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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
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
The Mastocytosis Society, Inc. (TMS) was founded finding. On the other hand, more advanced cases of
in 1995 by Bill Abbottsmith, Linda Buchheit, Olive aggressive Mastocytosis were also recognized during
Clayson, Iris Dissinger, Bill Hingst, and Joe Palk. At post-mortem exams, leading pathologists to identify
that time very little was known about Mastocytosis, all forms of Mastocytosis as having a high associated
so these pioneering individuals sought to fill a massive mortality rate. Fortunately, that prognosis has improved
void with some answers to their multitude of questions as more patients are diagnosed and treated sooner,
about this rare disease. They found one another and more physicians research and treat this disease.
through NORD, with sheer determination and Today, we know that pediatric patients have greater
extensive research. than a 75% chance of outgrowing their disease at
or before puberty, and adults with Indolent Systemic
The first support group meeting was held in Baltimore Mastocytosis can have a near normal life expectancy if
at the Inner Harbor in 1994 and was attended by Linda they avoid triggers and take their medication.
Buchheit and Bill Hingst. The second meeting was held
the following year at Linda Buchheit’s home in Ohio. Founding Members: Today’s accomplishments are built
Fourteen members attended that year. Little did they on the foundations laid by the early volunteers, and we
know how fruitful their efforts would be and what a are grateful for their efforts. TMS is where it is today
lifeline they would become as more and more patients because of the seeds that they planted in 1994 and
joined each year. in the early years. Since then there have been many
more champions who have served their fellow patients
Until 1990 many patients diagnosed with Mastocytosis and families affected by Mastocytosis and Mast Cell
were given a very grim prognosis. Up until that Activation Disorders by volunteering for TMS. We
time, Mastocytosis was not often considered when salute you!
physicians were making a differential diagnosis,
and many cases were completely missed, resulting Past Board Members: THANK YOU to all of our past
in patient death. At that point, signs of the disease board members as they are our strong foundation for
were then discovered on autopsy; however, because all the wonderful and exciting things happening now
so little was known about Mastocytosis, it was and in the future for TMS!
2 tmsforacure.org | Special Edition 2017-2018
The Mastocytosis Chronicles Mast Cell Disorder
Challenges Meetings
The Mastocytosis Society, Inc. | Spring 2017 - Volume 23 Issue 1
and US Network Update
By Susan Jennings, PhD, and Valerie Slee, RN,
BSN - February 2017
In this issue
Since 2014, The Mastocytosis Society, Inc. (TMS) has
5 Overview, Definitions, Diagnosis hosted small ancillary Mast Cell Disorder Challenges
and Classification meetings during the annual gatherings of several physician
specialty associations. The objectives of these meetings
9 Cytology of Mast Cells have been to bring together specialist physicians, drug
company representatives and members of the TMS
10 Cutaneous Mastocytosis Variants
Research Committee to identify the primary challenges
12 Systemic Mastocytosis Variants facing the mast cell disorder community in the United
States and to explore possible actions that would address
16 Mast Cell Activation Syndrome Variants those challenges. A key conclusion from our initial
Challenges meetings was that the establishment of a US
18 Signs, Symptoms And Triggers Network for Mast Cell Disorders would be extremely helpful
in overcoming many of the challenges faced by our disease
21 Tests community. During these meetings, our US physicians have
25 Treatments For Mast Cell Disorders received significant support from a number of international
mast cell disorder specialists, who have shared their
27 Medications To Treat Mast Cell Disorders experiences of forming networks in their own countries and
more broadly in Europe. TMS is committed to supporting
29 Pediatric Mast Cell Disorders: Facts in Brief activities that will lead to the formation of a US network
under the leadership of Cem Akin, MD, PhD, and Jason
36 Visual Guide to Diagnosing Mastocytosis Gotlib, MD, MS, as Co-Chairs. The American Academy
of Allergy, Asthma and Immunology (AAAAI) Mast Cell
40 Medical & Research Centers that Treat Patients
Disorder Committee has also agreed to participate in
with Mast Cell Diseases
this effort. Challenges meetings have been held while
43 Medical Advisory Board specialists have been gathered for American Society of
Hematology and AAAAI Annual Meetings and immediately
45 The Mastocytosis Society Printed Materials prior to the 2015 European Competence Network on
Mastocytosis (ECNM) Annual Meeting.
46 Medical Reference Highlights
Please see www.tmsforacure.org for more
49 Mast Cell Connect Patient Registry brochure
information and updates on our Mast Cell Disorder
51 Support Group Contacts 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 have within them small sacs, or granules,
surrounded by membranes (Figure 1). The sacs contain
Mast cells (MC) are immune system cells that live in many different kinds of substances called mediators,
the bone marrow and in body tissues, internal and which participate in all of the roles above, including
external, such as the gastrointestinal tract, the lining allergic response and anaphylaxis. The mediators are
of the airway, and the skin. Everyone has mast cells in selectively released when there is an allergic or mast cell
their body, and they play many complex and critical roles based reaction.1
in keeping us healthy. The positive roles that they play
include protecting us from infection, and helping our body There is a difference between someone who is healthy,
by participating in the inflammatory process. However, with mast cells that are functioning normally, and
mast cells are also involved in allergic reactions, from the someone with a mast cell disorder, whose mast cells
tiny swelling that appears after a mosquito bite to a life may be activating inappropriately in response to triggers,
threatening, full-blown anaphylaxis. or may also be proliferating and accumulating in organ
tissues.
Figure 1. Mast cell (electron micrograph) What are Mast Cell Disorders?
