Mast cell disorders

Mast Cell Disorders
By
Wat Mitthamsiri, MD.
Allergy and Clinical Immunology Fellow
King Chulalongkorn Memorial Hospital

Previous issues
• How long is the life span of mast cells in
circulation (not in tissue)?
J Hallgren and MF Gurich, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p14-28.

Previous issues
• What is non-pathological, physiological role of
mast cell?
– One of the first responder in innate defense
against infections
• Location
• Arrays of innate sensors:
– PRRs: TLR1-7 and TLR9, NLRP3
– Complement products receptors
– CRP, LPS-binding proteins, pentraxins, collectins
– Sensors for other peptide signals from other cells
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.

Ligands that can activate MCs

Microbial sensors of MCs

Previous issues
mast cell?
– One of the first responder in innate defense
against infections
• Arrays of weapons:
– Mediators
– Cytokines
– Antimicrobial peptides: Beta-defensins, cathelicidin
• Powerful response: Neutrophil recruitment

Previous issues
mast cell?
– Protection against toxic substances
• MC’s carboxypeptidase is required to limit effect of:
– Endothelin-1 (ET-1) peptide from peritonitis
– Pit viper venom
– Honeybee (Apis mellifera) venom
• MC’s proteases limit toxic effect of neurotensin, IL-6

Previous issues
mast cell?
– Enhance adaptive immune response
• MC-deficient mice had impaired T-cell activation and
had reduced DC migration
• MCs remotely enhance lymphocytes sequestration in
lymph nodes by using TNF-a
• Using MC-activating compound as an adjuvant with
some Ag can elicit protective immunity to the
corresponding pathogen only in host with normal MC
• MC activating compound can increase IgA secretion in
mucosal challange

Summary of MC’s defense model

Outline
• Classification and epidemiology
• Pathogenesis
• Clinical features
• Pathology
• Approach for diagnosis
• Treatment
• Prognosis

Classification
and
Epidemiology

Diseases of mast cells
P Bradding, H Saito., Middleton’s Allergy 8th edition, 2013, 228-251.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
Excessive mast
cell no/Fn
• Localized
mastocytosis
• Systemic
mastocytosis
Mast cell
deficiency
• Never been found

Localized mastocytosis
• Cutaneous mastocytosis
– Urticaria pigmentosa/maculopapular cutaneous
mastocytosis (UP/MPCM)
– Diffuse cutaneous mastocytosis (DCM)
– Solitary mastocytoma
• Extracutaneous mastocytoma
Horny H-P, et al. Mastocytosis. In: Swerdlow SH, et al, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008.

Systemic mastocytosis
• Indolent Systemic Mastocytosis (ISM)
• Systemic Mastocytosis with Associated Clonal,
Hematologic Non–Mast Cell Lineage Disease
(SM-AHNMD)
• Aggressive Systemic Mastocytosis (ASM)
• Mast Cell Leukemia (MCL)
• Mast Cell Sarcoma (MCS)
• Monoclonal mast cell activation syndrome
(MMAS)
• Mast cell activation syndrome (MCAS)

Epidemiology
• Unknown prevalence
– Estimated 20,000-30,000 in the USA
• Male/female ratio of 1 : 1 to 1 : 3
• Found in all ethnic backgrounds
– More frequently reported in Caucasians
• May occur at any age
• Familial occurrence is unusual

Pathogenesis
KIT-dependent
Apoptosis inhibition
Other modifying mutation

KIT-dependent
AM Gilfillan and C Tkaczyk, Nature Reviews Immunology, 2006, 6:218-230

KIT-dependent
Other names:
• Mast/stem cell growth
factor receptor (SCFR)
• Proto-oncogene c-Kit
• Tyrosine-protein kinase
Kit
• CD117
J Lennartsson and L Rönnstrand, Physiological ReviewsPublished 1 October 2012Vol. 92no. 4,1619-1649.
AM Gilfillan and C Tkaczyk, Nature Reviews Immunology, 2006, 6:218-230

