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Mastocytosis and Clonal Mast Cell
Activation Disorders
Cem Akin, MD, PhD
Brigham and Women’s Hospital
Division of Rheumatology, Immunology and
Allergy
E-mail: cakin@partners.org
Mast cell Basophil
Definition of Mastocytosis
Mastocytosis is a disease characterized by
the presence of excessive numbers of
mast cells in the skin and internal organs,
such as the bone marrow, gastrointestinal
tract, lymph nodes, liver and spleen
MASTOCYTOSIS
• Demographics
– Children and adults
– M/F equal
• Symptoms
– Mast cell derived mediators
• Histamine, prostaglandins, leukotrienes, cytokines
– Excess of mast cells
– Hematologic disorders
Mastocytosis: Common symptoms
• Episodic flushing
• Lightheadedness, presyncope, syncope,
hypotension
• Tachycardia
• Gastrointestinal cramping, nausea,
vomiting, diarrhea, presyncope or syncope
• Triggers: Heat, exercise, spicy foods,
alcohol, hymenoptera stings, drugs
(opioids, muscle relaxants, etc)
Mastocytosis: Common
presentations
• Skin rash (urticaria pigmentosa) 80%
– Pediatric (1st year of life)
– Adult
• Mast cell degranulation symptoms
– Recurrent anaphylaxis
• Hymenoptera
• Unexplained
• Hematologic abnormalities
• Osteoporosis and pathologic fractures
2
World Health Organization
Mastocytosis Consensus Classification
• Cutaneous mastocytosis
• Systemic indolent mastocytosis (without AHD)
• Systemic mastocytosis with an AHNMD
– MDS, MPD, AML, NHL
• Systemic aggressive mastocytosis
– Liver failure with ascites, malabsorption with weight loss,
bone marrow failure, pathologic fractures
• Mast cell leukemia
– >10% MC in circulation or >20% in aspirate smears
• Mast cell sarcoma
• Extracutaneous mastocytoma
WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, p:54-63, 2008
Urticaria Pigmentosa
Urticaria Pigmentosa Urticaria Pigmentosa
Urticaria Pigmentosa Diffuse cutaneous mastocytosis
3
Mastocytoma Mastocytoma
TMEP Histopathology of Urticaria Pigmentosa
Morphologic Abnormalities in Bone Marrow Mast Cells in
Systemic Mastocytosis
Normal Mastocytosis
Bone Marrow Lesions
H&E Tryptase
4
Schwartz et al. J Clin Invest 96:2702, 1995
Serum Tryptase Levels in Mastocytosis Tryptase release after anaphylaxis
Schwartz, LB. Immunology Allergy Clinics of N Amer. August 2006
Bone Marrow Mast Cell Immunophenotype in Mastocytosis
Kitamura et al. Immunology Allergy Clinics of North America,
August 2006
C-kit Mutations in Mastocytosis
Akin, C. J Mol. Diagn. 8:412-419, 2006
• Major:
–Characteristic multifocal dense infiltrates
of mast cells in bone marrow biopsy
• Minor:
–Morphology of mast cells: Spindle shaped
–Detection of a codon 816 c-kit mutation
–Flow cytometric co-expression of CD117,
CD2 and CD25 by the bone marrow mast
cell population
–Serum tryptase >20 ng/ml
WHO Diagnostic Criteria for Systemic Mastocytosis
Major +1 minor or 3 minor are needed
5
Prognosis of Mastocytosis
• Pediatric onset (Cutaneous)
– Good, usually self limited, symptomatic tx
– BMB if abnormal CBC, LAP, HSM or elevated
tryptase
• ISM: Good. Normal life expectancy
• SM-AHNMD: Depends on the hematologic dx.