Mast cell granule (sac) which contains mediators 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 Diagnosis and Classification13-17
It is important to note that the process of mast cell
activation can occur in anyone, even without a mast cell CM is diagnosed by the presence of typical skin lesions and
disorder, as well as in patients with both mastocytosis a positive skin biopsy demonstrating characteristic clusters
and MCAS.6 of mast cells. The preferred method of diagnosing SM is via
bone marrow (BM) biopsy. The WHO has established criteria
MASTOCYTOSIS for diagnosing SM, summarized18 as follows:
Definition Major ª: Multifocal dense infiltrates of mast cells
(MCs) (> 15 MCs in aggregate) in tryptase stained
Mastocytosis has been defined in the literature as an biopsy sections of the bone marrow or other
abnormal accumulation of mast cells in one or more extracutaneous organ
organ systems. Previously classified by the World Health
Organization (WHO) as a myeloproliferative neoplasm, Minorª:
mastocytosis is now classified in its own category •M
ore than 25% of MCs in bone marrow or
under myeloid neoplasms.7 Broadly separated other extracutaneous organ(s) show abnormal
into three categories – cutaneous morphology (i.e. are atypical MC type 1 or are
mastocytosis (CM), systemic mastocytosis spindle–shaped MCs) in multifocal lesions in
(SM) and mast cell sarcoma – these histologic examination
diseases occur in both children and
adults. CM is considered a benign • K IT mutation at codon 816V in extracutaneous
skin disease representing the organ(s) (in most cases bone marrow cells are
majority of pediatric cases. In examined)
67-80% of pediatric cases seen,
resolution will occur before or in • K IT+MCs in bone marrow show aberrant expression
early adulthood.8-10 In pediatric of CD2 and/or CD25
mastocytosis, symptoms of mast
cell mediator release may occur • S erum total tryptase > 20 ng/mL (does not count in
systemically as a result of mast cell patients who have SM-AHN-type disease.)
mediators released from skin lesions.10
This, however, does not necessarily Abbreviation Key:
indicate systemic disease. The incidence KIT: Mast cell growth receptor/tyrosine kinase receptor
of systemic pediatric disease was previously MC(s): Mast cells;
unknown, but systemic forms have now been SM-AHN: Systemic mastocytosis with associatiated
proven to exist in some children.8-10 The majority hematologic neoplasm.
of adult patients are diagnosed with systemic disease.
Skin involvement, typically maculopapular cutaneous ª If at least one major criterion and one minor criterion
mastocytosis/urticaria pigmentosa, is common in adult OR at least three minor criteria are fulfilled, the
patients and can provide an important clue to accurate diagnosis of systemic mastocytosis can be established.
diagnosis.11, 12 b
Activating mutations at codon 816, in most cases,
KIT D816V.
6 tmsforacure.org | Special Edition 2017-2018
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 The second required co-criterion for systemic mast cell
symptoms of mast cell mediator release who did not activation depends on documentation that mast cells are
fulfill the criteria for SM.25, 26 Thus began the evolution of directly involved in the symptomatology. An increase in the
discussions about other forms of mast cell disorders, both serum level of tryptase, above baseline and within a narrow
clonal and nonclonal, which became known as Mast Cell (generally accepted as one to two hour) window of time after
Activation Syndromes (MCAS).6, 27, 28 a symptomatic episode, is proposed as the preferred method
for providing evidence of mast cell involvement according
Diagnosis and Proposed Classification to these criteria.6, 28-30 The consensus article provides a
method for calculating the required minimum rise in serum
Recognition by specialist physicians of the importance tryptase.6 After a reaction, a level of serum tryptase that
of mast cell activation in disease led to an international is a minimum of 20% above the basal serum tryptase level,
Mast Cell Disorders Working Conference emphasizing plus 2 ng/ml, will meet the second criterion listed above
this topic in September of 2010. Consensus statements for a mast cell activation event. Consensus members also
were published regarding classification of and diagnostic agreed that when serum tryptase evaluation is not available
criteria for mast cell disorders,6 where mast cell activation or when the tryptase level does not rise sufficiently to meet
plays a prominent role. the required increase for the co-criterion, other mediator
tests could suffice. A rise in urinary n-methyl histamine,
Mediators produced by mast cells have a considerable prostaglandin-D2, or its metabolite, 11β-prostaglandin-F2α
effect on specific symptomatology. Symptoms, including, (24-hour urine test for any of the three), is considered an
but not limited to flushing, pruritis (itching), urticaria alternative for the co-criterion related to a requirement for
(hives), headache, gastrointestinal symptoms (including a mast cell mediator level rise during a systemic mast cell
diarrhea, nausea, vomiting, abdominal pain, bloating, activation event.6
gastroesophageal reflux), and hypotension (low blood
pressure), allow a patient to meet the first of three Finally, the third co-criterion requires a response (based
required co-criterion for systemic mast cell activation on response criteria15) to medications that inhibit the
when the patient exhibits symptoms involving two action of histamine.6 In addition, in those with typical
or more organ systems in parallel, which recur, or are mast cell activation symptoms, a “complete or major”
chronic, are found not to be caused by any other condition response to drugs that inhibit other mediators produced
or disorder other than mast cell activation, and require by mast cells or block mast cell mediator release can be
treatment or therapy.6, 28 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 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
1. Gilfillan AM, Austin SJ, Metcalfe DD. Mast cell biology: Health Organization (WHO) Classification of Tumours. Pathology
introduction and overview. Adv Exp Med Biol. 2011;716:2-12. and Genetics. Tumours of Haematopoietic and Lymphoid Tissues.
2. Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Lyon: IARC Press; 2008.
Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72. 17. Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C,
3. Horny HP, Sotlar K, Valent P, Hartmann K. Mastocytosis: a Brockow K, et al. Proposed diagnostic algorithm for patients with
disease of the hematopoietic stem cell. Dtsch Arztebl Int. 2008 suspected mastocytosis: a proposal of the European Competence
Oct;105(40):686-92. Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74.
4. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: 18. Valent P. Diagnostic evaluation and classification of mastocytosis.
proposed diagnostic criteria. J Allergy Clin Immunol. 2010 Immunol Allergy Clin North Am. 2006 Aug;26(3):515-34.
Dec;126(6):1099-104 e4. 19. Roberts LJ, 2nd, Oates JA. Biochemical diagnosis of systemic
5. Afrin LB. Presentation, diagnosis and management of mast cell mast cell disorders. J Invest Dermatol. 1991 Mar;96(3):19S-24S;
activation syndrome. In: Murray DB, editor. Mast cells: phenotypic discussion S-5S.
features, biological functions and role in immunity. Hauppauge: 20. Metcalfe DD. Classification and diagnosis of mastocytosis:
Nova Science Publishers, Inc.; 2013. p. 155-232. current status. J Invest Dermatol. 1991 Mar;96(3):2S-4S.
6. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter 21. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum
MC, et al. Definitions, criteria and global classification of mast S, Suzuki Y, et al. Identification of a point mutation in the
cell disorders with special reference to mast cell activation catalytic domain of the protooncogene c-kit in peripheral blood
syndromes: a consensus proposal. Int Arch Allergy Immunol. mononuclear cells of patients who have mastocytosis with an
2012;157(3):215-25. associated hematologic disorder. Proc Natl Acad Sci U S A. 1995
7. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau Nov 7;92(23):10560-4.
MM, et al. The 2016 revision to the World Health Organization 22. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al.
classification of myeloid neoplasms and acute leukemia. Blood. Somatic c-KIT activating mutation in urticaria pigmentosa and
2016 May 19;127(20):2391-405. aggressive mastocytosis: establishment of clonality in a human
8. Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis. mast cell neoplasm. Nat Genet. 1996 Mar;12(3):312-4.
Curr Opin Pediatr. 2012 Aug;24(4):480-6. 23. Escribano L, Orfao A, Diaz-Agustin B, Villarrubia J, Cervero C,
9. Fried AJ, Akin C. Primary mast cell disorders in children. Curr Lopez A, et al. Indolent systemic mast cell disease in adults:
Allergy Asthma Rep. 2013 Dec;13(6):693-701. immunophenotypic characterization of bone marrow mast cells
and its diagnostic implications. Blood. 1998 Apr 15;91(8):2731-6.
10. Meni C, Bruneau J, Georgin-Lavialle S, Le Sache de Peufeilhoux
L, Damaj G, Hadj-Rabia S, et al. Paediatric mastocytosis: 24. Horny HP. Mastocytosis: an unusual clonal disorder of bone
a systematic review of 1747 cases. Br J Dermatol. 2015 marrow-derived hematopoietic progenitor cells. Am J Clin Pathol.
Mar;172(3):642-51. 2009 Sep;132(3):438-47.
11. Berezowska S, Flaig MJ, Rueff F, Walz C, Haferlach T, Krokowski 25. Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M, Sperr
M, et al. Adult-onset mastocytosis in the skin is highly suggestive WR, et al. Diagnostic and subdiagnostic accumulation of mast
of systemic mastocytosis. Mod Pathol. 2014 Jan;27(1):19-29. cells in the bone marrow of patients with anaphylaxis: monoclonal
mast cell activation syndrome. Int Arch Allergy Immunol.
12. Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, 2007;142(2):158-64.
Alvarez-Twose I, et al. Cutaneous manifestations in patients with
mastocytosis: Consensus report of the European Competence 26. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E,
Network on Mastocytosis; the American Academy of Allergy, Noel P, et al. Demonstration of an aberrant mast-cell population
Asthma & Immunology; and the European Academy of with clonal markers in a subset of patients with “idiopathic”
Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016 anaphylaxis. Blood. 2007 Oct 1;110(7):2331-3.
Jan;137(1):35-45. 27. Horny HP, Sotlar K, Valent P. Evaluation of mast cell activation
13. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, syndromes: impact of pathology and immunohistology. Int Arch
et al. Diagnostic criteria and classification of mastocytosis: a Allergy Immunol. 2012;159(1):1-5.
consensus proposal. Leuk Res. 2001 Jul;25(7):603-25. 28. Valent P. Mast cell activation syndromes: definition and
14. Valent P, Horny H-P, Li CY, Longley JB, Metcalfe DD, Parwaresch classification. Allergy. 2013 Apr;68(4):417-24.
RM, et al. Mastocytosis. Jaffe ES, Harris NL, Stein H, Vardiman 29. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec
JW, editors. World Health Organization (WHO) Classification of AS, et al. The alpha form of human tryptase is the predominant
Tumours. Pathology and Genetics. Tumours of Haematopoietic and type present in blood at baseline in normal subjects and is
Lymphoid Tissues. Lyon: IARC Press; 2001. elevated in those with systemic mastocytosis. J Clin Invest. 1995
15. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, Dec;96(6):2702-10.
et al. Standards and standardization in mastocytosis: consensus 30. Schwartz LB, Irani AM. Serum tryptase and the laboratory
statements on diagnostics, treatment recommendations and diagnosis of systemic mastocytosis. Hematol Oncol Clin North
response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53. Am. 2000 Jun;14(3):641-57.
