Mastocytosis Presented by Athit Wutthisanwatthana, MD. September13, 2019

1. Mastocytosis
A Wutthisanwatthana

2. Outlines
• Mast Cells
• Biology
• Mast cell heterogeneity
• Mediators
• Mechanism of activation
• Mastocytosis

3. Introduction
• Present in all classes of vertebrates
• Present throughout connective tissues and mucosal surface
• Primary role
• Inflammation and repair
• Tissue homeostasis

4. Mast Cell Development and Survival

5. Multipotential hematopoietic stem cell
common lymphoid progenitor
common myeloid progenitor
mast cell-committed progenitor
Bradding P, Saito Hirohisa. Biology of mast cells and their mediators. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s
allergy principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105

6. Pluripotent
hematopoietic stem cell
CD117
- Mast/stem cell growth factor receptor,
proto-oncogene c-KIT, tyrosine-protein
kinase KIT
- Encoded by KIT
- Expressed on mast cells, hematopoietic
stem cell, melanocyte, germ cell lineages
SCF
• Kit ligand, steel factor
• Obligate mast cell growth factor
• Source: Epithelial and mesenchymal cells
• Soluble and membrane-bound form
Bradding P, Saito Hirohisa. Biology of mast cells and their mediators. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s
allergy principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105
Down regulate CD34

7. Effect of Environment on Mast Cell Differentiation
• In vitro
• Cell source: Bone marrow or circulating peripheral blood progenitor
• +SCF only
• Result: MCT phenotype (immature and contain predominantly lysosomal
granules of the tryptase-only type)
• +SCF + IL-6
• Result: MCT phenotype
• More mature in nuclear morphology and granular structure

8. Effect of Environment on Mast Cell Differentiation
• +Fibroblast or endothelial cell monolayer
• Result: MCTC phenotype
• Contain both tryptase and chymase
• Resemble skin mast cells

9. • Enhance growth/survival
• Nerve growth factor
• IL-3
• IL-6 (lung MCT,MCTC)
• IL-9
• IL-10
• Inhibit growth/differentiation
• GM-CSF
• Retinoids
• TGF-β
• IL-4
• Inhibit proliferation (immature
HPBMCs)
• Proliferate mature (mature
HPBMCs)
• IL-5, IFN-Ɣ
• Prolong HCBMC survival on SCF
withdrawal
• Inhibit immature HPBMCs
proliferation

10. Mast Cell Homing to Tissue
• Mice
• Mast cell:
• ɑ4β7 and CXCR2
• ɑ4β7 and ɑ4β1 (lung)
• CCR2/CCL2 pathway
• Intestinal endothelium: MAdCAM-1 and VCAM-1

11. Bradding P, Saito Hirohisa. Biology of mast cells and their mediators. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s
allergy principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105

12. Mast Cell Heterogeneity

13. Human Mast Cells
• MCT – tryptase
• Nasal and lower airway epithelium, bronchial lamina propria
• MCTC – tryptase, chymase, carboxypeptidase A, cathepsin G
• Connective tissue e.g. skin, airway smooth muscle, atherosclerotic lesion
• MCC – chymase, carboxypeptidase A
• Lung, nose, gut, kidney

14. Bradding P, Saito Hirohisa. Biology of mast cells and their mediators. In: Adkinson
NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s
allergy principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105

15. Metcalfe DD. Mastocytosis. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy principles and practice.
Philadelphia; Elsevier Saunders; 2014. 1095-105

16. Mechanism of Mast Cell Activation

17. Mechanism of Mast Cell Activation
1. Immunoglobulin E-dependent activation
2. Monomeric immunoglobulin E-dependent mast cell activation
3. Non-immunologic mast cell activation

18. Immunoglobulin E-Dependent Activation
• FcεRI (high-affinity IgE receptor)
• FcεRIɑ binds Fc portion of IgE
• FcεRIβ/MS4A2 – contain ITAM (immunoreceptor tyrosine-based activation motif)
• 2 FcεRIɣ - contain ITAM
• Stabilized on the cell surface by the binding of IgE
• IL-4 and IL-13 increase FcεRI expression
Oettgen HC. Immunobiology of IgE and IgE receptors. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF,
et al. Middleton’s allergy principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105

