Mastocytosis

Mastocytosis
Suparat Sirivimonpan
3/5/13

Outline
• Introduction
• Etiology and pathogenesis
• Clinical features and classification
• Diagnosis and evaluation
• Management
• Prognosis

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
– mast cell hyperplasia in the skin, GI tract, bone
marrow, liver, spleen, and lymph nodes
– frequent association of mast cell hyperplasia with
hematologic disorders
Dean D. Metcalfe .Middleton’s Allergy 7’th edition ,1051-1062.
Hematol Oncol Clin N Am 25 (2011) 1067–1083

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

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
– prominent cytoplasmic granules that contain histamine, and
other chemical mediators, and
– surface receptors that bind the Fc portion of IgE with high affinity

Mast cell
• Mast cells within tissues are often found adjacent to
blood vessels and under epithelial surfaces
– 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

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

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)
– codon 816, exon 17 of the gene
– more than 90% of patients with SM, including both indolent and
aggressive subgroups
– present in only one-third of pediatric patients
• A clear phenotype– genotype correlation could not be
demonstrated
Curr Allergy Asthma Rep (2011) 11:292–299

• cutaneous biopsies of
50 children with
mastocytosis
• mutations in c-kit in
codon 816 : 42%
• outside exon 17: 44%
J Invest Dermatol. 2010;130:804–15

J Invest Dermatol. 2010;130:804–15

Expert Rev. Hematol. 5(3), 261–274 (2012)

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

Etiology :
inhibition of MCs apoptosis
• A subset of patients with
– increased mast cells and peripheral eosinophilia and
– 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

Etiology
• Disease associated with mutations in c-kit may be
modified by the genetic composition of the affected
individual
– a polymorphism in the gene for the IL-4 receptor α-chain : less
extensive mast cell involvement, with disease usually localized
to the skin
– 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

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

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

Mastocytosis
2 main categories:
• Cutaneous mastocytosis (CM)
– MC infiltrate is confined to one or more lesions on the skin
• Systemic mastocytosis (SM)
– by MC infiltration of at least one extracutaneous organ with or
without evidence of skin involvement

• 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

Am J Med Sci 2011;342(5):409–415

Skin
• Urticaria pigmentosa (UP)/maculopapular
cutaneous mastocytosis (MPCM)
• Diffuse cutaneous mastocytosis (DCM)
• Solitary mastocytoma of the skin

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
– > 90% of ISM
– 50% of SM-AHNMD or ASM

UP: small yellowish-tan to reddish-brown macules or slightly raised papules
raised nodulesPlaque like lesions

UP
• Spare palms, soles, face, and scalp
• Darier’s 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
– changes in temperature, local friction, ingestion of hot beverages
or spicy foods, ethanol, and certain drugs

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
d’orange appearance
• spontaneous resolution has usually
occurred before 5 years of age

• 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
Extensive diffuse skin involvement Bullous eruption

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

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.

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

Musculoskeletal
• Musculoskeletal pain
• associated with osteopenia or osteoporosis  pathologic
fractures
• osteoporosis or pathologic fractures, or both may be the
initial manifestation of mastocytosis

Bone marrow
• The bone marrow is the most common site of pathologic
mast cell infiltrates
– BM>spleen>liver>LN
• Initial diagnosis
– palpable splenomegaly 48%
– Hepatomegaly 41%
– lymphadenopathy 26%

Bone marrow
• BM biopsy
– most useful biopsy site for diagnosis of systemic mastocytosis
– important prognostic information
– Immunohistochemical staining with antitryptase : visualize mast
cells
• The majority of infiltrates in the bone marrow are focal,
• Focal mastocytosis lesions are most commonly situated
– Paratrabecular > Perivascular > Parafollicular

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).

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:
– granulomas, myelofibrosis, Hodgkin’s disease, metastatic
carcinoma, Kaposi’s sarcoma, and histiocytosis X
– because these cells resemble fibroblasts and histiocytes.

Bone marrow
• Most sensitive and specific method to support the
diagnosis of SM in BM
– flow cytometry of bone marrow aspirates or by
immunohistochemical analysis of bone marrow
biopsies
– The co-expression of CD2 and/or CD25 in CD117
(Kit)-positive mast cells

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
– Parafollicular and follicular replacement, medullary cord and
sinus infiltration: less frequent
• Mastocytosis infiltrates in the spleen and lymph nodes : DDx
– follicular and T cell lymphomas, monocytoid B cell hyperplasia
and lymphoma, Kaposi’s sarcoma, hairy cell leukemia, and
histiocytosis X

HEPATIC AND SPLENIC INVOLVEMENT
Liver
• 61% of patients had evidence of liver disease
– Hepatomegaly 24%,
– elevated levels of ALP,AST,ALT,GGTP 54%
• SM-AHNMD or ASM
– Elevated ALP levels (frequently)
– May developed ascites or portal hypertension
• Mast cell infiltration
– more severe in patients with SM-AHNMD or ASM
– correlated with hepatomegaly, splenomegaly, alkaline
phosphatase levels, and GGTP levels
• Cirrhosis was not observed