8 tmsforacure.org | Special Edition 2017-2018
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 patients with mastocytosis. It can be elicited by stroking
Mastocytosis an existing CM lesion with a wooden tongue depressor,
approximately 5 times with moderate pressure. Within a few
Variants 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
An international consensus task force of mast cell disorder with antihistamines. If the testing procedure for Darier’s sign
specialists has recently proposed updates to the diagnostic is not done properly, false positives or false negatives may
criteria and classification for cutaneous disease.1 Typical skin result. Darier’s sign is to be applied to the evaluation of fixed
lesions found in mastocytosis, along with a positive Darier’s cutaneous lesions except in the case of a pediatric patient
sign (see below), is the major criterion for diagnosing skin with cutaneous mastocytoma or nodular lesions. Testing for
involvement in patients with mastocytosis. The two minor Darier’s sign may provoke a systemic reaction and should
criteria are identified via skin lesion biopsy: increased mast either be performed with the greatest of caution or avoided.
cell numbers and the presence of an (activating) KIT mutation.1,
2
Cutaneous mastocytosis (CM) includes three variants: Dermatographism is a skin reaction characterized by a
maculopapular cutaneous mastocytosis (MPCM), wheal and flare response when normal skin, not affected by
which includes urticaria pigmentosa (UP) and telangiectasia skin lesions, is stroked with a tongue depressor, finger nails
macularis eruptiva perstans (TMEP), diffuse cutaneous or other instrument. The nick-name for dermatographism is
mastocytosis (DCM), and cutaneous mastocytoma.1 The skin writing disease.
taskforce recommends that telangiectasia macularis eruptiva
perstans (TMEP) be removed as a separate category because, A macule is a lesion that is flat and even with the
although some adult patients may have telangiectatic lesions surrounding skin, identified by a change in color compared
on their chest, shoulders, neck and back, they may also to the surrounding skin.
demonstrate maculopapular lesions in other places, therefore A papule is a small bump or elevated lesion, up to 1 cm in
fulfilling criteria for MPCM. diameter, containing no visible fluid.
A nodule is a growth of abnormal tissue just below the skin.
Most cases of pediatric mastocytosis fall into one of the
A bulla is a large blister filled with fluid.
above categories and may or may not include symptoms
of systemic mast cell activation, including anaphylaxis, as Telangiectasia is a vascular lesion formed by dilatation
a result of mediators released from the skin.3, 4 Pediatric of a group of small blood vessels.
CM encompasses a variety of clinical manifestations. In
children, some forms of CM will spontaneously resolve,
VARIANTS OF CUTANEOUS MASTOCYTOSIS
some will go on to be diagnosed as indolent systemic
mastocytosis (ISM), with a smaller percentage identified
Maculopapular Cutaneous Mastocytosis (MPCM)/
as well-differentiated systemic mastocytosis (WDSM).5
Urticaria Pigmentosa (UP)1
In most adults with skin lesions typical for mastocytosis
• May be seen in infants, children or adults
(in particular, the maculopapular type), systemic disease
• Adults presenting with maculopapular lesions have
will ultimately be found, leading to a diagnosis of systemic
a very high likelihood of systemic disease, most
mastocytosis, usually in an indolent form (indolent
frequently indolent systemic mastocytosis (ISM)
systemic mastocytosis).1, 6
• Rarely, an adult presents with maculopapular lesions
who does not have systemic disease, and has a
Definitions1, 7
diagnosis of MPCM
• Red maculopapular lesions tend to wheal when
Darier’s sign is an important diagnostic finding of
scratched (positive Darier’s sign)
10 tmsforacure.org | Special Edition 2017-2018• Blister formation can occur with rubbing or stroking • Can involve up to 100% of the skin with the trunk,
of lesion and is associated with pruritis8 head and scalp heavily affected
• Encompasses several clinical entities with different • Can appear at birth or early infancy; may persist into
outcomes, including: pitted melanotic macules, reddish adulthood, possibly as well differentiated systemic
brown telangiectatic macules, lightly pigmented mastocytosis (WDSM)5
papules, brownish papules, and small nodules • Blisters, some of which are hemorrhagic, and bullae
• This group is divided into two sub-variants may be present and dermatographism may be
° Monomorphic variant prominent
- Mostly seen in adults and in a small subgroup • Flushing is a common symptom
of children • Tryptase may be elevated due to increased mast cell
- Small maculopapular lesions, similar in shape, burden in the skin and can be indicative of WDSM5
size and color
- Adults most typically express the KIT D816V Cutaneous Mastocytoma1
mutation in exon 17 of the KIT gene
- In adults, thigh, axilla, trunk, extremities and • Usually present at birth
neck may be involved • Elevated lesion(s) (up to a total of three lesions)
- 9 5% of adults diagnosed with ISM, 50% with which usually resolves during childhood
advanced systemic mastocytosis [systemic • Four cutaneous mastocytomas or more become a
mastocytosis with an associated hematologic diagnosis of MPCM
neoplasm (SM-AHN, formerly SM-AHMND) or • Multiple mastocytomas may evolve into adult WDSM5
aggressive systemic mastocytosis (ASM)] and
less than 50 % of mast cell leukemia patients References
exhibit this variant
1. Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC,
- Children presenting with this form may have Alvarez-Twose I, et al. Cutaneous manifestations in patients with
increased serum tryptase and a tendency toward mastocytosis: Consensus report of the European Competence Network
on Mastocytosis; the American Academy of Allergy, Asthma &
systemic disease that persists into adulthood Immunology; and the European Academy of Allergology and Clinical
- T he type of lesions can vary during the course Immunology. J Allergy Clin Immunol. 2016 Jan;137(1): 35-45.
of the disease, i.e., nodules during infancy may 2. V alent P, Akin C, Escribano L, Fodinger M, Hartmann
K, Brockow K, et al. Standards and standardization in
turn into plaques at age 6 mastocytosis: consensus statements on diagnostics, treatment
° Polymorphic variant recommendations and response criteria. Eur J Clin Invest. 2007
Jun;37(6):435-53.
