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Mast
ast Cell
Ce Activation
ct vat o Disorders
so de s
Mariana Castells, M.D., Ph.D.
Associate Professor in Medicine, Harvard Medical School
Director, Adverse Drug Reactions and Desensitization Program
Associate Director Mastocytosis Center of Excellence
Learning Objectives
 To recognize the symptoms of mast cell
activation
 To understand the diagnostic tools for
clonal mast cell activation diseases
 To establish prognostic factors for mast cell
activation syndromes MCAS
 To provide management options for MCAS
Learning Objective
 Tryptase :
under-utilized
under
utilized (mechanistic data)
poorly understood (elevation)
 C-kit mutation D816V:
diagnosis WHO criteria
clonality assessment
p
g
Clinicopathological
Conference
Medical Grand Rounds
NEJM 2011
Mandakolathur Murali, M.D.
Allergy Unit
Mariana C. Castells, M.D.
Allergy,Immunology and Rheumatology BWH
David M. Dudzinski, M.D., J.D.
Cardiology
James Song, M.D.
Radiology
Robert P. Hasserjian, M.D.
Pathology
y
g and hypotension"
yp
"A 32-year-old
man with flushing
32 y o marathon runner presenting with acute
flushing and hypotension after advil
advil, requiring
intubation and tryptase of >2000 ng/ml
Case # 1
Idiopathic Anaphylaxis
Anaphylaxis one episode every 1-2 months for 9 years
Flushing explosive N/V/D,
Flushing,
N/V/D hypotension,
hypotension syncope,
syncope DH
ER : fluids, steroids, epinephrine
Triggers:
Al h l stress,
Alcohol,
t
emotions,
ti
iinfections,
f ti
ffoods,
d NSAIDS
Complaints:
Unexplained flushing, chronic fatigue, depression, anxiety, bone
pain and chest pain (multiple r/o MI)
PE: (never been undressed in ER, never had skin exam)
Few macular lesions in chest compatible UP
c-kit staining
Bone Marrow - 40 x
Case #2
Osteoporosis in young male
30 y o male severe osteoporosis of both hips
Bilateral hip prosthesis
G t i t ti l symptoms
Gastrointestinal
t
Inability to concentrate, mental fogginess
Tryptase : 60 ng/ml
Review of the slides from the hip surgery revealed
aggregates of >50 mast cells, spindle shaped
Abnormal Spindle
p
Shaped
p Mast Cells ((EM))
Peri-Operative
Peri
Operative Anaphylaxis
Antibiotic allergy
 A 30-year-old woman with a near fatal anaphylactic event during
cesarean section at 39 weeks gestation in second pregnancy.
 She received an epidural anesthesia with chloroprocaine, lidocaine,
fentanyl, midazolam and phenyleprine and oxytocin and she delivered
a healthy baby. Cord clamping and 2g of cephazolin, two minutes later
the patient became profoundly hypotensive (57/20 mmHg),
tachycardia and unresponsive. Code called
 She was flushed and lips swollen. Fluids, 3 doses of ephinephrine (1
mg) IM, ranitidine, hydrocortisone, diphenhydramine Patient
responded within 30 min, surgery finished and blood pressure (120-72
mmHg) within 40 minutes.
Antibiotic anaphylaxis
 Tryptase level 39 ng/ml.
 Two months after delivery she was evaluated multiple hyperpigmented small
macules on the proximal lower extremities compatible with urticaria pigmentosa.
These skin lesions were overlooked before the anaphylaxis episode and had been
present for many years without changing.
 The patient had three vertebral fractures and osteoporosis since
 age 24 years
years, asthma and allergic rhinitis and was on IT for years
years.
 First pregnancy vaginal and no complications except for hypertension and

headache.
Antibiotic anaphylaxis?
 A BMB: aggregates of spindle-shaped mast cells positive for CD117
(KIT) and tryptase.
 An aspirate revealed clusters of spindle-shaped
spindle shaped mast cells.
 Skin testing.