• ASM: Poor. 50% survival in 3 years
• MCL: Very poor. Average survival 6-12 months
Treatment of Mastocytosis
• Symptomatic
– H1 and H2 blockers
– Epinephrine
– Systemic steroids
– Oral cromolyn (gastrocrom)
– (Topical steroids or PUVA for skin lesions)
– Omalizumab (2 case reports)
• Treatment of the associated hematologic
disorder
• IFN-alpha, 2-CDA for aggressive disease
• No specific chemotherapy for the mast cell
component
Akin, et al. Exp Hematol. 31:686, 2003
Mast cells carrying D816V c-kit mutation
are resistant to Imatinib (STI571) Imatinib (Gleevec) resistance in mastocytosis
Akin and Metcalfe J Allergy Clin Immunol. 114:13, 2004
Mast Cells in Allergic Reactions
B cell Th2 cell
Antigen
IgE
Mast cell
IL4
IgE
Receptors
Granule Associated Mediators
Histamine
Tryptase
Carboxypeptidases
Chymase
Heparin, chondroitin sulfate E
Lipid-Derived Mediators
Prostaglandin D2
Leukotriene C4
Platelet activating factor
Leukotriene B4
Mediator Release from Activated Mast Cells
Cytokines/Chemokines
Interleukins 3, 4, 5, 6, 8, 10, 13
GM-CSF, TNF
MCP-1, MIP-1Rantes
6
Food
Drug
Exercise
Hymenoptera
Idiopathic
CAUSES OF ANAPHYLAXIS
Cianferoni et al. Ann Allergy, 2004, 92:464 Webb et al. JACI 2004, 113:241
Yocum et al. Mayo Clin Proc, 1994, 69:16
Study of mast cell disease in “idiopathic”
anaphylaxis
Akin et al. Blood 2007
Monoclonal mast cell activation syndrome
Anaphylaxis with a clonal mast cell disorder
(Monoclonal mast cell activation syndrome)
• Recurrent syncope or presyncope associated with
hypotension, flushing and abdominal symptoms
• No tissue evidence of pathologic mast cell increase
– UP skin lesions
– No mast cell clusters in bone marrow
• Clonal CD25+ mast cells carrying D816V c-kit mutation
– By primer specific PCR or mast cell enrichment
• Tryptase <20 ng/ml
• 20-40% of cases of recurrent anaphylaxis
• Does not progress into full-blown SM
University of Michigan
• Over 300 patients evaluated (2004-2009)
• Referred from most of the 50 U.S. and
Canada
• Children and adults
• Established flow cytometric methods and
mutational analysis
U. Michigan cohort
Molecular basis of mast cell disease
• April 2004-2008
• 132 patient enrolled
– Referrals due to suspected or confirmed mast cell disease
– Signed consent
– BMB
– Flow cytometry
– Mutational analysis
– Tryptase levels
• 58 had mastocytosis
• 7 had MMAS
• 19 IA
• 42 with “mast cell activation” symptoms but no clonal mast cells
• 6 non-mast cell disease (AML, MDS etc)
7
Patient #1
• 40 year-old female
• Multiple episodes since age 16
• Flushing, crampy abdominal pain, nausea, diarrhea,
itchy palms, weakness
• Last about 2 hours
• Symptoms more severe for the last year, now leading to
hypotension and syncope
• Generally after eating. Food testing negative
• No hives or wheezing
• Physical exam: Unremarkable. No UP.
• Tryptase 7 ng/ml baseline, 33 ng/ml after a reaction
Patient #1
Diagnostic findings
• Bone marrow biopsy and aspirate:
– Normal maturation
– Scattered mast cells with no clustering
– Aspirate smear with spindle shaped mast cells
– Flow cytometry CD25+ mast cells
– C-kit D816V mutation positive
• Diagnosis: Systemic mastocytosis
Patient 1 Bone marrow Patient #2
• 47 year old male
• Episodic flushing, abdominal cramping, diarrhea,
hypotension, syncope for 6 years
• Most episodes between 6 pm-3 am.
• Tryptase 2.2 ng/ml baseline, 40 ng/ml after an episode
• On prednisone 40 mg daily
• PE: Unremarkable, no UP
Patient #2
• Bone marrow biopsy and aspirate:
– Normal maturation
– Scattered mast cells with no clustering
– Aspirate smear and flow cytometry too few mast cells to evaluate
– C-kit D816V mutation positive
• Diagnosis: Monoclonal mast cell activation syndrome
ISM IA
Symptoms Number (%) Number (%)
Urticaria 0 (0) p<0.005* 5 (33)
Hypotension 6 (40) ns 7 (47)
Angioedema 2 (13) ns 4 (27)
Syncope 10 (67) ns 10 (67)
Gastrointestinal 9 (60) ns 11 (73)
Flushing 12 (80) ns 10 (67)
Bronchospasm 4 (27) ns 3 (33)
8
0
20
40
60
80
100
Urticaria
Angioedema
Dyspnea
Presyncope
Syncope
Hypotension
Flushing
Palpitations
Headhache
Cardiac arrest
HTA
Abdominal cramping
Diarrhea
Nausea/Vomiting
Paresthesias
Fever
Rhinoconjunctivitis
Number of patients (%)
Clinical Symptoms during MC-mediators Release Episodes
Non clonal SMCAD (n=32)
ISMs- (n=51)
p=.006
p=.002
p<.001
p=.035
p<.001
p<.001
Courtesy of Luis Escribano, 2010
Scoring system for clonal mast cell disease
Alvarez-Twose I et al JACI 2010. 125:1269
Triggers of MC-mediators Acute Release
Episodes
Insects Drugs Idiopathic Food/fish Others
p=0.002
p=0.006
0
20
40
60
80
100
ISMs+ ISMs- Non clonal MCAD
Number of patients (%)
(n=28) (n=51) (n=32)
P=0.001
P=0.001
Courtesy of Luis Escribano, 2010
Patient #3
• 58 year-old female with 2 episodes of anaphylaxis 5
years apart
• 1999: 2 yellowjacket stings, felt lightheaded, hoarse,
passed out. No angioedema or shortness of breath.
