Mastocytosis is a group of disorders characterized by abnormal mast cell proliferation in various organs. The document discusses the etiology, pathogenesis, clinical manifestations, diagnosis, and management of mastocytosis. Key points include: mastocytosis is caused by mutations in the c-kit gene leading to mast cell hyperplasia; clinical features vary depending on extent of disease but commonly involve skin, gastrointestinal tract, bone marrow and may include pruritus, flushing and pain; diagnosis involves biopsy of affected tissues and molecular testing for c-kit mutations; management focuses on treatment of symptoms and long-term prognosis depends on disease subtype and severity.
2. Outline
⢠Introduction
⢠Etiology and pathogenesis
⢠Clinical features and classification
⢠Diagnosis and evaluation
⢠Management
⢠Prognosis
3. Introduction
⢠Mast cell disease, or mastocytosis : variety of disorders
that are characterized by clonal, neoplastic proliferations
of mast cells in one or multiple organs
⢠The most remarkable pathologic features
â mast cell hyperplasia in the skin, GI tract, bone
marrow, liver, spleen, and lymph nodes
â frequent association of mast cell hyperplasia with
hematologic disorders
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
Hematol Oncol Clin N Am 25 (2011) 1067â1083
4. Introduction
⢠Clinical features : pruritus, flushing, nausea, vomiting,
diarrhea, abdominal pain, and vascular instability
⢠The prevalence of the disease is unknown
⢠Mastocytosis occurs in all ethnic groups
⢠may present at any age
⢠Cutaneous mastocytosis : children
⢠Systemic mastocytosis : adults
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
Hematol Oncol Clin N Am 26 (2012) 1143â1168
6. Mast cell
⢠Human mast cells develop from a bone marrow-derived
hematopoietic pluripotential precursor cell (CD34+, Kit
[CD117]+)
⢠complete maturation in vascularized peripheral tissues
⢠During this maturation : downregulate CD34 but remain
CD117+
⢠Mature mast cells have
â prominent cytoplasmic granules that contain histamine, and
other chemical mediators, and
â surface receptors that bind the Fc portion of IgE with high affinity
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
7. Mast cell
⢠Mast cells within tissues are often found adjacent to
blood vessels and under epithelial surfaces
â prominent in GI, respiratory tracts, lymphoid tissues, skin
⢠Mature mast cells normally do not circulate, are long-
lived, and appear to retain a limited capacity to
proliferate
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
8. Mast cell
⢠SCF-Kit system plays a role in the development of mast cells
⢠Stem cell factor (SCF) : mast cell growth
⢠c-kit (protooncogene) encodes Kit (CD117) : transmembrane
tyrosine kinase receptor for SCF
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
Hematol Oncol Clin N Am 26 (2012) 1143â1168
9. Etiology : c-kit mutation
⢠Activating point mutation of the c-kit gene
⢠most common mutation consists of a substitution of
valine for aspartic acid (ASP 816 VAL) (KIT D816V)
â codon 816, exon 17 of the gene
â more than 90% of patients with SM, including both indolent and
aggressive subgroups
â present in only one-third of pediatric patients
⢠A clear phenotypeâ genotype correlation could not be
demonstrated
Hematol Oncol Clin N Am 26 (2012) 1143â1168
Curr Allergy Asthma Rep (2011) 11:292â299
10. ⢠cutaneous biopsies of
50 children with
mastocytosis
⢠mutations in c-kit in
codon 816 : 42%
⢠outside exon 17: 44%
J Invest Dermatol. 2010;130:804â15
14. Etiology
⢠The downstream signal transduction pathways
responsible for oncogenesis by these point mutations
are not fully understood
⢠play a role in ligand-independent growth and
suppression of apoptosis
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
15. Etiology :
inhibition of MCs apoptosis
⢠A subset of patients with
â increased mast cells and peripheral eosinophilia and
â increase in serum tryptase levels
has been described that carry the Fip1-like-1-platelet-
derived growth factor receptor (FIP1L1-PDGFRA) fusion
oncogene in pluripotential hematopoietic progenitor cells,
which results from an approximately 800-kb interstitial
deletion of chromosome 4q12
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
16. Etiology
⢠Disease associated with mutations in c-kit may be
modified by the genetic composition of the affected
individual
â a polymorphism in the gene for the IL-4 receptor Îą-chain : less
extensive mast cell involvement, with disease usually localized
to the skin
