1) Mastocytosis is defined by abnormal mast cell expansion and accumulation in tissues like bone marrow and skin. It is more common in Caucasians and prevalence is about 1 in 10,000 people. 2) Mast cells develop from bone marrow stem cells and require stem cell factor (SCF) to survive. Gain of function mutations in c-Kit, the receptor for SCF, are found in most mastocytosis cases. 3) Mastocytosis manifestations range from isolated skin lesions to systemic involvement. Skin findings include rashes and lesions. Systemic symptoms involve gastrointestinal, bone, and neurological problems. Disease severity is classified by the WHO based on clinical and pathological criteria.

1. Puttatida Chetwong
19‐Feb‐2021

2. Introduction
• Mastocytosis is defined by abnormal clonal mast cell
expansion and accumulation in various tissues, such as the
bone marrow and skin.
• Disease prevalence ‐ approximately 1 per 10,000
• More frequently reported in Caucasians
• Male to female 1:1 to 1:3
• May occur at any age, or present at birth
• Familial occurrence is unusual
Middleton's Allergy 9th edition, 2019.

3. Pathogenesis and Etiology

4. Mast Cell
• Human mast cells develop from a bone marrow‐derived
hematopoietic pluripotential precursor cell (CD34+, CD117+ [Kit])
• Kit – transmembrane tyrosine
kinase receptor for SCF, encoded
by protooncogene c‐Kit
Middleton's Allergy 9th edition, 2019.

5. Stem cell factor
• Cytokine that bines to CD117
• Produced by fibroblasts and epithelial cells
• Obligate human mast cell growth factors
• Removal of SCF leads to rapid mast cell apoptosis
• Cofactors
‐ Enhance MC growth and promote survival:
Nerve growth factor, IL‐3, IL‐6, IL‐9, IL‐10
‐ Inhibit MC growth and differentiation:
GM‐CSF, retinoids, TGF‐β
Middleton's Allergy 9th edition, 2019.

6. • Mature mast cells
• Prominent cytoplasmic granules that contains mediators
• Express FcεRI that binds Fc portion of IgE with high affinity
• Do not circulate, long‐lived
• Location
• Found adjacent to blood vessels, under epithelial surface
• Prominent in GI, respiratory tract, lymphoid tissues, skin
J Histochem Cytochem. 2014 Oct;62(10):698‐738.
Middleton's Allergy 9th edition, 2019.

7. J Histochem Cytochem. 2014 Oct;62(10):698‐738.

8. Etiology ‐ KIT mutation
• Gain‐of‐function KIT mutation
• Most common mutation:
‐ substitution of valine for aspartic acid (ASP 816 VAL)
• Activating point mutation at codon 816
‐ found in most adults with mastocytosis
• Other mutations
• V560G
• D816Y, D816F, D816I, D816H
• E839K‐dominant inactivating mutation – several cases of pediatric mastocytosis
Middleton's Allergy 9th edition, 2019.

9. Etiology – Inhibition of mast cell apoptosis
• FIP1L1/PDGFRA fusion gene
• increased mast cells and peripheral eosinophilia and an increase in
serum tryptase levels
• PRKG2‐PDGFRB fusion gene
• a rare case of systemic mastocytosis and chronic basophilic leukemia
Middleton's Allergy 9th edition, 2019.

10. Classification

11. WHO Diagnostic Criteria for
Cutaneous and Systemic Mastocytosis
Middleton's Allergy 9th edition, 2019.

12. Middleton's Allergy 9th edition, 2019.

13. “B” Findings
“C” Findings
Middleton's Allergy 9th edition, 2019.

14. Clinical Spectrum
Pardanani A. Am J Hematol. 2019.

15. Clinical Presentation

17. Theoharides TC, et al. N Engl J Med. 2015.

18. Immunol Allergy Clin North Am. 2014 Feb;34(1):181‐96.

19. Skin Involvement
• Most common in children and adult: urticaria pigmentosa
• Now also called maculopapular cutaneous mastocytosis (MPCM)
• Observed in more than 90% of ISM patients
50% of SMAHN or ASM patients
• Monomorphic variant ‐ small maculopapular lesions
‐ seen in adults
• Polymorphic variant ‐ larger lesions, variable size and shape
‐ seen in children
Middleton's Allergy 9th edition, 2019.

20. ‐ Yellowish tan to reddish brown
macules or slightly raised papules
‐ Raised nodules or plaque‐like
lesions are also seen
‐ Palms, soles, face, scalp – spare
‐ Darier sign = urtication and
erythema over and around the
macules upon rubbing of the
lesion
‐ May be associated with pruritus
‐ Diagnosis by histology ‐ increase in
dermal mast cells approx. 10
times that of normal skin
MPCM
Middleton's Allergy 9th edition, 2019.