KIT-dependent
J Lennartsson and L Rönnstrand, Physiological ReviewsPublished 1 October 2012Vol. 92no. 4,1619-1649.
Chromosome image: http://ghr.nlm.nih.gov/gene/KIT
Chromosome4
Position 12
(4q12)

KIT-dependent
• Most common mutation = ASP 816 VAL
(D816V)
• Inheriable to next generation? No
Chromosome image: http://ghr.nlm.nih.gov/gene/KIT
evidence
• Other mutations:
• V560G (MCL cell line)
• D816Y, D816F, D816H, E839K (pediatric
mastocytosis)
• F522C
• R815K, D820G, V533D, V559A, del419,
K509I, and A533D (Exceedingly rare <1%)

Apoptosis inhibition
FIP1L1-PDGFRA fusion
PRKG2-PDGFRB fusion
Anti-apoptotic proteins

FIP1L1-PDGFRA
Oncogene in pluripotential hematopoietic
progenitor cells
Results from ~800-kb interstitial deletion
of chromosome 4q12
Patients:
• ↑ Mast cells
• Peripheral eosinophilia
• ↑ Serum tryptase levels

PRKG2-PDGFRB
Chronic basophilic
leukemia
Rare

Anti-apoptotic proteins
AB Gustafsson and RA Gottlieb, American Journal of Physiology - Cell Physiology,1 January 2007Vol. 292no. 1, C45-C51

Clinical features
Systemic symptoms
Dermatologic symtoms
GI symtoms
Musculoskeletal symptoms
Hepatosplenic symptoms
Neuropsychiatric sypmtoms

Systemic symptoms
• Caused by mast cell’s mediators

Systemic symptoms
• Flushing and episodic hypotension
• Hypotension may be provoked by
– Alcohol
– Aspirin
– Insect stings
– Infection
– Exposure to iodinated contrast materials
• No increased risk in bacterial, fungal, or viral
infections

Dermatologic symptoms
• Urticaria pigmentosa (UP)/maculopapular
cutaneous mastocytosis (MPCM)
– Most common pattern of skin involvement in both
adults and children
– Found in >90% of ISM patients
– Found in ~50% of SM-AHNMD or ASM patients

Urticaria pigmentosa
• Tend to spare palms, soles, face, and scalp
• Rubbing the lesions => urtication and erythema
over and around the macules (Darier sign)
• May be associated with pruritus exacerbated by:
– Changes in temperature
– Local frictionIngestion of hot beverages or spicy foods
– Ethanol
– Drugs
• Petechiae, ecchymoses, or telangiectasias may be
present in or adjacent to UP lesions

Darier sign
http://www.allergikos.gr/%CE%BC%CE%B1%CF%83%CF%84%CE%BF%CE%BA%CF%85%CF%84%CF%84%CE%AC%CF%81%CF%89%CF%83%CE%B7/

Diffuse cutaneous mastocytosis

Both UP and DCM
• May have bullous
eruptions with
hemorrhage
• Blisters may erupt
spontaneously or
in association
with infection or
immunization

Solitary mastocytomas
• Fairly common cutaneous variant
• May be present at birth but usually before age
3 months
• Usually spontaneously involute during
childhood
• Solitary extracutaneous mastocytomas of the
lung have been reported in adults

Solitary mastocytomas
(http://dermaamin.com/site/images/clinical-pic/m/mastocytoma-solitary_
mastocytoma/mastocytoma-solitary_mastocytoma1.jpg)
DM Thappa,B. Jeevankumar, Indian Pediatrics 2005; 42:390

Mast cell sarcomas
• Exceedingly rare
• Characterized by a tumor consisting of highly
atypical immature mast cells
• Distant spread is possible
• Leukemia phase may occur

Telangiectasia macularis
eruptiva perstans (TMEP)
• Found <1% of mastocytosis patients
• Reported only in adults
• Characteristic skin lesion
– Telangiectatic, red macule on a tan-brown
background
– 2-6 mm in diameter
– No sharply defined borders
• Pruritus, purpura, blister -> Uncommon
• May become edematous when rubbed
• Occasionally coexist with UP