19. Multivalent allergen binds to allergen-specific IgE bound to the FcεRIɑ chain  FcεRI aggregation
Oettgen HC. Immunobiology of IgE and IgE receptors. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy
principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105
LYN-mediated phosphorylation of ITAM
SYK bind to the doubly phosphorylated ITAM
 phosphorylated ITAMs
 promote SYK activation loop
SYK phosphorylate LAT leading to recruit
signal signaling intermediate
Activation of inositol triphosphate
IP3 induces Ca2+ mobilization from
intracellular rough endoplasmic reticulum
stores  influx of extracellular Ca2+
Release of both preformed and newly generated
mediators and of several Ca2+-dependent cytokines

20. Monomeric immunoglobulin E-dependent mast cell activation
• HCBMCs
• CCL1, CCL3, GM-CSF without histamine release
• HLMCs
• Histamine, LTC4, CXCL8
• Underlying mechanisms are uncertain but are thought in part to
involve FcεRI aggregation

21. Non-Immunologic Mast Cell Activation
TLR 1-7, 9
SHIP: src homology 2-containing inositol phosphatase

22. Mastocytosis
• Epidemiology
• Pathogenesis and etiology
• Clinical feature
• Diagnosis
• Treatment

23. Epidemiology
• Unknown prevalence/incidence
• Estimated 20,000-30,000 cases in US
• Male/female
• 1:1-1:3
• Slight male predominance in childhood
• Slight female predominance in adulthood
• Frequently reported in Caucasians

24. Pathogenesis
• Gain-of-function point mutation
D816V – most adult
• NRAS mutation
• FIP1L1-PDGFRA fusion gene –
eosinophilia
• PRKG2-PDGFRA fusion gene -
chronic basophilic leukemia
Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment
recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53

25. Metcalfe DD. Mastocytosis. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy principles and practice.
Philadelphia; Elsevier Saunders; 2014. 1095-105

26. B Findings
1. Bone marrow biopsy showing greater than 30% infiltration by mast
cells (focal, dense aggregates) and/or serum total tryptase level
greater than 200 ng/mL
2. Signs of dysplasia or myeloproliferation in non–mast cell lineages,
but insufficient criteria for definitive diagnosis of a hematopoietic
neoplasm with normal or slightly abnormal blood counts.
3. Hepatomegaly without impairment of liver function, and/or
palpable splenomegaly without hypersplenism, and/or
lymphadenopathy.

27. C Findings
1. Bone marrow dysfunction manifested by one or more cytopenia
(ANC <1.0 × 109/L, Hb <10 g/dL, or platelets <100 × 109/L), but no
obvious non–mast cell hematopoietic malignancy.
2. Palpable hepatomegaly with impairment of liver function, ascites,
and/or portal hypertension.
3. Skeletal involvement with large osteolytic lesions and/or pathologic
fractures.
4. Palpable splenomegaly with hypersplenism.
5. Malabsorption with weight loss caused by gastrointestinal mast cell
infiltrates.

28. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405
Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001
Jul;25(7):603-25
Systemic mastocytosis with associated clonal, hematologic non-mast cell lineage disease (SM-AHNMD)
B C
No
≥2 No
Yes

29. Monoclonal Mast Call Activation Syndrome
• 1 or 2 minor diagnostic criteria
• Identified in idiopathic anaphylaxis and anaphylaxis to stinging insects
• Most have tryptase <20 ng/mL
• Rx
• Anaphylaxis guideline
• Yearly follow up, physical examination, tryptase, CBC

30. Mast Cell Activation Disorder/Syndrome
• Clinical findings are due to MC activation that is neither associated
with mastocytosis nor with a defined allergic or inflammatory
reaction
Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast
Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol. 2012 Feb; 157(3): 215–225

31. Clinical Features

32. Clinical Feature
• Skin, GI tract, lymph nodes, liver, spleen, bone marrow, skeletal
system
• Respiratory tract, endocrine, renal – seldom
• Flushing
• Episodic hypotension
• Alcohol, aspirin, inset stings, infection, iodinated contrast materials
• Not increase in bacterial, fungal, or viral infection

33. Skin
• Urticaria pigmentosa (UP)/maculopapular cutaneous mastocytosis (MPCM)
• ISM 90%
• SM-AHD or ASM 50%
• Diffuse cutaneous mastocytosis
• Solitary mastocytoma
• Mast cell sarcoma
• Possible distal spread and leukemia phase

34. • Small, yellowish tan to reddish brown
• Macules or slightly raise papules,
occasionally nodules or plaque
• Palms, soles, face, and scalp tend to
remain free of lesion
• Rubbing leads to urtication and
erythema
Metcalfe DD. Mastocytosis. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy principles and practice.
Philadelphia; Elsevier Saunders; 2014. 1095-105