-M ostly seen in children
3. M atito A, Carter M. Cutaneous and systemic mastocytosis in
- C an be macular, plaque or nodular, with lesions children: a risk factor for anaphylaxis? Curr Allergy Asthma Rep.
of variable shape, color and size 2015 May;15(5):22.
-A lthough children typically express mutations 4. M eni C, Bruneau J, Georgin-Lavialle S, Le Sache de Peufeilhoux
L, Damaj G, Hadj-Rabia S, et al. Paediatric mastocytosis:
in exon 8, 9, 11 or 17 of the KIT gene, KIT a systematic review of 1747 cases. Br J Dermatol. 2015
mutations may be negative Mar;172(3):642-51.
- Usually involving head, neck and extremities 5. T orrelo A, Alvarez-Twose I, Escribano L. Childhood
mastocytosis. Curr Opin Pediatr. 2012 Aug;24(4):480-6.
- May involve blistering upon irritation until 3
years of age 6. B erezowska S, Flaig MJ, Rueff F, Walz C, Haferlach T,
Krokowski M, et al. Adult-onset mastocytosis in the skin is
- Prognosis is favorable with regression of highly suggestive of systemic mastocytosis. Mod Pathol. 2014
Jan;27(1):19-29.
disease in adolescence or young adulthood
7. Venes D, Thomas CL. Taber’s cyclopedic medical dictionary. 19
ed. Philadelphia: F.A. Davis Co.; 2001.
Diffuse Cutaneous Mastocytosis (DCM)1
8. C astells M, Metcalfe DD, Escribano L. Diagnosis and
treatment of cutaneous mastocytosis in children: practical
• Skin thickened, hyperpigmented and diffusely infiltrated recommendations. Am J Clin Dermatol. 2011 Aug 1;12(4):259-70.
tmsforacure.org | Special Edition 2017-2018 11Systemic Mastocytosis Variants
Systemic mastocytosis (SM) consists of a group of tryptase, and CD25 should be performed on sections of
rare, heterogeneous disorders involving growth and the biopsy.1-5
accumulation of abnormal mast cells (MC) in one or
multiple extracutaneous (non-skin) organ systems Recent Updates in Diagnosis
(Table 1). Standard technique can be used to obtain
an iliac crest bone marrow (BM) biopsy and aspirate A new diagnostic algorithm has been proposed by the
smear for diagnosis. Aspirated BM should be allocated European Competence Network on Mastocytosis for
for flow cytometry to assess for the presence of mast evaluating patients with suspected mastocytosis.6
cells with aberrant phenotype (i.e., co-expression Recommendations for KIT mutation analysis, including in
of CD25). Immunohistochemistry for KIT, mast cell 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 2017-2018Table 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 systemic category, despite that 91% of patients
with WDSM have childhood onset of disease, with
The majority of adult patients fit into this category, fulfilling familial involvement in 39%. There is a heterogeneous
the criteria for indolent systemic mastocytosis (ISM).2, 10-12 presentation of lesions, maculopapular, nodular and
The bone marrow, gastrointestinal tract, skeletal system, diffuse cutaneous, that may involve a large percentage of
nervous system and skin may be affected. Some patients the skin.17 Severe mast cell symptoms can occur and the
may have enlarged livers and spleens and lymphadenopathy. variant may persist into adulthood in a low percentage
Mediator-related symptoms are common, but the grade of of cases. The mast cells often do not express CD25 or
bone marrow infiltration is low (usually less than 5 percent) CD2 that are part of the minor World Health Organization
with the bone marrow fulfilling the criteria for SM and (WHO) criterion for SM, but may have CD30. Also, roughly
80-90% of the patients exhibiting a positive D816V KIT 90% of WDSM patients don’t have the KIT D816V or
mutation. In most patients the serum tryptase concentration other exon 17 KIT mutations.17 Bone marrow analysis
exceeds 20 ng/mL, but a normal level of tryptase does not identifies mast cells in WDSM patients as notably large,
rule out either mastocytosis or another mast cell activation round, mature-appearing mast cells with the absence
disorder. Treatment usually includes mediator-targeting of the spindle-shaped mast cells typically seen in SM.15
drugs, including antihistamines, but does not usually require Baseline serum tryptase levels
cytoreductive agents, although there are exceptions. 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 13Systemic Mastocytosis Variants
Continued from page 13
in these patients are usually lower than what is frequently MAST CELL LEUKEMIA21
detected in SM, except in a variable percentage of
children at onset. Imatinib mesylate has been used in In this rare variant, mast cell leukemia (MCL) patients fit
some patients with severe cases of WDSM, since these the criteria for SM, and a bone marrow aspirate smear
patients do not usually carry the KIT D816V mutation, shows that 20% or more of the cells are mast cells, or
which causes resistance to imatinib.18 10% or more mast cells are seen in circulating blood.8,
21, 22
The mast cells have malignant features. A 2014
SMOLDERING SYSTEMIC MASTOCYTOSIS international consensus proposal recommends that MCL
be separated into acute and chronic23 subvariants based
Smoldering systemic mastocytosis (SSM) was recently on whether or not C findings (Table 2) are present.21 In