21. Diffuse cutaneous mastocytosis
Middleton's Allergy 9th edition, 2019.

22. Bullous eruption
‐ Blisters may erupt spontaneously or in
association with infection or immunization
Solitary mastocytoma
‐ Often appear before age 3 months
‐ Usually spontaneously involute
during childhood
Middleton's Allergy 9th edition, 2019.

23. Gastrointestinal Symptoms
• Almost as common as pruritus or flushing
• Symptoms
• Abdominal pain
• Diarrhea
• Nausea, vomiting
• Malabsorption – 30% of patients, mild steatorrhea
• Multifactorial: gastric acid hypersecretion, hypermotility,
mucosal edema
• Commonly involved sites with mast cell infiltration
• Colon, ileum, duodenum, stomach
Middleton's Allergy 9th edition, 2019.

24. Muskuloskeletal Pain
• Osteopenia or osteoporosis
• Pathologic fractures
• Back pain from vertebral compression
• Superscan pattern in skeletal scintigraphy
– bone marrow infiltration
Pinto‐Lopes P, et al. Sao Paulo Med J. 2013.
Middleton's Allergy 9th edition, 2019.

25. Hepatic and Splenic Involvement
• Hepatomegaly (24% of patients) and splenomegaly
• Elevated ALP, SGOT, SGPT, GGT
• Severe liver disease: uncommon unless aggressive disease
Neuropsychiatric Abnormalities
• Adults – cognitive impairment, depressive‐anxiety‐like
symptoms
• Children – no specific increase in behavioral difficulties
Middleton's Allergy 9th edition, 2019.

26. Monoclonal Mast Cell Activation Syndrome
• Patients present with
• idiopathic anaphylaxis
• anaphylaxis to stinging insects
• symptoms of mast cell activation without cutaneous findings
• Investigation
• either the KIT D816V mutation and/or CD25+ mast cells in bone marrow
• lack the full diagnostic criteria for systemic mastocytosis
• tryptase levels below 20 ng/mL
Middleton's Allergy 9th edition, 2019.

27. Monoclonal Mast Cell Activation Syndrome
• Treatment
• Under guidelines of anaphylaxis
• Follow‐up yearly
• Physical examination to rule out evolving organomegaly or lymphadenopathy
• Serum tryptase level
• Complete blood count to help rule out an evolving hematologic disorder
Middleton's Allergy 9th edition, 2019.

28. Mast Cell Activation Syndrome
• Diagnostic criteria: all must be met
• episodic multisystem symptoms consistent with mast cell activation
• appropriate response to medications targeting mast cell activation with
mediator release
• an increase in a validated urinary or serum marker of mast cell activation
(e.g., tryptase) with an episode
• Primary MCAS – associated with MMAS or mastocytosis
• Secondary MCAS – due to IgE‐mediated allergies, physical stimuli,
drugs, other inflammatory and neoplastic disorders
Middleton's Allergy 9th edition, 2019.

29. Pathology

30. •Urticaria pigmentosa
• Increase in the number of mast cells (10‐20 fold increase) beneath
associated macules and papules
• Increased number of dilated capillaries of the superficial venous
plexus
• Correlate with skin lesion to distinguish from chronic urticaria
•Diffuse cutaneous mastocytosis
• Prominent bandlike infiltrates are observed that may be
indistinguishable from some lesions of UP/MPCM or from
mastocytomas
Dermis
Middleton's Allergy 9th edition, 2019.

31. Bone Marrow
• Most common tissue to examine for a pathologic mast cell infiltrate in
mastocytosis
• Immunohistochemical staining with antitryptase – method of choice
to visualize mast cells
• Other stains: Wright‐Giemsa, toluidine blue
• The expression of CD25 and/or CD2 in CD117 (KIT)–positive mast
cells by flow cytometry of bone marrow aspirates or by IHC analysis
of bone marrow biopsies :
• most sensitive and specific method to support the diagnosis of
SM in bone marrow
Middleton's Allergy 9th edition, 2019.

32. • CD30
• more commonly expressed in more advanced forms of mastosytosis
• CD123
• α‐subunit of the IL‐3 receptor
• expressed on neoplastic mast cells at 100%, 61%, 57% and 0% in ASM, ISM,
SMAHN and MCL respectively
Paratrabecular aggregate of spindle‐shaped mast cells. Hematopoietic marrow is hypercellular, and bone
trabeculae are slightly thickened. This patient has an aggressive form of systemic mastocytosis.
Middleton's Allergy 9th edition, 2019.

33. • Spleen
• Most common finding ‐ trabecular fibrotic thickening
• Lymph node
• Most common location ‐ paracortical mast cell infiltrate
• Liver
• Mast cell infiltration is more severe in patients with SMAHN or ASM
• Correlates with hepatomegaly, splenomegaly, ALP and GGT levels
Spleen and Liver
Middleton's Allergy 9th edition, 2019.