Telangiectasia macularis
eruptiva perstans (TMEP)
Ahmet AltinerMD, Julia Tzu MD, Rishi Patel MD, Shane Meehan MD, Miguel Sanchez, et al., Dermatology Online Journal 17 (10): 7

GI symptoms
• 80% of patients had significant GI symptoms
• Abdominal pain = Most common GI symptom
– Followed by diarrhea and N/V
– 70% of patients with dyspeptic pain had evidence
of gastric acid hypersecretion
– PU occured in 4-44% of all patients
– Plasma concentration of histamine correlated with
basal acid output
• GI bleeding -> Uncommon

GI symptoms
• Diarrhea, from:
– Altered intestinal secretion
– Structural disease of the small intestinal mucosa
– Hypermotility or transit disorder
• Malabsorption
– Found in 31% of patients
– Usually not severe
– Primarily occurred as mild steatorrhea with
impaired absorption of d-xylose or vitamin B12
– Diffuse, small intestinal mucosal dysfunction has
been proposed as the cause

Musculoskeletal symptoms
• Uncertain etiology
– Unless associated with osteopenia or osteoporosis
• Osteoporosis leading to pathologic fractures
– Back pain from osteoporosis
– Vertebral compression fractures
– May be the initial manifestation of mastocytosis

Hepatosplenic symptoms
• ~60% of patients had evidence of liver disease
– 24% -> Hepatomegaly
– 54% -> Elevated ALP and GGT
• ALP levels correlated with GGT levels, hepatomegaly,
splenomegaly, and liver mast cell infiltration and
fibrosis
• In SM-AHNMD or ASM patients
– Elevated ALP -> More frequently
– Reported 5 cases of ascites or portal hypertension
• Severe liver disease is uncommon
– Except in patients with aggressive disease

Neuropsychiatric symptoms
• In adults
– Decreased attention span
– Memory impairment
– Irritability
– May caused by therapeutic medicines as well as
circulating mediators
• In children
– No clear excess pathology
– No specific behavioral pattern implicating
histamine overproduction was identified

Pathology
Dermatologic pathology
Bone marrow pathology
Radiologic pathology
Liver pathology
Spleen pathology
Lymph nodes pathology

• Increased mast cells (>/= 10x of normal)
within the papillary dermis
• With variable extension throughout reticular
dermis and into the subcutaneous fat
• Absence of other pathology
• Gross skin examination must be correlated
with the number of mast cells in the skin

http://www.skinpathology.org/wp-content/uploads/Urticaria-Pigmentosa-Histopathology-1024x768.jpg

http://www.skinpathology.org/wp-content/uploads/Urticaria-Pigmentosa-Histology-1024x768.jpg

TMEP
Ahmet AltinerMD, Julia Tzu MD, Rishi Patel MD, Shane Meehan MD, Miguel Sanchez, et al., Dermatology Online Journal 17 (10): 7

• Most common site of pathologic mast cell
infiltrates in mastocytosis
• Most useful Bx site for pathologic diagnosis
• Majority of infiltrates are focal (may be diffuse
in some cases)

• Often situated
paratrabecularly
• Consist of nodular
aggregates of
spindle-shaped mast
cells, which may be
accompanied by
lymphocytes and
eosinophils

• Hypercellular marrow, as a prognostic factor
– With ↓percentage of fat cells = Significant predictor
of poor prognosis
– 1/3 of patients had associated hematologic disorders
• Dysmyelopoietic syndromes
• Myeloproliferative disorders
• Acute leukemia
• Malignant lymphoma
• Chronic neutropenia
• Had significantly reduced 5-year survival rates
• In most patients, hematologic disorder is detected after
mastocytosis is diagnosed

