1. Mast Cell Disorders
By
Wat Mitthamsiri, MD.
Allergy and Clinical Immunology Fellow
King Chulalongkorn Memorial Hospital
2. 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.
3. 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.
4. Ligands that can activate MCs
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
5. Ligands that can activate MCs
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
6. Microbial sensors of MCs
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
7. Previous issues
• What is non-pathological, physiological role of
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
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
8. Previous issues
• What is non-pathological, physiological role of
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
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
9. Previous issues
• What is non-pathological, physiological role of
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
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
10. Summary of MC’s defense model
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
11. Summary of MC’s defense model
CP Shellburne and SN Abraham, Mast Cell Biology: Contemporary and Emerging Topic, Springer Science+Business Media, 2011, p162-185.
12. Mast Cell Disorders
By
Wat Mitthamsiri, MD.
Allergy and Clinical Immunology Fellow
King Chulalongkorn Memorial Hospital
13. Outline
• Classification and epidemiology
• Pathogenesis
• Clinical features
• Pathology
• Approach for diagnosis
• Treatment
• Prognosis
18. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
33. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
34. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
38. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
41. Both UP and DCM
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
• May have bullous
eruptions with
hemorrhage
• Blisters may erupt
spontaneously or
in association
with infection or
immunization
42. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
44. Mast cell sarcomas
• Exceedingly rare
• Characterized by a tumor consisting of highly
atypical immature mast cells
• Distant spread is possible
• Leukemia phase may occur
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
45. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
46. 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
47. 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
48. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
49. GI symptoms
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
• 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
50. Musculoskeletal symptoms
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
• 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
51. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
52. Neuropsychiatric symptoms
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
• 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
55. Urticaria pigmentosa
• 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
59. TMEP
Ahmet AltinerMD, Julia Tzu MD, Rishi Patel MD, Shane Meehan MD, Miguel Sanchez, et al., Dermatology Online Journal 17 (10): 7
60. Bone marrow pathology
• 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)
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
61. Bone marrow pathology
• Often situated
paratrabecularly
• Consist of nodular
aggregates of
spindle-shaped mast
cells, which may be
accompanied by
lymphocytes and
eosinophils
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
62. Bone marrow pathology
• 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
63. Bone marrow pathology
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
• 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
65. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
• Skeletal scintigraphy
– More sensitive than radiographic surveys in
detecting and locating active lesions
– May aid in evaluating the extent of disease and
disease progression
66. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
67. Spleen pathology
• Most common finding = Trabecular fibrotic
thickening
• Splenic mast cell lesions have been found in
– Paratrabecular
– Parafollicular
– Follicular
– Diffuse red pulp
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
69. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
70. LN pathology
John Lazarchick, http://imagebank.hematology.org/Content/740/3803/3803_full.JPG
71. LN pathology
John Lazarchick, http://imagebank.hematology.org/AssetDetail.aspx?AssetID=3804
81. 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
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
82. Systemic mastocytosis
• 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)
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
83. Systemic mastocytosis
• 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)
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
84. 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.
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
85. Varients of mastocytosis
• “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)
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
86. Varients of mastocytosis
• 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
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
87. Varients of mastocytosis
• 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)
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
88. Varients of mastocytosis
• 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
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
89. Varients of mastocytosis
• 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
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
90. Varients of mastocytosis
• 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
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.
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
91. Varients of mastocytosis
• 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
92. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
93. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
94. 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)
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
97. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
98. MC-mediated symptoms
• 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
99. MC-mediated symptoms
• 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
100. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
101. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
102. 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
103. Hematologic abnormality
• 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
104. Hematologic abnormality
• 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
105. Hematologic abnormality
• 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
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
107. 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)
DD Metcalfe., Middleton’s Allergy 8th edition, 2013, 1224-1236.