moved out of the WHO ISM category and into its own addition, it recommends a distinction between a primary
category under SM.9 In SSM, two or more B findings, but form of MCL and a secondary form that evolves from
no C findings (Table 2) are found and there is a greater an existing mast cell neoplasm, such as ASM or mast
possibility that the disease will progress to a more cell sarcoma. There is a prognostic pre-phase identified
aggressive variant. in patients with ASM with 5-19% mast cells in bone
marrow smears, associated with rapid progression. It
Advanced Systemic has been proposed that this condition be called “ASM
in transformation to MCL” (ASM-t). Prognosis can be
Mastocytosis Variants8 variable based on the form of disease; life expectancy
has been extended, in some cases, due to advances
SM WITH AN ASSOCIATED HEMATOLOGIC in cytoreductive therapy.24 It is important to note that
NEOPLASM (SM-AHN) myelomastocytic leukemia (MML), which is a differential
diagnosis, is not regarded by mast cell disorder specialists
SM-AHN is the recently updated term for SM-AHNMD as a subvariant of MCL or SM and should be considered a
from the 2016 WHO classification of mastocytosis.9 These secondary condition.21
patients fit the criteria for SM and they fit the WHO criteria
for myelodysplastic syndrome (MDS), myeloproliferative References
neoplasm (MPN), MDS/MPN overlap disorder, or acute
1. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K,
myeloid leukemia (AML), with or without skin lesions.8, 19, 20 et al. Standards and standardization in mastocytosis: consensus
Patients are treated for both the SM component and for the statements on diagnostics, treatment recommendations and
response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53.
associated hematologic neoplasm.
2. Alvarez-Twose I, Morgado JM, Sanchez-Munoz L, Garcia-
Montero A, Mollejo M, Orfao A, et al. Current state of biology and
AGGRESSIVE SYSTEMIC MASTOCYTOSIS diagnosis of clonal mast cell diseases in adults. Int J Lab Hematol.
2012 Oct;34(5):445-60.
In this rare variant, aggressive systemic mastocytosis 3. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art.
Pathobiology. 2007;74(2):121-32.
(ASM) patients fit the criteria for SM, with or without skin
4. Horny HP, Valent P. Diagnosis of mastocytosis: general
lesions, and also meet criteria for one or more C findings histopathological aspects, morphological criteria, and
(Table 2).8 Patients with ASM often require chemotherapy. 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.
14 tmsforacure.org | Special Edition 2017-20186. Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, 16. Fried AJ, Akin C. Primary mast cell disorders in children. Curr
Brockow K, et al. Proposed diagnostic algorithm for patients with Allergy Asthma Rep. 2013 Dec;13(6):693-701.
suspected mastocytosis: a proposal of the European Competence
Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74. 17. Alvarez-Twose I, Jara-Acevedo M, Morgado JM, Garcia-
Montero A, Sanchez-Munoz L, Teodosio C, et al. Clinical,
7. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, immunophenotypic, and molecular characteristics of well-
Escribano L, et al. KIT mutation analysis in mast cell neoplasms: differentiated systemic mastocytosis. J Allergy Clin Immunol.
recommendations of the European Competence Network on 2016 Jan;137(1):168-78 e1.
Mastocytosis. Leukemia. 2015 Jun;29(6):1223-32.
18. Alvarez-Twose I, Gonzalez P, Morgado JM, Jara-Acevedo M,
8. Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, et Sanchez-Munoz L, Matito A, et al. Complete response after
al. International Working Group-Myeloproliferative Neoplasms imatinib mesylate therapy in a patient with well-differentiated
Research and Treatment (IWG-MRT) & European Competence systemic mastocytosis. J Clin Oncol. 2012 Apr 20;30(12):e126-9.
Network on Mastocytosis (ECNM) consensus response
criteria in advanced systemic mastocytosis. Blood. 2013 Mar 19. Stoecker MM, Wang E. Systemic mastocytosis with
28;121(13):2393-401. associated clonal hematologic nonmast cell lineage disease:
a clinicopathologic review. Arch Pathol Lab Med. 2012
9. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau Jul;136(7):832-8.
MM, et al. The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia. Blood. 20. Wang SA, Hutchinson L, Tang G, Chen SS, Miron PM, Huh
2016 May 19;127(20):2391-405. YO, et al. Systemic mastocytosis with associated clonal
hematological non-mast cell lineage disease: clinical
10. Carter MC, Metcalfe DD, Komarow HD. Mastocytosis. Immunol significance and comparison of chomosomal abnormalities
Allergy Clin North Am. 2014 Feb;34(1):181-96. in SM and AHNMD components. Am J Hematol. 2013
Mar;88(3):219-24.
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. 21. Valent P, Sotlar K, Sperr WR, Escribano L, Yavuz S, Reiter A, et al.
Refined diagnostic criteria and classification of mast cell leukemia
12. Pardanani A. Systemic mastocytosis in adults: 2013 update on (MCL) and myelomastocytic leukemia (MML): a consensus
diagnosis, risk stratification, and management. Am J Hematol. proposal. Ann Oncol. 2014 Sep;25(9):1691-700.