• In mast cell leukemia
– Diffuse infiltration by atypical, immature mast
cells
– Mast cells account >/= 10% of the peripheral WBC
• In aggressive mastocytosis with a terminal
leukemic phase
– Circulating mast cells appear late in the disease
course
– Percentage of circulating mast cells is relatively
low

• BM Mast cell hyperplasia in non-mast cell
diseases
– Uremia
– Osteoporosis
– Hematologic conditions (lymphomas,
preleukemias, leukemias)

Radiologic pathology
• Radiographically detectable BM infiltration are
up to 70% of patients
– Proximal long bones = Most often affected
– Followed by the pelvis, ribs, and skull
• Skeletal scintigraphy
– More sensitive than radiographic surveys in
detecting and locating active lesions
– May aid in evaluating the extent of disease and
disease progression

Liver pathology
• Mast cell infiltration in liver
– More severe in patients with SM-AHNMD or ASM
– Correlates with hepatomegaly, splenomegaly, ALP
levels, and GGT levels
• Portal fibrosis correlates with mast cell
infiltration and portal inflammation
• Nodular regenerative hyperplasia, portal
venopathy, and venoocclusive disease may
contribute to portal hypertension

Spleen pathology
• Most common finding = Trabecular fibrotic
thickening
• Splenic mast cell lesions have been found in
– Paratrabecular
– Parafollicular
– Follicular
– Diffuse red pulp

Spleen pathology
http://www.webpathology.com/image.asp?case=385&n=2

LN pathology
• Most common location of infiltration =
Paracortical region
• Less frequent
– Parafollicular and follicular replacement
– Medullary cord
– Sinus infiltration
• May resemble follicular and T cell
lymphomas, monocytoid B cell hyperplasia
and lymphoma, Kaposi sarcoma, hairy cell
leukemia, and histiocytosis X

LN pathology
John Lazarchick, http://imagebank.hematology.org/Content/740/3803/3803_full.JPG

LN pathology
John Lazarchick, http://imagebank.hematology.org/AssetDetail.aspx?AssetID=3804

Proposed algorithm
P. Valent, et al., Int Arch Allergy Immunol 2012;157:215–225.

Proposed algorithm
= WHO’s criteria

Classification of MCAS

Classification of MC disorders

Diagnosis
(WHO’s criteria for Dx)

Cutaneous mastocytosis
• Typical clinical findings of:
– Urticaria pigmentosa/maculopapular cutaneous
mastocytosis (UP/MPCM)
– Diffuse cutaneous mastocytosis (DCM)
– Or solitary mastocytoma
• With typical infiltrates of mast cells in a
multifocal or diffuse pattern on skin biopsy

• 1 major+1 minor, or 3 minor criteria are
required
– Major Criterion
• ≥15 foci of mast cells infiltrates in sections of bone
marrow and/or another extracutaneous organ
• (Confirmed by tryptase immunohistochemistry or
other special stains)

• 1 major+1 minor, or 3 minor criteria are
required
– Minor Criteria
• >25% of mast cells are abnormal:
– Spindle shape or atypical morphology (in Bx of BM/other
extracutaneous organs)
– Immature or atypical morphology (in BMA specimens)
• Detection of activating point mutation at codon 816 of
KIT in BM, blood, or another extracutaneous organ
• Mast cells in BM, blood, or another extracutaneous
organ express CD117 with CD2 and/or CD25
• Serum total tryptase persistently >20 ng/mL (without
associated clonal myeloid disorder)

Varients of mastocytosis
• “B” findings
– >30% infiltration by mast cells (focal, dense
aggregates) in BMBx and/or serum total tryptase
>200 ng/mL
– Signs of dysplasia or myeloproliferation in non–
mast cell lineages (but insufficient for Dx of a hematopoietic
neoplasm) + normal/slightly abnormal blood counts
– Hepatomegaly without impairment of LFT, and/or
palpable splenomegaly without hypersplenism,
and/or lymphadenopathy.