Prick test to cephazolin was negative,

I t d
Intradermal
l (0.3
(0 3 mg/ml)
/ l) positive
iti wheal
h l andd flare
fl (6x12
(6 12 mm).
) Prick
Pi k
and intradermal testing were performed to midazolam, loracepam,
diacepam, fentanyl, lidocaine, bupivacaine, chloroprocaine and latex with
negative results.
results
IgE : 36 UI/ml, specific IgE: negative to penicillin and latex.
 Baseline Tryptase : 19 ng/ml
Hymenoptera Anaphyaxis
 42 y o healthy male stung by wasp while working
in yard
 Within
i hi 15 min
i has
h severe flushing,
fl hi di
dizziness
i
and
d
collapse, 911: BP 50/?
 Epinephrine IM and tryptase 40 ng/ml
 What is the best long term management options (s)
after he recovers ?
Tryptase
 At the time of the anaphylactic reaction : 40
g
ng/ml
 Baseline 2 months after the episode:
32 ng/ml
Why is the tryptase still elevated?
Bone Marrow Biopsy:
Mast Cell Tryptase Staining
Courtesy of Dr. Jason Hornick, BWH Department of Pathology
Systemic Mastocytosis
Diagnostic Criteria
Leukemia Research 2001,, 2010
Major Criteria :
multifocal infiltrates of 15 of more mast cells in
bone marrow and/or extracutaneous organs
-
Minor Criteria:
> 25% spindle shaped mast cells
c-kit mutations (codon 816)
aberrant expression of CD2 and CD25
Tryptase >20 ng/ml
Mastocytosis
Cutaneous
Accumulation of mast cells in skin
Urticaria Pigmentosa, Mastocytoma, Diffuse (DCM),
Mac lar Telangiectasia (TMEP)
Macular
Systemic :
Accumulation of mast cells in bone marrow and in
other organs
Criteria :1 Major+1 Minor or 3 Minor
Cutaneous Mastocytosis
Limited to the skin
Forms:
 Urticaria Pigmentosa
 Solitary mastocytoma
 Diffuse cutaneous mastocytosis
y
 Telangiectasia macularis eruptive perstans
Pathology:
gy increased numbers of subepidermal
p
and
epidermal accumulations of mature, scroll-poor tryptase
and chymase positive mast cells, frequently in perivascular
locations
Urticaria Pigmentosa
g
Mastocytoma
y
Bony
y Erosion
Erythrodermic
y
Bullous Mastocytosis
y
Skin Biopsy
p y - Urticaria Pigmentosa
g
Systemic Mastocytosis
 Mast cells infiltrate bone marrow and
g
with or without skin
internal organs
involvement
 Diagnosis made if:
 One
O major
j criteria
it i and
d one minor
i
criteria
it i
present OR
 Three minor criteria present
Criteria for Clonal Mast Cell Disease
Abnormal Spindle Shaped
Mast Cells (EM)
Criteria for Clonal Mast Cell Disease
CD25 expression
From: Escribano, L. et. al., Leukemia Research 25: 563-570, 2001.
Criteria for Clonal Mast Cell Disease
Tryptase Levels 20 ng/ml
S h t NEJM1987
Schwartz,
Criteria for Clonal Mast Cell Disease
From: Longley, B.J. et. al., Leukemia Research 25: 571-576, 2001.
SM: Types and prognosis
Indolent SM 80%
 Most common
 Normal life span
 Morbidity
Morbidit from effects of mast cell mediators and mast cell mass
SM with hematologic malignancy 15%
 Prognosis depends on underlying malignancy
Aggressive SM 4%
 Life span limited to 12-24 months after diagnosis
Mast cell leukemia/sarcoma <1%
 Life span limited to 6-12 months after diagnosis
Mastocytosis : Presentation to Diagnosis
R Horan,
o , K F Austen
us e 1991
99
 Review of 40 patients BWH
 Onset of symptoms: from 7 to 69 years,
years
mean of 37 years
 Initial
I i i l manifestation
if
i off ill
illness was a
cutaneous eruption in 100%
 Mean interval time between symptoms and
diagnosis : 9.5 years (longest 35 years)
Mast Cell Mediator related Symptoms
Castells M , Austen KF,
KF 2002

 Histamine:
 Pruritus, urticaria, gastric
hypersecretion,
bronchoconstriction
 Increased vasopermeability
and systemic hypotension
 Heparin:
p
 Local anticoagulation and
osteoporosis

Proteases:

Tryptase:
Tryptase: Fibrinogen
degradation stimulation of
degradation,
fibroblast proliferation

