent P. Current
and immunohistology. Int Arch Allergy Immunol.
treatment options in patients with
2012;159(1):1-5. http://www.ncbi.nlm.nih.gov/
mastocytosis: status in 2015 and future
pubmed/22555026
perspectives. Eur J Haematol. 2015 Jun;94(6):474-
49. Horny HP, Sotlar K, Valent P. Mastocytosis: state 90. http://www.ncbi.nlm.nih.gov/pubmed/25753531
of the art. Pathobiology. 2007;74(2):121-32. http://
56. Rossini M, Zanotti R, Orsolini G, Tripi G, Viapiana O,
www.ncbi.nlm.nih.gov/pubmed/17587883
Idolazzi L, et al. Prevalence, pathogenesis, and
50. Horny HP, Valent P. Diagnosis of treatment options for mastocytosis-related
mastocytosis: general histopathological osteoporosis. Osteoporos Int. 2016 Feb 18. http://
aspects, morphological criteria, and www.ncbi.nlm.nih.gov/pubmed/26892042
immunohistochemical findings. Leuk Res. 2001
57. Gotlib J, Kluin-Nelemans HC, George TI, Akin C,
Jul;25(7):543-51. http://www.ncbi.nlm.nih.gov/
Sotlar K, Hermine O, et al. Efficacy and Safety
pubmed/11377679
of Midostaurin in Advanced Systemic
51. Jawhar M, Schwaab J, Hausmann D, Clemens Mastocytosis. N Engl J Med. 2016 Jun
J, Naumann N, Henzler T, et al. Splenomegaly, 30;374(26):2530-41. http://www.ncbi.nlm.nih.gov/
elevated alkaline phosphatase and mutations pubmed/27355533
in the SRSF2/ASXL1/RUNX1 gene panel are
58. Ustun C, Arock M, Kluin-Nelemans HC, Reiter A,
strong adverse prognostic markers in patients
Sperr WR, George T, et al. Advanced systemic
with systemic mastocytosis. Leukemia. 2016
mastocytosis: from molecular and genetic
Dec;30(12):2342-50. http://www.ncbi.nlm.nih.gov/
progress to clinical practice. Haematologica.
pubmed/27416984
2016 Oct;101(10):1133-43. http://www.ncbi.nlm.nih.
52. Matito A, Morgado JM, Sanchez-Lopez P, gov/pubmed/27694501
Alvarez-Twose I, Sanchez-Munoz L, Orfao A, et
59. Gotlib J. Tyrosine Kinase Inhibitors and
al. Management of Anesthesia in Adult and
Therapeutic Antibodies in Advanced
Pediatric Mastocytosis: A Study of the Spanish
Eosinophilic Disorders and Systemic
Network on Mastocytosis (REMA) Based on 726
Mastocytosis. Curr Hematol Malig Rep. 2015
Anesthetic Procedures. Int Arch Allergy Immunol.
Dec;10(4):351-61. http://www.ncbi.nlm.nih.gov/
2015;167(1):47-56. http://www.ncbi.nlm.nih.gov/
pubmed/26404639
pubmed/26160029
60. Jennings S, Russell N, Jennings B, Slee V, Sterling L,
53. Dewachter P, Castells MC, Hepner DL, Mouton-Faivre
Castells M, et al. The Mastocytosis Society survey
C. Perioperative Management of Patients with
on mast cell disorders: patient experiences
Mastocytosis. Anesthesiology. 2013 Oct 16. http://
and perceptions. J Allergy Clin Immunol Pract.
www.ncbi.nlm.nih.gov/pubmed/24135579
2014 Jan-Feb;2(1):70-6. http://www.ncbi.nlm.nih.gov/
54. Carter MC, Uzzaman A, Scott LM, Metcalfe DD, pubmed/24565772
Quezado Z. Pediatric mastocytosis: routine
anesthetic management for a complex disease.
Anesth Analg. 2008 Aug;107(2):422-7. http://www.

48 tmsforacure.org | Special Edition 2017-2018

What Is Mast Cell Connect? About Mastocytosis

49
What
WhatIsIsMast
MastCell
CellConnect?
Connect? About
AboutMastocytosis
Mastocytosis
Mast Cell Connect is an electronic patient registry Mastocytosis is a rare disease in which immune cells