• “C” findings :
– BM dysfunction: >/= 1 of
• ANC <1.0 x109/L
• Hb <10 g/dL
• Platelets <100 × 109/L)
• And no obvious non–mast cell hematopoietic malignancy
– Palpable hepatomegaly + impaired LFT, ascites,
and/or portal hypertension
– Skeletal involvement + large osteolytic lesions and/or
pathologic fractures
– Palpable splenomegaly + hypersplenism
– Malabsorption + Wt loss (from GI mast cell infiltrates)

• Indolent Systemic Mastocytosis (ISM)
– Meets criteria for systemic mastocytosis
– No “C” findings
– No evidence of an associated clonal, hematologic
non–mast cell lineage disease (AHNMD)
– In this variant the mast cell burden is low, and skin
lesions are usually present
• BM mastocytosis
– ISM + BM involvement, but no skin lesions
• Smoldering systemic mastocytosis
– ISM, with >/=2 “B” findings and no “C” findings

• Systemic Mastocytosis with Associated Clonal,
Hematologic Non–Mast Cell Lineage Disease
(SM-AHNMD)
– Meets criteria for SM
– And criteria for AHNMD
• (MDS, MPN, AML, lymphoma, or other hematologic
neoplasm that meets criteria for distinct entity in WHO
classification)

• Aggressive Systemic Mastocytosis (ASM)
– Meets criteria for SM with one or more “C” findings
– No evidence of mast cell leukemia.
– Usually without skin lesions
– Lymphadenopathic mastocytosis with eosinophilia
– Progressive lymphadenopathy
• With peripheral blood eosinophilia
• Often with extensive bone involvement, and
hepatosplenomegaly
• Usually without skin lesions
– Cases with rearrangement of PDGFRA are excluded

• Mast Cell Leukemia (MCL)
– Meets criteria for SM
– BMBx: Diffuse infiltration by atypical, immature
mast cells
– BMA smears: >/= 20% mast cells + mast cells >/=
10% peripheral WBC
• Variant:
– Leukemic mast cell leukemia as above
– <10% of WBC are mast cells
– Usually without skin lesions

• Mast Cell Sarcoma (MCS)
– Unifocal mast cell tumor
– No evidence of SM
– Destructive growth pattern; high-grade cytology
• Extracutaneous Mastocytoma
– Unifocal mast cell tumor
– No evidence of SM.
– No skin lesions; nondestructive growth pattern;
low-grade cytology

• Proposed additional criteria
– Monoclonal mast cell activation syndrome (MMAS)
• BM examination to have met 1-2 minor diagnostic criteria
for mastocytosis
• But lack the full diagnostic criteria for systemic
mastocytosis
– Mast cell activation syndrome (MCAS)
• Episodic allergy-like signs and symptoms (e.g., flushing,
urticaria, diarrhea, wheezing) involving >/=2 organ
systems
• Without identifiable etiology

Other surrogate markers
• Serum histamine and 24-hr urinary histamine
metabolites (N-methylhistamine, and methylimidazoleacetic
acid)
– Less often used
– Disadvantages
• Variability among healthy individuals and patients
• Difficulty in assay standardization
• False-positive
• Easily altered result
• Nonspecific

Other surrogate markers
• Metabolites of arachidonic acid
– Urinary PGD-M or 9α,11β- dihydroxy-15-oxo-
2,2,18,19-tetranorprost-5-ene-1,20-dioxic acid
– Plasma thromboxane B2 and its metabolites
– Limitations
• Source is not exclusively limited to mast cells ->
insufficient specificity for diagnostic purposes
• 24-hr urinary 5-hydroxyindoleacetic acid and
urinary metanephrines
– For R/O carcinoid tumor/pheochromocytoma

Other W/U
• Other tissue Bx
• Bone scans or skeletal surveys
• Abdominal U/S or CT scan
• Upper GI series
• Small bowel radiography
• Endoscopy (to R/O PU or GERD)
• Dual-energy x-ray absorptiometry (DEXA)
scan (to monitor osteoporosis)