Chymases:
Chymases: Activation of
procollagenases and tissue
remodeling

Carboxypeptidase A
Cysteinyl Leukotrienes
Leukotrienes::

Increased vasopermeability,
vasopermeability
p
y,
y,
vasodilation,
bronchoconstriction

LTD4, LTC4, LTE4
Classification of Diseases associated with
Mast Cell Activation
Akin , Metcalfe, Valent JACI 2010
Case #1
44-year-old female referred to Allergy &
Immunology for Idiopathic Anaphylaxis, no UP
4 years prior developed seasonal rhinitis and was
skin test + grasses, weeds, cat
Immunotherapy initiated (IT)
Multiple adverse effects IT : burning hands and feet,
chest pressure – received epinephrine
2nd episode of local reaction with lightheadedness
requiring epinephrine
IT discontinued
Case #1
 3 years prior to presentation– developed
persistent nasal congestion
 One episode – Japanese restaurant - upset
stomach, tongue and facial swelling, burning
hands and feet. No hives. SOB and wheezing
 ER and given epinephrine.
 3 more similar episodes– no identifiable
triggers
 Not all food related
Case #1
 In 2008: multiple episodes of severe cramping
abdominal pain,
pain nausea,
nausea vomiting,
vomiting feeling very
dizzy, feet and hand burning and a feeling of
impending doom but no hives
 April 2008: several hours after cooking ham.
 ER: severe hypotensive to 60/30s - given epi.
Resolution of symptoms and discharged home.
Case #1
 In 2009- monthly symptoms: starting
y
burningg
around her menstrual cyclehands and feet, nausea, vomiting, feeling
of doom. No hives.
 Multiple trips to ED (> 20 )
 Multiple epinephrine administration (>
30)
LABS







tryptase 8.75 ng/ml total, <1 ng/ml mature
Prostaglandin E2 308 pg WNL
24h urine histamine 57.6 (range 0-30)
IgE : 18 IU/ml; Specific IgE foods (-)
()
BMB: no MC aggregates, spindle MC
Positi e CD25 MC in BM
Positive
PB : c-kit D816V mutation +
Tryptase
Tryptase
CD25
Monoclonal Mast Cell Activation
Syndrome MMCAS Akin et al 2007





12 patients with idiopathic anaphylaxis
5 had 1 or more minor criteria
3 had c-kit D816V in BM mc
CD25 mast cells,
CD25+
ll spindle
i dl shaped
h d
No mast cell aggregates
Demonstration of aberrant mast cells with
clonal markers in a subset of patients with
idiopathic anaphylaxis
Akin C, et all Blood 2007
Demonstration of aberrant mast cells with clonal
markers in a subset of patients with idiopathic
Akin C, et all Blood 2007
anaphylaxis
Monoclonal Mast Cell
Activation Disorder
Systemic
Mastocytosis
Akin Metcalfe
Akin,
Metcalfe, Valent JACI 2010
Classification of Diseases associated with
Mast Cell Activation
Akin , Metcalfe, Valent JACI 2010
Non Clonal Mast Cell Activation Syndrome
Hamilton et al JACI 2011
Hamilton et al 2011 JACI
Hamilton et al
2011 JACI
Non Clonal MCAS : Response to treatment
Hamilton t al JACI 2011
CR Complete response, MR Major response
PR Partial response
NR No response
Hamilton, Castells et al JACI 2011
Proposed Criteria for the Diagnosis of
non clonal Mast Cell Activation Syndrome
Akin, Metcalfe, Valent JACI 2010
Clonal versus non Clonal
Mast Cell Activation Disease
Alvarez-Towse et al JACI 2010
Clonal versus non Clonal Mast Cell Activation Disease
Alvarez Towse et al JACI 2010
Alvarez-Towse
Austen et al NEJM 1979
Oral (25 mg/kg/day) and topical (4% QID) sodium cromoglicate in the treatment of
diffuse cutaneous mastocytosis in an infant
Alan Martin Edwards, 1 Štěpánka Čapková
2, 2011 1 UK ; 2 Prague, Czech Republic
Brigham and Women’s Hospital
Boston, Massachussetts
Mastocytosis Center of Excellence
Drug Hypersensitivity and Desensitizations Program