• Skin testing positive to yellowjacket only at highest
concentration.
• VIT for 5 years. Repeat skin test and RAST negative.
VIT d/c’ed
• 2004: Yellowjacket sting on ankle. Tachycardia, nausea,
vomiting, passed out.
• Baseline tryptase 97 ng/ml.
Patient #3
• Review of systems negative
• Physical exam: No UP
• CBC with diff normal.
• Bone marrow biopsy:
– Small clusters of up to 5 mast cells in biopsy
– Spindle shaped mast cells in bone marrow aspirate
– CD25+
– C-kit D816V positive
– Diagnosis: Systemic mastocytosis
Hymenoptera anaphylaxis and mast
cell disease
(Bonadonna et al. JACI, 123:680-686, 2009 )
• 379 patients
• 44 (11.6%) had tryptase >11.4 ng/ml
• 31 had anaphylaxis
• 34 had a bone marrow biopsy
– 21 (62%) had systemic mastocytosis
– 9 had MMAS
– All with anaphylaxis had clonal mast cell disease
• Conclusions:
– Serum tryptase should be checked in all patients with
anaphylactic hymenoptera reactions
– A bone marrow examination is indicated for patients
with elevated baseline tryptase
9
Serum baseline tryptase increases the risk of
anaphylactic reactions in venom immunotherapy
Rueff et al. JACI, 2010. 126(1):105-11.
Food and drug anaphylaxis
(Bonadonna et al. Allergy, 64:1379-82, 2009)
• 137 patients
– 86 with drug allergy
– 51 with food allergy
• 9 had tryptase >11.4 ng/ml
– 2 had mastocytosis
• Conclusion: Clonal mast cell disease is
associated preferentially with venom allergy as
compared to food and drug allergies.
Baseline tryptase levels in patients with food allergy
Anaphylactic Non-anaphylactic
0.0
2.5
5.0
7.5
10.0
Severity of the reaction
Tryptase (ng/ml)
Mansoor et al. AAAAI, 2011
Proposed workup for patients with
anaphylaxis
IgE mediated cause found
Yes
Food/drug/
Insect/latex
No
Baseline tryptase
<20 >20
Bone marrow biopsy
Hypotensive episodes
and lack of urticaria/angioedema
Likely IA No Yes
Mast cell activation disorders:
A mechanistic classification
Akin, Valent and Metcalfe, JACI, 2010.
• Primary (clonal)
– Anaphylaxis associated with proliferative clonal mast cell
disease (systemic mastocytosis)
– MMAS
• Secondary (non-clonal)
– Allergic disorders
– Chronic inflammatory and neoplastic disorders
– Physical urticarias
– Chronic autoimmune urticaria
• Idiopathic
– Anaphylaxis
– Angioedema
– Urticaria
– MCAS
TMS survey of 426 patients
Cutaneous
Systemic
MCAD
IA
Not sure
Other
Not answered
23%
45%
21%
1.6%
The Mastocytosis Society Survey, 2010. Unpublished data
10
“Mast cell activation syndrome”
• Results in considerable number of
referrals
• WHO criteria absent
• A subset presents with elevated tryptase
levels
• Some may have subtle mast cell
morphologic abnormalities
• Lack of classification, definition and
diagnostic criteria
Molderings et al. Scand J Gastroenterol 2007
Q252 c-kit splice variant in all 17 patients but none of the 5 controls
Idiopathic Systemic Mast Cell Activation
Disorder: Proposed criteria
Akin, Valent and Metcalfe, 2010. JACI
1. Recurrent symptoms consistent with MC
activation in at least 2 organ systems
Skin, GI, cardiovascular, respiratory, nasoocular
2. Positive response to treatment with
medications targeting mast cell mediators
H1 and H2 antihistamines, cromolyn
3. Biochemical evidence of mast cell activation
Tryptase, urine N-MH or PGD2
4. Rule out primary and secondary causes and
other defined idiopathic entities
Akin, Valent and Metcalfe, JACI 2010.