35. Metcalfe DD. Mastocytosis. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy principles and practice.
Philadelphia; Elsevier Saunders; 2014. 1095-105

36. Nair B, Sonthalia S, Aggarwal I. Solitary mastocytoma with positive Darier's sign. Indian Dermatol Online J. 2016 Mar-Apr; 7(2): 141–142
After 30 s of gentle stroking with a key
Pronounced lesional and perilesional
erythema and edema within 2 min

37. Urticaria Pigmentosa
• Pruritus that is exacerbated by changes in temperature, local friction,
ingestion of hot beverages or spicy foods ethanol, and certain drugs
• Collection of mast cells within the papillary
dermis
• Variable extension throughout the reticular
dermis and into the subcutaneous fat
Hamodat M. Mastocytosis of skin. Pathologyoutlines.com

38. Diffuse Cutaneous Mastocytosis
• Diffuse mast cell infiltration into the dermis
• No discrete lesion
• Skin is normal to yellowish brown, thickened
• May exhibit peau d’orange appearance
Metcalfe DD. Mastocytosis. In: Adkinson NF, Jr, Bocher BS,
Burks AW, Busse WW, Holgate ST, Lemanske RF, et al.
Middleton’s allergy principles and practice. Philadelphia;
Elsevier Saunders; 2014. 1095-105

39. Metcalfe DD. Mastocytosis. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy principles and practice.
Philadelphia; Elsevier Saunders; 2014. 1095-105x
Bullous eruptions with hemorrhage
• Spontaneous
• Associated with infection or immunization

40. Sukesh MS, Dandale A, Dhurat R, Sarkate A, Ghate S. Case report: Solitary mastocytoma treated successfully with topical tacrolimus. F1000Research 2014, 3:181
• Common variant of CM
• May present at birth, often before 3 month
Solitary Mastocytosis

41. Telangiectasia Macularis Eruptiva Perstans
• Only reported in adult
• Telangiectatic, red macule on a
tan-brown background
• 2-6 mm without sharply
defined borders
• Not generally associated with
pruritus, purpura, blister
Costa DLM, Moura HH, Rodrigues R, Pineiro-Maceira J, Marcia Ramos-e-Silva M. Telangiectasia macularis eruptiva perstans a rare form of adult mastocytosis. J Clin
Aesthet Dermatol. 2011 Oct; 4(10): 52–54

42. Gastrointestinal Symptoms
• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• GI bleeding
• Peptic ulcer
Uncommon
Multifactorial pathogenesis
• Peptic ulcer disease
• Edema/urticarial lesion of the GI tract
• Motility disorder
• Altered intestinal secretion
• Structural disease of the small intestinal mucosa
• Hypermotility/transit disorder
• Gastric hypersecretion
• Malabsorption

43. Musculoskeletal Pain
• Uncertain etiology
• Pain associated with osteoporotic fracture
• Radiographically detectable lesion 70%
• Proximal long bone, pelvis, ribs, skull

44. Fritz J, Fishman EK, Carrino JA, Horger MS. Advanced imaging of skeletal manifestations of systemic mastocytosis. Skeletal Radiology. 2012 Aug; 41(8):887-97
Focal sclerosis
Skeletal metastasis, Erdheim-Chester disease, tuberous sclerosis
Osteosclerosis
Idiopathic myelofibrosis, fluorosis, sickle cell anemia, Paget’s disease, renal
osteodystrophy

45. Fritz J, Fishman EK, Carrino JA, Horger MS. Advanced imaging of skeletal manifestations of systemic mastocytosis. Skeletal Radiology. 2012 Aug; 41(8):887-97
Focal marrow involvement
• Enostoses
• Sarcoidosis
• Hypoparathyroidism
• Osteopoikilosis
Diffuse marrow involvement
• Osteopetrosis
• Myelofibrosis
• Fluorosis
• Sclerosing bone dysplasias (e.g., Ribbing
disease, Camurati–Engelmann)

46. Patterns of Skeletal Abnormalities
• Osteosclerosis (histamine stimulate fibroblastic activity)
• Osteopenia
• Heparin lead to glycosaminoglycan-mediated calcium binding and
precipitation, enhance bone resorption
• Prostaglandins stimulate bone resorption
• Protease degrade bone matrix

47. Hepatic and Splenic Involvement
• 24% hepatomegaly
• 54% ↑ALP, ɣ-glytamyl transpeptidase, serum aminotransferase, 5’-
nucleotidase
• Ascites
• Portal hypertension
ALP ∝ - GGTP
- hepatomegaly
- splenomegaly
- liver mast cell infiltration and fibrosis