â the bone marrow cells of patients with mastocytosis have been
found to constitutively express the antiapoptotic proteins Bcl-XL
and Bcl-2
⢠This may explain the long survival of these cells and
perhaps their resistance to chemotherapy-induced
apoptosis
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
17. PATHOLOGIC EFFECTS OF INCREASED
MAST CELLS
⢠The pathologic changes observed in mastocytosis are
the result of the increased number of mast cells residing
within tissues, and the release of mast cell-dependent
mediators within tissues
⢠Mast cell-derived mediators also circulate through the
bloodstream and lymphatic system to produce biologic
effects
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
18. Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
20. Clinical feature
⢠Skin, GI tract, lymph nodes, liver, spleen, bone marrow,
and skeletal system : common
⢠RS, Endocrine, Renal systems : seldom
⢠Patients in every category of mastocytosis sometimes
experience flushing and/or episodic hypotension
⢠Occasionally, hypotension may be provoked by alcohol,
aspirin, insect stings, infection, or exposure to iodinated
contrast materials
⢠Patients with mastocytosis do not suffer from an
increase in bacterial, fungal, or viral infection
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
21. Mastocytosis
2 main categories:
⢠Cutaneous mastocytosis (CM)
â MC infiltrate is confined to one or more lesions on the skin
⢠Systemic mastocytosis (SM)
â by MC infiltration of at least one extracutaneous organ with or
without evidence of skin involvement
Hematol Oncol Clin N Am 26 (2012) 1143â1168
22. Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
23. ⢠The symptoms of SM are usually grouped into 4
categories:
(1) constitutional symptoms : fatigue, weight loss, sweats, and fever
(2) skin symptoms
(3) MC mediator-related symptoms
(4) musculoskeletal symptoms, which include bone,
muscle, and joint pain
Hematol Oncol Clin N Am 26 (2012) 1143â1168
25. Skin
⢠Urticaria pigmentosa (UP)/maculopapular
cutaneous mastocytosis (MPCM)
⢠Diffuse cutaneous mastocytosis (DCM)
⢠Solitary mastocytoma of the skin
26. Urticaria pigmentosa(UP)
⢠The most common skin manifestation of mastocytosis in
both children and adults
⢠It is the most common pattern of skin involvement in CM
⢠UP is also observed in
â > 90% of ISM
â 50% of SM-AHNMD or ASM
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
27. Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
UP: small yellowish-tan to reddish-brown macules or slightly raised papules
raised nodulesPlaque like lesions
28. Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
29. UP
⢠Spare palms, soles, face, and scalp
⢠Darierâs sign : rubbing of the lesions usually leads to urtication
and erythema over and around the macules,
⢠UP is sometimes associated with pruritus that is
exacerbated by
â changes in temperature, local friction, ingestion of hot beverages
or spicy foods, ethanol, and certain drugs
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
30. Diffuse cutaneous mastocytosis (DCM)
⢠extremely rare form of CM
⢠diffuse mast cell infiltration in the dermis
⢠no discrete lesions
⢠entire cutaneous integument is involved
⢠Onset < age of 3 years
⢠The skin is normal to yellowish-brown
and is thickened
⢠may exhibit discoloration with a peau
dâorange appearance
⢠spontaneous resolution has usually
occurred before 5 years of age
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
Hematol Oncol Clin N Am 26 (2012) 1143â1168
31. ⢠Young children with UP or DCM may have bullous eruptions with
hemorrhage
⢠Blisters may erupt spontaneously or in association with infection or
immunization
⢠Blisters may also occur at birth
⢠CM is thus included in the differential diagnosis of neonatal disorders
with blisters
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
Extensive diffuse skin involvement Bullous eruption
32. Solitary mastocytoma
⢠presents in the first 3 months of life
⢠1-3 plaques or nodules , >1 cm in
diameter
⢠brown or orange
⢠usually located on the extremities
⢠spare the palms and soles of the
feet
⢠usually spontaneously involute
during childhood
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
Hematol Oncol Clin N Am 26 (2012) 1143â1168
33. Telangiectasia macularis eruptiva perstans
(TMEP)
⢠< 1% of cases of mastocytosis
⢠report only in adults
⢠telangiectatic, red macule on a tan-brown background
⢠Individual lesions are 2-6mm in diameter and are without
sharply defined borders
⢠TMEP may occasionally coexist with UP.