108. 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 cells in circulation are immature. They just migrate to tissue, then stay there for 6 to 12 mo before apoptosis
-MCs use complement products to binds with salmonella and Schistosoma mansonii
-MCs use mannose-binding lectin (1 of collectins), surfactant protein A (SpA) and C1q to fight against L.monocytogenes and yeast
-MC can sense peptides from epithelium/neuron cells, eg. bradykinin, somatostatin, substance-P, ACTH, calcitonin-related peptide, CRH, vasoactive intestinal peptide, neurotensin, beta-defensin
NLRP3 = NOD like receptor pyrin domain 3
-MCs use complement products to binds with salmonella and Schistosoma mansonii
-MCs use mannose-binding lectin (1 of collectins), surfactant protein A (SpA) and C1q to fight against L.monocytogenes and yeast
-MC-deficient mice have 5x less neutrophil than wild type mice in enterobacterial challenge
-MMAS = BM examination to have met 1-2 minor diagnostic criteria for mastocytosis but lack the full diagnostic criteria for systemic mastocytosis
-MCAS = Pt with episodic allergy-like signs and symptoms (e.g., flushing, urticaria, diarrhea, wheezing) involving >/=2 organ systems without identifiable etiology
KIT, the transmembrane tyrosine kinase receptor for SCF.
KIT is expressed on mast cells, hematopoietic stem cells, melanocytes, and germ cell lineages.
Loss-of-function mutations in KIT are involved in the hereditary disease piebaldism, which is characterized by loss of pigmentation.
Gain-of-function point mutations have been identified in patients with systemic mast cell proliferative disorders
-Protooncogene c-kit ,located on the long (q) arm of chromosome 4 at position 12 (4q12) encodes KIT
-An activating point mutation at codon 816 in KIT is present in most adults with various forms of mastocytosis
An activating point mutation at codon 816 in KIT is present in most adults with various forms of mastocytosis.
Secondary or coexisting events giving rise to the mastocytosis disease variants.
G=Glycine, Y=Tyrosine, F=phenylalanine, E=Glutamate, H=Histidine, C=Cysteine, A=Alanine, K=Lysine, I=Isoleucine, D=Aspartate, V=Valine
Bone marrow cells of patients with mastocytosis constitutively express the antiapoptotic proteins Bcl-XL and Bcl-2.
Models of Bcl-2 protein regulation in apoptosis.
A: BH3-only proteins bind to and neutralize antiapoptotic Bcl-2 proteins, allowing Bax/Bak to become activated and initiate apoptosis.
B: BH3-only proteins directly activate proapoptotic Bax/Bak protein.
C: antiapoptotic Bcl-2 proteins sequester BH3-only proteins and keep them inactive
Bcl-2 (B-cell lymphoma 2)
Urticaria pigmentosa in childhood.
Occasionally as raised nodules or plaquelike lesions (C, D)
Lesions in A are smaller and more discrete than lesions in B.
C, Example of nodular lesions of urticaria pigmentosa, with close-up view in D.
Urticaria pigmentosa in adult. Patient has indolent systemic mastocytosis
Lesions are small, yellowish tan to reddish brown macules or slightly raised papules
Urticaria pigmentosa in adult. Patient has indolent systemic mastocytosis
Lesions are small, yellowish tan to reddish brown macules or slightly raised papules
-Skin is normal to yellowish brown, thickened, and may exhibit discoloration with a peau d’orange appearance
-Generalized erythroderma may be present
-Onset usually before age 3 years
-Yellow and cream-colored papules (resemble xanthomas and pseudoxanthoma elasticum) have been described
-Dx is confirmed by the demonstration of diffuse mast cell infiltrates in the skin
Characteristic skin lesion
Telangiectatic, red macule on a tan-brown background
2-6 mm in diameter
No sharply defined borders
Characteristic skin lesion
Telangiectatic, red macule on a tan-brown background
2-6 mm in diameter
No sharply defined borders
-GI symptoms -> second only to pruritus, and almost 2x common as flushing
-Pathogenesis of abdominal symptoms =multifactorial
-Abdominal pain =from peptic ulcer disease, edema or urticarial lesions of the GI tract, or a motility disorder
2-3x increases have been noted in patients with recurrent anaphylaxis, scleroderma, chronic urticaria, and prolonged antigenic contact, so the diagnosis of UP cannot be made solely on the basis of small increases in the number of dermal mast cells.
2-3x increases have been noted in patients with recurrent anaphylaxis, scleroderma, chronic urticaria, and prolonged antigenic contact, so the diagnosis of UP cannot be made solely on the basis of small increases in the number of dermal mast cells.