tmsforacure.org | Special Edition 2017-2018

Mast
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caregivers
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enter
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information
information about
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flushing, shortness
shortness of of
breath
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anaphylactic shock.
shock.
living with the disease directly into a secure, web-based The signs, symptoms and severity of mastocytosis vary
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data collection tool. Those who participate in Mast Cell widely, but in more severe cases, mast-cell accumulation
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of responses from other patients, and can choose to
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andandcancan
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receive information about ongoing clinical trials and In patients with mastocytosis, mast cells can accumulate
receive
receive information
information about
about ongoing
ongoingclinical
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andand In In
patients
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in tissues
tissues
tissuesincluding
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mastocytosis,
mastocytosis,
mastocytosis,oror
or SM).
SM).
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disease.
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families.
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treatments
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Questions?
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andand there
there is is
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disease.
disease. Together,
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research
research
Connect
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registry,
registry, contact
contact
contact the
thethe
study
study
study doctor
doctor
doctor at at
mastcellregistry@blueprintmedicines.com
mastcellregistry@blueprintmedicines.com
mastcellregistry@blueprintmedicines.com oror
or at at
at
617-714-6678.
617-714-6678.
617-714-6678.
For
For For
allallother
all
other
other
questions,
questions,
questions, contact
contact
contact the
thethe
Mast
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Connect registry
registry
registry coordinator
coordinator
coordinator atat
at
coordinator@mastcellconnect.org.
coordinator@mastcellconnect.org.
coordinator@mastcellconnect.org.
MastCellConnect.org
MastCellConnect.org
MastCellConnect.org MastCellConnect.org
MastCellConnect.org
MastCellConnect.org
 Getting Involved
GettingInvolved Additional
Additional Resources
Resources
Here are more resources that you may find useful if you
join? Here are more resources that you may find useful if you
Who
Whocan
canjoin?
have mastocytosis, care for someone with mastocytosis, or
People with a diagnosis of mastocytosis, including have mastocytosis, care for someone with mastocytosis, or
People with a diagnosis of mastocytosis, including would like to learn more about participating in clinical trials
cutaneous mastocytosis would like to learn more about participating in clinical trials:
systemic
systemicmastocytosis
mastocytosis(SM),
(SM),cutaneous mastocytosis
(CM)
(CM)and
andtheir
theirvariants,
variants,are invited
areinvited toto join
join Mast
Mast CellCell
Connect. To join, you must be able to provide informed
Connect. To join, you must be able to provide informed
consent.
consent.Anyone
Anyoneunder
under18,
18,oror adults
adults who
who cannot
cannot make
make
their own medical decisions or would prefer to have
their own medical decisions or would prefer to have
someone
someoneelse
elseenter
entertheir information,
theirinformation, must
must have
have a a
www.systemicmastocytosis.com
www.systemicmastocytosis.com
family
familymember,
member,medical caregiver,
medicalcaregiver, legal
legal guardian
guardian or or
other
otherdesignee
designeetotoregister
registeronon their
their behalf.
behalf.
TheThe Mastocytosis
Mastocytosis Society
Society
Join?
Why Join?
Why www.tmsforacure.org
www.tmsforacure.org
What
Whatdoes
doesparticipating
participatingininthe
theregistry involve?
registry involve?
IfIfyou
youjoin
joinMast
MastCell
CellConnect,
Connect,you
you
willwill
bebeasked
asked
to to National Organization for Rare Diseases (NORD):
about National Organization for Rare Diseases (NORD):
The
Themore
moreweweunderstand
understand about complete
completeaaquestionnaire
questionnaireabout
about your
your experience living
experience living Mastocytosis
Mastocytosis
mastocytosis
mastocytosisand andthe more people
the more with
withmastocytosis,
mastocytosis,asaswell share
wellasastoto medical
share records
medical records www.rarediseases.org/rare-diseases/mastocytosis
www.rarediseases.org/rare-diseases/mastocytosis
clinical that
thatdescribe
describeyour
yourdiagnosis,
diagnosis, treatments, symptoms
treatments, symptomsandand
participate
participateininresearch
research and
and clinical
changes You may occasionally European Competence Network on Mastocytosis
changesininthe
thedisease
diseaseover
overtime.
time. You may occasionally European Competence Network on Mastocytosis
trials,
trials,the
themore
morewe wecan
can help advance
help advance be asked additional survey questions, and to ensure www.mastocytosis.eu
be asked additional survey questions, and to ensure thethe www.mastocytosis.eu
research
researchandandspeed development of
speeddevelopment of registry’s accuracy, you will be asked to update your
registry’s accuracy, you will be asked to update your
new treatments for mastocytosis. information a few times a year.
new treatments for mastocytosis. information a few times a year.
About
About Sponsor
thethe Sponsor
Learn from other patients’ experiences. Who has access to Mast Cell Connect?
Learn from other patients’ experiences. Who has access to Mast Cell Connect? About Blueprint Medicines
By participating, you will gain access to data and insights The broader medical community, including researchers, About Blueprint Medicines
Blueprint Medicines is a biotechnology company developing a new
By participating, you will gain access to data and insights The broader medical community, including researchers, Blueprint Medicines biotechnology company developing a new
physicians, patient advocacy groups and companies investigational treatment foris asystemic mastocytosis (SM). At Blueprint
gleaned from other patients’ responses that may be investigational treatment for systemic mastocytosis (SM). At Blueprint
gleaned from other patients’ responses that may be physicians, patient advocacy groups and companies Medicines, we are motivated by one goal: to dramatically improve the
useful in better understanding your own disease. engaged in mastocytosis research, can request access to livesMedicines, we are
of people with motivated
debilitating diseases.
by oneOurgoal: to dramatically
investigational improve the
therapies
useful in better understanding your own disease. engaged in mastocytosis research, can request access to lives of people debilitating Our investigational therapies
the registry. All information in the registry is de-identified, are currently in clinical
withstudies for SM,diseases.
gastrointestinal stromal tumors
the registry. All information in the registry is de-identified, and are
hepatocellular clinical studies
currently incarcinoma. for SM,
For more gastrointestinal
information, stromal tumors
please visit
Find out about clinical trials and other meaning it has been stripped of information that
and hepatocellular carcinoma. For more information, please visit
www.blueprintmedicines.com.
Find out about clinical trials and other meaning it has been stripped of information that
research studies. You can sign up to be notified could be used to identify you. As a participant, you www.blueprintmedicines.com.
research studies. can sign be notified have be used to
couldimmediate identify
access to the
you.pool
As aofparticipant,
de-identifiedyou About PatientCrossroads
about clinical trials and
Youother research
up tostudies that you
have immediate PatientCrossroads is a leader in building web-based patient registries
About PatientCrossroads
about
may clinical trials
be eligible forand other
based on research
the information that
studiesyou you
enter survey answers. access to the pool of de-identified designed to advance research and connect patients with researchers,
PatientCrossroads is a leader in building web-based patient registries
may be eligible for based on the information you enter survey answers. advocates
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Support Group Contacts
United States
CALIFORNIA
 MICHIGAN OHIO
Northern California
 Julia Stewart Michelle Cox
Michelle Lamanna michigansupport@tmsforacure.org ohiosupport@tmsforacure.org
northerncaliforniasupport@tmsforacure.org
Midwest OREGON/WASHINGTON-
San Francisco Cheri Smith Pacific Northwest
Cay Oglesby midwestsupport@tmsforacure.org Jan Groh