2013 May 30.
22. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO,
13. Z anotti R, Bonadonna P, Bonifacio M, Artuso A, Schena D, Rossini Hermine O, Damaj G. Mast cell leukemia. Blood. 2013 Feb
M, et al. Isolated bone marrow mastocytosis: an underestimated 21;121(8):1285-95.
subvariant of indolent systemic mastocytosis. Haematologica.
2011 Mar;96(3):482-4. 23. Valent P, Sotlar K, Sperr WR, Reiter A, Arock M, Horny HP.
Chronic mast cell leukemia: a novel leukemia-variant with distinct
14. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. morphological and clinical features. Leuk Res. 2015 Jan;39(1):1-5.
A novel form of mastocytosis associated with a transmembrane
c-kit mutation and response to imatinib. Blood. 2004 Apr 24. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K,
15;103(8):3222-5. Hermine O, et al. Efficacy and Safety of Midostaurin in
Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun
15. Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis. 30;374(26):2530-41.
Curr Opin Pediatr. 2012 Aug;24(4):480-6.
Mast Cell Sarcoma1, 2
Mast cell sarcoma is a rare tumor that may present in References
many different anatomic locations and age groups, and
prognosis is generally poor. Mast cell sarcoma is often 1. V alent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB,
et al. Diagnostic criteria and classification of mastocytosis: a
misdiagnosed because the presenting cells bear little consensus proposal. Leuk Res. 2001 Jul;25(7):603-25.
resemblance to normal mast cells and spindle-shaped 2. H
orny HP, Akin C, Metcalfe DD, Escribano L, Bennett JM, Valent
mast cells frequently seen in systemic mastocytosis.3 The P, et al. Mastocytosis (mast cell disease) Swerdlow SH, Campo E,
Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health
cells of mast cell sarcoma more closely resemble “atypical Organization (WHO) Classification of Tumours. Pathology and
type II mast cells” or “promastocytes” that are associated Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon:
IARC Press; 2008.
with some cases of aggressive systemic mastocytosis.1, 3
3. R yan RJ, Akin C, Castells M, Wills M, Selig MK, Nielsen GP, et
Pathological examination of the tumor has shown it to be al. Mast cell sarcoma: a rare and potentially under-recognized
highly malignant with an aggressive growth pattern.3, 4 diagnostic entity with specific therapeutic implications. Mod
Pathol. 2013 Apr;26(4):533-43.
Patients with this tumor do not fulfill the criteria for SM.1
4. Georgin-Lavialle S, Aguilar C, Guieze R, Lhermitte L, Bruneau J,
The imatinib mesylate-resistant KIT D816V mutation has Fraitag S, et al. Mast cell sarcoma: a rare and aggressive entity-
not been found in reported mast cell sarcomas, such that -report of two cases and review of the literature. J Clin Oncol.
2013 Feb 20;31(6):e90-7.
use of imatinib has been attempted in some patients.3
tmsforacure.org | Special Edition 2017-2018 15Mast Cell Activation Syndrome Variants1-3
PRIMARY MCAS IDIOPATHIC MCAS
Primary MCAS results from a clonal population of mast Idiopathic MCAS is proposed as a final diagnosis
cells, where a genetic alteration in the cells exists, and after proposed MCAS criteria have been fulfilled and
may be due to mastocytosis or to monoclonal Mast a thorough evaluation has excluded the possibility of
Cell Activation Syndrome (MMAS). Primary MCAS another known underlying cause for this activation.2,
with mastocytosis can be diagnosed if the patient 12
Idiopathic MCAS is therefore nonclonal, with regard
fulfils criteria for MCAS and fulfills the WHO criteria for to current diagnostic capabilities related to mast cell
mastocytosis. MMAS is a distinct disease characterized analyses, and has been presented and discussed in the
by the presence of abnormal mast cells and fulfillment literature by a variety of mast cell disorder specialists.1-3,
of criteria for MCAS, but where sufficient criteria for a 9-13
Review of other causes of MCAS to aid physicians in
diagnosis of mastocytosis are not identified.1-10 evaluation for the exclusionary diagnosis of idiopathic
MCAS have also been provided.1-3, 10
SECONDARY MCAS
Additional Considerations for MCAS
Secondary MCAS is diagnosed when mast cell activation
occurs as an indirect result of another disease or It is recognized by researchers that current diagnostic
condition.1-3, 9, 11 Physician awareness of the presence of
methods for capturing a rise in mast cell mediators
secondary MCAS will allow for more appropriate mast
after a symptomatic episode are not ideal.12, 14, 15 Some
cell activation-targeted treatments, in addition to primary
patients who present with typical and recurrent signs
disease-related medications, to be provided. In addition
to the widespread example of IgE-dependent allergy as a and symptoms of mast cell activation do not present
cause of secondary MCAS, other diseases that can cause with elevated levels of mediators for which we are
secondary MCAS have been reviewed in the literature.1-3, 11 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 multiple mast
sometimes be more reliable.13, 14 Additionally, there is a
cell (or mast cell mediator) very narrow window of time (1-2 hours after symptoms
begin) during which to obtain a serum tryptase test
blocking therapies must to indicate mast cell activation,2 such that obtaining
be tried before successful laboratory evidence of the event can prove difficult in
many circumstances. Some specialists suggest that
symptom resolution is despite lack of proof of elevated mast cell mediators,
attained. 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
16 tmsforacure.org | Special Edition 2017-2018displaying a rise in mediators, then a diagnosis of 3. Valent P. Mast cell activation syndromes: definition and
classification. Allergy. 2013 Apr;68(4):417-24.