48. Neuropsychiatric Abnormalities
• ↓attention span
• Memory impairment
• Irritability

49. Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the
European Competence Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74
Score
+, in a majority (>50%) of patients
+/-, seen in a subset of patients (5–
50%)
-/+, rarely seen (1 to <5%)
- never or almost never seen (<1%)

50. Patient Evaluation

51. Patient Evaluation
• CM confirmed by skin biopsy
• Suspect mastocytosis in unexplained ulcer disease, malabsorption,
radiographic/Tc99 bone scan abnormality, hepatomegaly,
splenomegaly, lymphadenopathy, peripheral blood abnormalities,
unexplained flushing or anaphylaxis  BMBx
• Tryptase
• >20 ng/mL
• <20 ng/mL detected in CM and limited SM

52. Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the
European Competence Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74

53. Patient Evaluation
• Examination of other tissue specimen help define the extent
• LN, spleen, liver, GI mucosa
• Only when necessary
• Bone scans or skeletal surveys, ultrasound or CT scan of the
abdomen, upper GI series, small bowel radiography, endoscopy
• Genetic marker
• D816V mutation from bone marrow
• FIP1L1/PDGFRA – eosinophilia
• Dual energy x-ray absorptiometry (DEXA) to monitor osteoporosis

54. Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the
European Competence Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74

55. Alvarez-Twose I, Gonzalez-de-Olano D, Sanchez-Mun~oz L, Matito A, Jara-Acevedo M, Teodosio C et al. Validation of the REMA score for predicting mast cell clonali- ty
and systemic mastocytosis in patients with systemic mast cell activation symptoms. Int Arch Allergy Immunol 2012;157:275–280
Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the
European Competence Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74

56. Treatment

57. Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment
recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53

58. • 8-methoxypsoralen with long-wave ultraviolet photochemotherapy to
relieve pruritis and whealing
• 1-2 months of treatment
• Relapse within 3-6 months after discontinuation
• Topical steroids under plastic wrap occlusion for UP, DCM
• 8 h a day, 8-12 wks
• Improvement in cutaneous lesion up to 1 year
• Lesions eventually recur after discontinuation

59. Cardiovascular
Recurrent hypotension
1. H1 + H2RA
2. Glucocorticoids
3. Aspirin
Recurrent shock
1. H1 + H2RA
2. H1 + H2RA and low dose oral glucocorticoids
Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment
recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53

60. Gastrointestinal Symptoms
Peptic ulcer disease + bleeding (ASM/MCL)
1. H2RA
2. PPI + H2RA
Diarrhea, abdominal pain, abdominal cramping, nausea, vomiting
1. H1 + H2RA
2. Oral cromolyn sodium
3. Leukotriene antagonists
4. Short-term glucocorticoids
Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment
recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53

61. Skeletal Pain
1. Analgesics, NSAIDs (if tolerated), opiates in severe case
2. Palliative radiotherapy
3. IFN-α2b
Osteoporosis
• Calcium supplementation
• Estrogen replacement in postmenopausal women
• Oral  intravenous bisphosphonate
• IFN-α2b
Headache
• H1 + H2RA
• Oral cromolyn sodium
Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment
recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53

62. ASM/MCL
Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment
recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53

63. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017 Mar 16;129(11):1420-1427

64. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017 Mar 16;129(11):1420-1427

65. Prognosis
• Indolent systemic mastocytosis
• Progress slowly or not at all
• 3% progress to more severe form: SM-AHN, ASM, MCL
• 10-15% ISM + UP regression of UP
• Normal life expectancy
• Smoldering systemic mastocytosis
• 18% progress to ASM, MCL within months or year
• Aggressive systemic mastocytosis
• May rapidly decline over 12-24 months

66. Prognosis
• 342 patients
• Follow for median 21 months (0-35 years)
Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, McClure RF, Li CY, Pardanani A. Systemic mastocytosis in 342 consecutive adults: survival studies and
prognostic factors. Blood. 2009;113(23):5727
Case Median OS (months)
Progression to
ASM/leukemia (%)
ISM 137 301 3
SSM 22 120 18
ASM 41 41 5
SM-AHN 138 24 13
MCL 4 2

67. Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, McClure RF, Li CY, Pardanani A. Systemic mastocytosis in 342 consecutive adults: survival studies and
prognostic factors. Blood. 2009;113(23):5727
Estimated median overall survival 5 years