sfbaysupport@tmsforacure.org pnwsupport@tmsforacure.org
MINNESOTA /
Southern California NORTH CENTRAL STATES PENNSYLVANIA
Davita Greewald Kris Greer Kathie Murphy
southerncaliforniasupport@tmsforacure.org Melissa Lovett pennsylvaniasupport@tmsforacure.org
minnesotasupport@tmsforacure.org
COLORADO TENNESSEE/SOUTHEAST STATES
northcentralsupport@tmsforacure.org
Jan Marie Smith Cheri Smith
coloradosupport@tmsforacure.org MISSOURI
 Patty Smith
Kansas City
 southeastsupport@tmsforacure.org
FLORIDA Cheri Smith
Michele Kress VIRGINIA / MARYLAND /
ksmosupport@tmsforacure.org
floridasupport@tmsforacure.org DELAWARE
St. Louis Maria Dastur
ILLINOIS
 Cheri Smith virginiasupport@tmsforacure.org
Cheri Smith
stlouissupport@tmsforacure.org
Illinoissupport@tmsforcure.org WASHINGTON DC
NORTH CAROLINA Patricia Beggiato
Chicago Emily Bolden washingtondcsupport@tmsforacure.org
Jeanie Dunn
Sharon Renfroe
chicagosupport@tmsforacure.org
northcarolinasupport@tmsforacure.org
INDIANA NORTHEAST / NEW ENGLAND
Pam Hodge
STATES
indianasupport@tmsforacure.org
Rita Barlow
northeastsupport@tmsforacure.org

International
AUSTRALIA CANADA
David Mayne Shawna Lechner-Rumpel, President
info@mastocytosis.com.au shawna.lechner@sasktel.net support@mastocytosis.ca

Brazil UNITED KINGDOM

Lisa Morrison Thuler
Mastocitose Brasil: Dawn Brogden, Co-Chair
mastocitosebrasil@gmail.com dawn@ukmasto.org
Jess Hobart, Co-Chair
jess@ukmasto.org

tmsforacure.org | Special Edition 2017-2018 51

The Mastocytosis Chronicles
P.O. Box 416
Sterling, MA 01564

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TMS Launches New Website!

In February 2017, TMS launched our new and vastly improved website for patients,
families, caregivers, physicians and others with an interest in mast cell disorders,
including mastocytosis and mast cell activation syndromes. The site contains
an expanded version of information displayed in this publication, with reference
hyperlinks, resource materials, research grant information, articles written by our
specialist physicians, stories about our community, and much more, updated regularly.

TMS Needs Your Help! The Mastocytosis Society,

Inc. Invites you to stop by our
If you find the information and support provided by exhibitor booths at the following
TMS helpful for you or your patients, please consider
Medical Conferences:
making a monetary contribution to our organization.
Donations, easily made through our website,
www.tmsforacure.org, help us fulfill our mission of American Academy of Pediatrics
Research, Education, Advocacy and Support for Mast American Society of Hematology
Cell Disorders. TMS is an all-volunteer organization
that receives funding directly from people affected by American Academy of Dermatology
mast cell disorders. Any donation is appreciated! American Academy of Allergy, Asthma and Immunology