idiopathic MCAS remains open for consideration, as
4. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E,
long as other diagnoses continue to be considered Noel P, et al. Demonstration of an aberrant mast-cell population
(please see Valent article noted below for more with clonal markers in a subset of patients with “idiopathic”
anaphylaxis. Blood. 2007 Oct 1;110(7):2331-3.
information on differential diagnoses). The patient
should be periodically monitored to try to capture a rise 5. Valent P, Akin C, Escribano L, Fodinger M, Hartmann
K, Brockow K, et al. Standards and standardization in
in any of the mediators for which commercial testing mastocytosis: consensus statements on diagnostics, treatment
is both available and recognized as a widely accepted recommendations and response criteria. Eur J Clin Invest. 2007
Jun;37(6):435-53.
diagnostic standard.12
6. Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M,
Sperr WR, et al. Diagnostic and subdiagnostic accumulation of
Even the co-criterion requiring a response to mast cell mast cells in the bone marrow of patients with anaphylaxis:
monoclonal mast cell activation syndrome. Int Arch Allergy
targeted therapy can be difficult to obtain in some Immunol. 2007;142(2):158-64.
patients. Sometimes multiple mast cell (or mast cell 7. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi
mediator) blocking therapies must be tried before S, Dal Fior D, et al. Clonal mast cell disorders in patients with
systemic reactions to hymenoptera stings and increased
successful symptom resolution is attained.3, 16 Also, it is serum tryptase levels. J Allergy Clin Immunol Pract. 2009
reported in another study, that only one third of MCAS Mar;123(3):680-6.
patients experience a complete resolution with treatment; 8. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, Matito
A, Esteban-Lopez MI, Vega A, et al. Clinical, biological, and
one third have a major response and another third have molecular characteristics of clonal mast cell disorders presenting
with systemic mast cell activation symptoms. J Allergy Clin
a minor response, and a combination of drugs is usually Immunol. 2010 Jun;125(6):1269-78 e2.
required to achieve control of symptoms.10 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
Please see the following article for more Press; 2011. p. 245-56.
information on mast cell activation syndromes, 10. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding
spectrum of mast cell activation disorders: monoclonal and
including potential causes, symptoms, variants, idiopathic mast cell activation syndromes. Clin Ther. 2013
May;35(5):548-62.
effects of comorbidities and other possible
11. Valent P, Horny HP, Triggiani M, Arock M. Clinical and laboratory
diagnoses to exclude: 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
Valent P. Mast cell activation syndromes: definition and manifestations of non-clonal mast cell activation syndrome. Curr
Allergy Asthma Rep. 2013 Feb;13(1):10-8.
classification. Allergy. 2013 Apr;68(4):417-24.
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
References Jul;128(1):147-52 e2.
14. Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell
1. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: activation disease: a concise practical guide for diagnostic
proposed diagnostic criteria. J Allergy Clin Immunol. 2010 workup and therapeutic options. J Hematol Oncol. 2011;4:10.
Dec;126(6):1099-104 e4. 15. Afrin LB. Polycythemia from mast cell activation syndrome:
lessons learned. Am J Med Sci. 2011 Jul;342(1):44-9.
2. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter
16. Afrin LB. Presentation, diagnosis and management of mast
MC, et al. Definitions, criteria and global classification of mast cell activation syndrome. In: Murray DB, editor. Mast cells:
cell disorders with special reference to mast cell activation phenotypic features, biological functions and role in immunity.
syndromes: a consensus proposal. Int Arch Allergy Immunol. Hauppauge: Nova Science Publishers, Inc.; 2013. p. 155-232.
2012;157(3):215-25.
tmsforacure.org | Special Edition 2017-2018 17Signs, Symptoms And Triggers
Mast cells can be activated through both IgE and SYMPTOMS AND TRIGGERS OF MAST
non-IgE-related mechanisms, resulting in the release CELL ACTIVATION (MASTOCYTOSIS
of mediators, such as tryptase, histamine, heparin, AND MCAS)
leukotrienes and prostaglandins.1 This activation can
occur in a healthy person, for example in response Mast Cell Activation and Triggers
to a mosquito bite, and in patients with both
mastocytosis and mast cell activation syndrome Mast cells can be activated to release mediators by
(MCAS). Patients with mastocytosis have extra mast multiple triggers. Possible triggers of mediator release
cells that can activate and release their mediators, are shown below in Figure 1. Please note that any patient
in addition to the possibility of mast cells that may with a mast cell disorder can potentially react to any
more readily release mediators, resulting in increased trigger, and triggers can change over the course of the
mediator-induced symptoms. Patients with MCAS disease. In addition, patients may experience reactions to
may also have mast cells that are signaled to release virtually any medications, including medications that they
their mediators more easily; this may depend on have tolerated previously. Common medication reactions
genetics, tissue location of the reacting mast cells, in mast cell disorder patients include, but are not limited
the trigger that initiates the response, or even to: opioids, antibiotics, NSAIDs, alcohol-containing
coexisting conditions.2, 3 Symptomatology can arise medicines and intravenous vancomycin. Use with caution.
from both mediator release and/or from mast cell More information related to drug hypersensitivity in mast
proliferation, accumulation and infiltration in tissues, cell disorders is available in a position paper by European
depending on the form of mast cell disease. Triggers specialists (http://onlinelibrary.wiley.com/doi/10.1111/
can be common to both patients with mastocytosis all.12617/full).4
and MCAS, but may be different for each patient.
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.)
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