34. Patient Evaluation

35. • Total serum tryptase levels should be measured in all
patients with suspected mastocytosis of any severity
• If the tryptase level is elevated during a symptomatic event,
it should be measured again at least 24 hours after
symptoms resolve.
Serum mast cell tryptase
Theoharides TC, et al. N Engl J Med. 2015.

36. Serum mast cell tryptase
• Most frequently used surrogate marker for mastocytosis
• A total tryptase level greater than 20 ng/mL
• suggests mastocytosis
• is a minor criterion in the diagnosis of SM
• Tryptase levels less than 20 ng/mL have been detected in patients
with CM and in those with limited SM
• Higher tryptase values increase the likelihood of multiorgan
involvement
Middleton's Allergy 9th edition, 2019.

37. • Patients with cutaneous disease
 Skin biopsy to confirm cutaneous mastocytosis
• Patients without skin lesions should be considered for the
diagnosis of mastocytosis if one or more of these is present
• unexplained ulcer disease or malabsorption
• Radiographic or technetium‐99 bone scan abnormalities
• hepatomegaly, splenomegaly, lymphadenopathy
• peripheral blood abnormalities
• Flushing or anaphylaxis, the latter sometimes following insect stings
 Bone marrow biopsy and aspiration should be considered
Based on Skin Lesion
Middleton's Allergy 9th edition, 2019.

38. Theoharides TC, et al. N Engl J Med. 2015.

39. RT‐PCR for KIT D816V mutation
‐ Peripheral blood
‐ Bone marrow (best)
Theoharides TC, et al. N Engl J Med. 2015.

41. Treatment

42. Mast Cell Mediator Symptoms
• H1‐receptor antagonist
• H2‐receptor antagonist
• Leukotriene‐receptor antagonist
• Cromolyn sodium – inhibit mast cell degranulation
• Ketotifen – antihistamine with mast cell stabilizer
• Epinephrine IM
• Methoxsalen (Psoralens) with long‐wave ultraviolet
photochemotherapy (PUVA)
• Topical steroid under plastic wrap 8 h/day for 8‐12 weeks – UP, DCM
Middleton's Allergy 9th edition, 2019.

43. GI Symptoms
• Gastric acid hypersecretion – H2 antagonist, PPI
• Diarrhea – anticholinergics
• Severe malabsorption – oral steroid
• Ascites – portacaval shunt
Middleton's Allergy 9th edition, 2019.

44. Osteoporosis
• Unrecognized in patients with milder forms ‐ DEXA scan for
evaluation
• Treatment of osteoporosis
• Calcium supplement
• Estrogen replacement in postmenopausal women
• Bisphosphonate
• Treatment for bone pain
• Narcotic analgesics – may potentiate mast cell degranulation
• Radiotherapy
• Interferon alpha‐2b
Middleton's Allergy 9th edition, 2019.

45. Cytoreductive Therapy
• Indicated in aggressive systemic mastocytosis and mast‐cell leukemia
• Imatinib (tyrosine kinase inhibitor)
• Approved by FDA for treatment of
‐ chronic myelogenous leukemia
‐ KIT‐positive gastrointestinal stromal tumors
‐ aggressive forms of mastocytosis without KIT D816V mutation
• Also for the treatment of patients with increased mast cells and peripheral
eosinophilia that carry the FIP1L1‐PDGFRA
• Midostaurin (tyrosine kinase inhibitor)
• inhibits the growth and survival of mast cells (including cells bearing KIT
D816V) as well as IgE‐dependent mast‐cell activation
• approved by the FDA for treatment of patients with ASM, SMAHN, and MCL
Middleton's Allergy 9th edition, 2019.

46. Cytoreductive Therapy
• IFN‐α2b
• Improve symptoms of MC degranulation, decrease BM MC infiltration, and
ameliorate mastocytosis‐related ascites/hepatosplenomegaly, cytopenias,
skin findings, and osteoporosis
• Side effects such as fever, malaise, nausea, and hypothyroidism
• A significant proportion of patients will relapse within a short period of
IFN‐α treatment being discontinued
• Cladribine (2‐chloro‐2‐deoxyadenosine, nucleotide analog)
• Reasonable therapeutic approach in treating aggressive forms of mastocytosis
that need a rapid reduction in mast cell burden
• Potential toxicities include myelosuppression, lymphopenia and opportunistic
infections.
Middleton's Allergy 9th edition, 2019.

47. Hematopoietic stem cell
transplantation
• Candidates: advanced systemic mastocytosis
• May provide extended survival in selected patients, particularly for
those with SMAHN
Middleton's Allergy 9th edition, 2019.

48. Prognosis
• Variables strongly associated with poor survival:
• advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess
bone marrow blasts
• Best prognosis: CM only, ISM
• For children with isolated UP  at least 50% of cases resolve by adulthood
• UP in adulthood may evolve into systemic disease
• Survival time ‐ MCL: usually less than 12 months
‐ ASM: 2 to 4 years with aggressive symptomatic management
Middleton's Allergy 9th edition, 2019.