2-3x increases have been noted in patients with recurrent anaphylaxis, scleroderma, chronic urticaria, and prolonged antigenic contact, so the diagnosis of UP cannot be made solely on the basis of small increases in the number of dermal mast cells.
DCM
Prominent bandlike infiltrates
May be indistinguishable from some lesions of UP or mastocytomas
TMEP
Cutaneous mast cell hyperplasia is observed around the capillary venules of the superficial plexus
A Giemsa stain shows mast cells surrounding dilated, thin-walled blood vessels in the papillary dermis. There are about 11 to 17 mast cells per high-powered field.
Immunohistochemical (IHC) staining of the bone marrow biopsy with antitryptase is the method of choice to visualize mast cells
In pt with tryptase+ round cell infiltrates with >95% round cells and >5% spindle-shaped cells, additional IHC markers to confirm Dx of SM should be applied as possible (e.g., 2D7 or BB1) because basophils and sometimes blast cells also express tryptase.
Coexpression of CD2 and CD25 in CD117 (KIT)+ mast cells by flow cytometry of BMA or by IHC analysis of BMBx is generally accepted as the most sensitive and specific method to support Dx of SM in BM
Immunohistochemical (IHC) staining of the bone marrow biopsy with antitryptase is the method of choice to visualize mast cells
Spleen is almost always involved in systemic mastocytosis. Sections reveal ill-defined, fibrotic, granuloma-like nodules usually centered around a vessel. These nodules contain a mixed infiltrate consisting of mast cells, eosinophils, lymphocytes, and histiocytes
diagnosis of CM should be confirmed by skin biopsy
Mastocytosis should be suspected in patients without skin lesions if
-unexplained ulcer disease or malabsorption, radiographic or Tc-99 bone scan abnormalities, hepatomegaly, splenomegaly, lymphadenopathy, peripheral blood abnormalities, and unexplained flushing or anaphylaxis
-Elevated levels of plasma/urinary histamine/histamine metabolites, urine PGD2 metabolites, or plasma (total) mast cell tryptase1 are NOT definitive diagnostic findings but are consistent with the diagnosis of mastocytosis
-Tryptase <20 ng/mL have been detected in pts with CM and with limited SM
-Higher tryptase values increase the likelihood of multiorgan involvement
-c-kit mutations are best performed on BM and specifically on sorted malignant mast cells to increase sensitivity
-Inability to identify 816 mutation in c-kit does not R/O the disease.
-In patients with coexisting eosinophilia, FIP1L1/PDGFRA fusion gene in peripheral blood should be searched
-Most sensitive assays (RT-PCR + restriction fragment length polymorphism (RFLP) testing, PNA-mediated PCR, or allele-specific PCR) shoud be used
-c-kit mutations (e.g., D816V) are also detectable in a few patients with germ cell tumors or other non–mast cell tumors, too.
monoclonal mast cell activation syndrome (MMAS)
-False-positive results (caused by presumed synthesis of histamine by bacteria in the urinary tract and sample)
-Easily altered result: Ingestion of histamine-rich foods and improper storage of urine sample
-Nonspecific: Basophils also contain histamine
. However, elevations in one or more mast cell mediators raise the suspicion of mastocytosis and warrant further diagnostic evaluation.
-Other tissue: LN, spleen, liver, and GI mucosa
-Performed only when necessary. For example, a GI workup is dictated by symptoms of GI involvement, and lymph nodes are biopsied if lymphoma is suspected
Narcotic analgesics should be used with care, particularly at high doses
Cladribine, a nucleoside analog, does not appear to require cells in active cell cycle to exert its cytotoxic activity, and thus appears beneficial in slowly progressing neoplastic processes
(Gleevec) is approved by the U.S. Food and Drug Administration for treatment of chronic myelogenous leukemia and KIT-positive gastrointestinal stromal tumors, too
In vitro studies found that drug effectively inhibited wild-type KIT and KIT-bearing juxtamembrane activating mutations BUT it failed to inhibit KIT-bearing codon 816 mutations associated with most common forms of SM
-Drug has strong in vitro cytotoxic effect on mast cells bearing wild-type KIT, whereas mast cells with codon 816 mutation from BMA of patients with mastocytosis were relatively resistant to the drug.