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
34. GI
⢠Common(80%) : as frequent as pruritus(88%) or flushing (43%)
⢠Abdominal pain is the most common GI symptom,
followed by diarrhea, nausea, and vomiting
⢠GI bleeding is uncommon
⢠Peptic ulcer disease is relatively infrequent (4-44%)
despite hyperhistaminemia
⢠The pathogenesis of abdominal symptoms appears
multifactorial
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
35. Musculoskeletal
⢠Musculoskeletal pain
⢠associated with osteopenia or osteoporosis ď pathologic
fractures
⢠osteoporosis or pathologic fractures, or both may be the
initial manifestation of mastocytosis
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
36. Bone marrow
⢠The bone marrow is the most common site of pathologic
mast cell infiltrates
â BM>spleen>liver>LN
⢠Initial diagnosis
â palpable splenomegaly 48%
â Hepatomegaly 41%
â lymphadenopathy 26%
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
37. Bone marrow
⢠BM biopsy
â most useful biopsy site for diagnosis of systemic mastocytosis
â important prognostic information
â Immunohistochemical staining with antitryptase : visualize mast
cells
⢠The majority of infiltrates in the bone marrow are focal,
⢠Focal mastocytosis lesions are most commonly situated
â Paratrabecular > Perivascular > Parafollicular
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
38. Fig. 60.8 (A) Paratrabecular aggregate of spindle-shaped mast cells. The hematopoietic
marrow is hypercellular, and the bone trabeculae are slightly thickened. This patient has
an aggressive form of systemic mastocytosis. (Hematoxylin-eosin stain; 20.)
(B) Higher power demonstrates the spindle shape of the mast cells and the faint granularity of
the cytoplasm. (Giemsa stain; plastic imbedded; 250).
39. Bone marrow
⢠Early stage : MCs infiltrate(cellular)
⢠Late stage : mast cells number may decrease and the
lesions may become fibrotic
⢠osteosclerotic or osteolytic changes in the bone
trabeculae
⢠DDX:
â granulomas, myelofibrosis, Hodgkinâs disease, metastatic
carcinoma, Kaposiâs sarcoma, and histiocytosis X
â because these cells resemble fibroblasts and histiocytes.
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
40. Bone marrow
⢠Most sensitive and specific method to support the
diagnosis of SM in BM
â flow cytometry of bone marrow aspirates or by
immunohistochemical analysis of bone marrow
biopsies
â The co-expression of CD2 and/or CD25 in CD117
(Kit)-positive mast cells
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
41. HEPATIC AND SPLENIC INVOLVEMENT
Spleen
⢠The most common finding is trabecular fibrotic thickening
⢠found in a paratrabecular, parafollicular, follicular, or diffuse
red pulp distribution
Lymph node
⢠The most common location is the paracortical region
â Parafollicular and follicular replacement, medullary cord and
sinus infiltration: less frequent
⢠Mastocytosis infiltrates in the spleen and lymph nodes : DDx
â follicular and T cell lymphomas, monocytoid B cell hyperplasia
and lymphoma, Kaposiâs sarcoma, hairy cell leukemia, and
histiocytosis X
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
42. HEPATIC AND SPLENIC INVOLVEMENT
Liver
⢠61% of patients had evidence of liver disease
â Hepatomegaly 24%,
â elevated levels of ALP,AST,ALT,GGTP 54%
⢠SM-AHNMD or ASM
â Elevated ALP levels (frequently)
â May developed ascites or portal hypertension
⢠Mast cell infiltration
â more severe in patients with SM-AHNMD or ASM
â correlated with hepatomegaly, splenomegaly, alkaline
phosphatase levels, and GGTP levels
⢠Cirrhosis was not observed
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
43. NEUROPSYCHIATRIC ABNORMALITIES
⢠Headache, dizziness
⢠Seizures
⢠Decreased attention span, memory impairment, and irritability
⢠Depression
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
48. Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
49. Hematol Oncol Clin N Am 25 (2011) 1067â1083
impaired organ function
⼠2 B findings, no C findingď smoldering mastocytosis
⼠1 C ď aggressive SM (ASM)
50. Systemic mastocytosis
⢠Indolent systemic mastocytosis
â involves skin and bone marrow
â most common form of SM
⢠Smoldering systemic mastocytosis
â 2 or more âB findingsâ are present , no C finding
â mainly affects older patients
â more constitutional symptoms
Hematol Oncol Clin N Am 25 (2011) 1067â1083
51. Systemic mastocytosis
⢠SM-AHNMD
â usually a myeloid malignancy, but may also include lymphomas
or plasma cell neoplasms
â Symptoms and prognosis typically reflect the associated nonâ
mast cell disease
⢠Aggressive systemic mastocytosis