Treatments
MC-mediated
symptoms
GI symptoms
Osteoporosis
Hematologic
abnormality

MC-mediated symptoms
• Epinephrine
– Rx episodes of systemic hypotension
– Patients should be taught to administer this
medication themselves
– Intensive therapy as for anaphylaxis might be needed
• H1 & H2 receptor antagonist
– Mainly reduce flushing
– Anti-H1 first, if inadequate response, then use anti-H2
• LTRA
– Add on to antihistamines to help flushing

• Disodium cromoglycate (cromolyn sodium)
– Inhibits degranulation of mast cells
– Relief of GI complaints
– Not reduce plasma or urinary histamine levels
• 8-methoxypsoralen with PUVA (or even natural
sunlight in some cases)
– Relieve pruritus&whealing in adult after 1-2 mo of Rx
– Associated with transient decrease dermal mast cells
– Pruritus relapsed in 3-6 months after discontinuation
– Used only in patients with extensive cutaneous
disease unresponsive to other therapy

• Topical steroids with plastic wrap occlusion
for 8 hr/day x 8-12 wks
– Used to treat UP or DCM
– Number of mast cells decreases as lesions resolve
– Lesions recur after Rx discontinuation but may be
last for up to 1 year

GI symptoms
• Gastric acid hypersecretion symptoms (peptic
symptoms and PU)
– H2 RA and PPI
• Diarrhea
– Anticholinergics -> partial relief
• Severe malabsorption
– Oral steroids
• Ascites
– Portacaval shunt

Osteoporosis
• Calcium supplementation
• Estrogen replacement (postmenopausal women)
• Bisphosphonates
• Narcotic analgesics
– May potentiate mast cell degranulation
• Radiotherapy
– Palliative role in decreasing bone pain in patients with
aggressive forms of disease
• IFN-α2b
– Relieve musculoskeletal pain
– Improve bone mineralization

Hematologic abnormality
• Managed as dictated by associated specific
hematologic abnormality
• IFN-α2b and 2-chloro-2-deoxyadenosine
(cladribine, 2-CdA)
– Potential first-line therapy for patients with
aggressive forms
• BMT
– Good for associated hematologic disorders
– Poor effect on mast cell hyperplasia

• Imatinib mesylate
– Approved for Rx of aggressive forms of mastocytosis
in patient without D816V mutation
– May be useful in unusual presentations of
mastocytosis, which are associated with novel
mutations in c-kit
– Patients with increased mast cells + peripheral
eosinophilia + FIP1L1-PDGFRA fusion oncogene also
respond
– Mutational analysis of lesions are essential before Rx
• Other tyrosine kinase inhibitors eg. midostaurin
(PKC412)
– Able to inhibit KIT with the D816V mutation in vitro
– Now in clinical study

• Chemotherapy
– Unable to produce remission
– Unable to prolong survival in MCL
– Has no place in the treatment of indolent
mastocytosis
– But may be considered for advanced disease

• Splenectomy
– May improve survival times in mastocytotic
patients with with poor prognosis
• Radiotherapy
– Used in the management of refractory bone pain
in patients with aggressive disease
• BMT
– May be considered for extremely ill patients,
– May yield a better prognosis if mast cell
suppression is attempted before BM

Prognosis
• Patients with CM only = Best prognosis, followed by
those with ISM
• >50% of children with isolated UP resolve by
adulthood
• UP in adulthood may evolve into systemic disease
• Occasionally, ISM converts to SM-AHNMD
• Course depends largely on prognosis of specific
hematologic disorder and response to Rx
• Mean survival of MCL pt: <12 months
• Survival time ASM pt: 2-4 years (with aggressive
symptomatic management)

Take Home Message
• Mast cell disorders vary greatly in clinical
presentations
• Primary pathomechanism is the activating
mutation in KIT
• Signs and symptoms are caused by:
– Mast cell mediators
– Increased mast cell burden
– Associated hematologic disorder
• Treatments
– Symptomatic Rx for mastocytosis
– Specific Rx for associated hematologic disorders

Mast cell disorders

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