NEUROPSYCHIATRIC ABNORMALITIES
• Headache, dizziness
• Seizures
• Decreased attention span, memory impairment, and irritability
• Depression

impaired organ function
≥ 2 B findings, no C finding smoldering mastocytosis
≥ 1 C  aggressive SM (ASM)

Systemic mastocytosis
• Indolent systemic mastocytosis
– involves skin and bone marrow
– most common form of SM
• Smoldering systemic mastocytosis
– 2 or more “B findings” are present , no C finding
– mainly affects older patients
– more constitutional symptoms

Systemic mastocytosis
• SM-AHNMD
– usually a myeloid malignancy, but may also include lymphomas
or plasma cell neoplasms
– Symptoms and prognosis typically reflect the associated non–
mast cell disease
• Aggressive systemic mastocytosis
– typically lacking skin lesions
– presenting with one or more “C findings” that indicate organ
dysfunction owing to mast cell infiltration

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
– episodes of mediator-related symptoms
– later develop constitutional symptoms, including weight loss and
bone pain, and symptoms and signs of organomegaly

Diagnosis
• Mastocytosis should be suspected in patients without
skin lesions if ≥1 of the following features is present:
– unexplained ulcer disease or malabsorption
– radiographic or technetium 99 bone scan
abnormalities,
– hepatomegaly, splenomegaly, lymphadenopathy
– peripheral blood abnormalities
– unexplained flushing or anaphylaxis
 BM biopsy and aspiration

Investigation
Skin biopsy
• Cutaneous disease should be confirmed by skin biopsy
• UP : increase mast cells in the dermal papillae,
particularly near blood vessels
– DDX : recurrent anaphylaxis, scleroderma, chronic urticaria,and
prolonged antigenic contact

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

MCs in Bone marrow

Evaluation
Serum tryptase :
• most commonly used surrogate marker for SM
• Total tryptase >20 ng/mL : minor criterion (SM)
• Tryptase levels < 20ng/mL
– cutaneous mastocytosis
– those with limited systemic disease
• higher tryptase values  likelihood of multiorgan
involvement
• increased serum tryptase levels are not specific for SM
– also found in association with acute myeloid leukemia, chronic
myeloid leukemia, and myelodysplasia

Evaluation
• Other surrogate disease markers
– serum histamine
– 24-hour urine sampling for the urinary histamine metabolites N-
methylhistamine, and methylmidazole acetic acid
– less commonly used
• Disadvantages
– variability of histamine levels among healthy individuals and
patients
– difficulty in assay standardization
– false-positive results due to presumed synthesis of histamine by
bacteria in the urinary tract and sample

Evaluation
• Examination of other tissue specimens can help define
the extent of mast cell involvement
– lymph nodes, spleen, liver, and GI mucosa
– performed only when necessary
• Identification of genetic markers
– point mutations of c-kit, help support the diagnosis of
mastocytosis
– In patients with coexisting eosinophilia, peripheral blood should
be examined for the presence of the FIP1L1/PDGFRA fusion
gene

Evaluation
• Additional diagnostic studies
– bone scans or skeletal surveys
– ultrasound or computed tomography scan of the abdomen
– upper GI series
– small bowel radiography
– endoscopy

Am. J. Hematol. 87:402–411, 2012

Treatment
• Counseling and education
• Management of MC mediator-release symptoms
• Cytoreductive treatement

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

Antihistamine
• H1-receptor antagonists
– classic or non-sedating antihistamines
– reduce pruritus and flushing
• H2 antagonist
– If H1 is insufficient
– ranitidine, cimetidine or famotidine may be beneficial
• Many patients continue to complain of musculoskeletal
pain, headaches, and flushing
– inability of histamine antagonists to block the effects of high
levels of histamine , presence of other mast cell mediators
–  adding a leukotriene-modifying agent.

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  osteopenia or osteoporosis
Topical steroids
• treat UP or DCM
• Lesions recur after discontinuation of therapy

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

Epinephrine
• treat episodes of systemic hypotension
• Self-administer IM epinephrine

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

Cytoreductive Therapy
• Use in aggressive SM, SM-AHNMD,MCL
• interferon-α2b 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
– cytarabine, fludarabine, and hydroxyurea

Cytoreductive Therapy
• Specific tyrosine kinase inhibitors
– patients who are negative for D816V but have non–
codon 816 mutations or wild-type KIT
– such as imatinib, or other tyrosine kinase inhibitors

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

Curr Allergy Asthma Rep (2011) 11:292–299

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

Prognosis
Expert Rev. Hematol. 5(3), 261–274 (2012)

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

Mastocytosis

Recommandé

Recommandé

Contenu connexe

Tendances

Tendances (20)

Similaire à Mastocytosis

Similaire à Mastocytosis (20)

Plus de Chulalongkorn Allergy and Clinical Immunology Research Group

Plus de Chulalongkorn Allergy and Clinical Immunology Research Group (20)

Dernier

Dernier (20)

Mastocytosis