â typically lacking skin lesions
â presenting with one or more âC findingsâ that indicate organ
dysfunction owing to mast cell infiltration
Hematol Oncol Clin N Am 25 (2011) 1067â1083
52. MCL
⢠rare
⢠characterized by circulating MCs and 20% or greater
MCs on the bone marrow aspirate smear
⢠Most patients are adults
⢠Cutaneous lesions are typically absent
⢠present with
â episodes of mediator-related symptoms
â later develop constitutional symptoms, including weight loss and
bone pain, and symptoms and signs of organomegaly
Hematol Oncol Clin N Am 26 (2012) 1143â1168
54. Diagnosis
⢠Mastocytosis should be suspected in patients without
skin lesions if âĽ1 of the following features is present:
â unexplained ulcer disease or malabsorption
â radiographic or technetium 99 bone scan
abnormalities,
â hepatomegaly, splenomegaly, lymphadenopathy
â peripheral blood abnormalities
â unexplained flushing or anaphylaxis
ď BM biopsy and aspiration
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
55. Investigation
Skin biopsy
⢠Cutaneous disease should be confirmed by skin biopsy
⢠UP : increase mast cells in the dermal papillae,
particularly near blood vessels
â DDX : recurrent anaphylaxis, scleroderma, chronic urticaria,and
prolonged antigenic contact
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
56. Investigation
Bone marrow biopsy & aspiration
⢠show multifocal, sharply demarcated, compact infiltrates of MCs
⢠MCs are a mixture of both round and spindle shaped forms
⢠Immunohistochemical and molecular studies are recommended
to distinguish reactive from malignant MC infiltrates
⢠Antibodies to tryptase detect all MCs and MC progenitors
,neoplastic MCs
⢠malignant MC populations, which express tryptase/chymase
and CD117 and aberrantly coexpress CD2/CD25
Hematol Oncol Clin N Am 26 (2012) 1143â1168
57. MCs in Bone marrow
Hematol Oncol Clin N Am 26 (2012) 1143â1168
58. Evaluation
Serum tryptase :
⢠most commonly used surrogate marker for SM
⢠Total tryptase >20 ng/mL : minor criterion (SM)
⢠Tryptase levels < 20ng/mL
â cutaneous mastocytosis
â those with limited systemic disease
⢠higher tryptase values ď likelihood of multiorgan
involvement
⢠increased serum tryptase levels are not specific for SM
â also found in association with acute myeloid leukemia, chronic
myeloid leukemia, and myelodysplasia
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
Hematol Oncol Clin N Am 26 (2012) 1143â1168
59. Evaluation
⢠Other surrogate disease markers
â serum histamine
â 24-hour urine sampling for the urinary histamine metabolites N-
methylhistamine, and methylmidazole acetic acid
â less commonly used
⢠Disadvantages
â variability of histamine levels among healthy individuals and
patients
â difficulty in assay standardization
â false-positive results due to presumed synthesis of histamine by
bacteria in the urinary tract and sample
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
60. Evaluation
⢠Examination of other tissue specimens can help define
the extent of mast cell involvement
â lymph nodes, spleen, liver, and GI mucosa
â performed only when necessary
⢠Identification of genetic markers
â point mutations of c-kit, help support the diagnosis of
mastocytosis
â In patients with coexisting eosinophilia, peripheral blood should
be examined for the presence of the FIP1L1/PDGFRA fusion
gene
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
61. Evaluation
⢠Additional diagnostic studies
â bone scans or skeletal surveys
â ultrasound or computed tomography scan of the abdomen
â upper GI series
â small bowel radiography
â endoscopy
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
64. Treatment
⢠Counseling and education
⢠Management of MC mediator-release symptoms
⢠Cytoreductive treatement
65. Management of mediator-release symptoms
⢠Most prominent among these are systemic hypotension,
gastric hypersecretion, GI cramping, and pruritus
⢠Antihistamine
⢠Corticosteroid
⢠Disodium cromolyn (cromolyn sodium)
⢠Biphosphonates
⢠UV light irradiation
⢠Epinephrine
⢠Leukotriene antagonis
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
66. Antihistamine
⢠H1-receptor antagonists
â classic or non-sedating antihistamines
â reduce pruritus and flushing
⢠H2 antagonist
â If H1 is insufficient
â ranitidine, cimetidine or famotidine may be beneficial
⢠Many patients continue to complain of musculoskeletal
pain, headaches, and flushing
â inability of histamine antagonists to block the effects of high
levels of histamine , presence of other mast cell mediators
â ď adding a leukotriene-modifying agent.
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
67. Corticosteroids
Oral steroids
⢠control malabsorption,abdominal pain, nausea and
vomiting
⢠prevention or treatment of anaphylaxis
⢠should only be used for short periods as a second- or
third-line therapy ď osteopenia or osteoporosis
Topical steroids
⢠treat UP or DCM
⢠Lesions recur after discontinuation of therapy
Hematol Oncol Clin N Am 26 (2012) 1143â1168
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
68. Disodium cromoglycate (cromolyn
sodium)
⢠inhibits degranulation of mast cells and
⢠relief of GI complaints
Ketotifen
⢠antihistamine with mast cell stabilizing properties
⢠relieving the pruritus and whealing
⢠no advantage over hydroxyzine
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
69. Epinephrine
⢠treat episodes of systemic hypotension
⢠Self-administer IM epinephrine
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
70. UV light irradiation
⢠Oral methoxypsoralen with UVA (PUVA)
⢠relieve pruritus and whealing after 1-2 months of
treatment
⢠Relapse occurs within 3-6 months after discontinuation
of therapy
⢠Photochemotherapy should be used only in instances of
extensive cutaneous disease unresponsive to other
forms of therapy
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
71. Cytoreductive Therapy
⢠Use in aggressive SM, SM-AHNMD,MCL
⢠interferon-ι2b and 2-chloro-2-deoxyadenosine (cladribine,
2-CdA) are potential first- and second-line therapeutic
options
⢠In highly aggressive or relapsed cases : combination
chemotherapy followed by a hematopoietic stem cell
transplant should be considered
â cytarabine, fludarabine, and hydroxyurea
Hematol Oncol Clin N Am 26 (2012) 1143â1168
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
72. Cytoreductive Therapy
⢠Specific tyrosine kinase inhibitors
â patients who are negative for D816V but have nonâ
codon 816 mutations or wild-type KIT
â such as imatinib, or other tyrosine kinase inhibitors
Hematol Oncol Clin N Am 26 (2012) 1143â1168
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
73. Bone marrow transplantation
⢠treatment option for patients with advanced categories of
mastocytosis associated with poor survival in only a few
reported instances
⢠may yield a better prognosis if mast cell suppression is
attempted prior to the transplantation
Hematol Oncol Clin N Am 26 (2012) 1143â1168
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
77. Prognosis
⢠Patients with CM only have the best prognosis
⢠For children with isolated UP, at least 50% of cases are
reported to resolve by adulthood
⢠UP in adulthood may evolve into systemic disease
⢠Occasionally, ISM converts to SM-AHNMD
Dean D. Metcalfe .Middletonâs Allergy 7âth edition ,1051-1062.
80. Take home messages
⢠Mastocytosis is associated with a pathologic increase in
mast cells in one or more organ systems
⢠Most adult patients have an activating mutation in Kit
⢠Serum tryptase is usually elevated
⢠The signs and symptoms are due to release of mast cell
mediators, the increase in mast cell burden, and, in
some patients, an associated hematologic disorder
⢠Treatment is largely symptomatic, with specific treatment
of any associated hematologic disorder