Mastocytosis
Cem Akin, MD, PhD
Harvard Medical School
Brigham and Women’s Hospital
Department of Medicine
Division of Rheumatology, Immunology and Allergy
Boston, MA
e-mail: cakin@partners.org
WHO Mastocytosis Consensus Classification
• Cutaneous mastocytosis
• Indolent systemic mastocytosis (without AHD)
– Smoldering systemic mastocytosis
– Isolated bone marrow mastocytosis
• Systemic mastocytosis with an AHNMD
– MDS, MPD, AML, NHL
• Aggressive systemic mastocytosis
• Mast cell leukemia
• Mast cell sarcoma
• Extracutaneous mastocytoma
Leukemia Research, 25(7):603-625, 2001
WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, p:293-302, 2001
Diagnostic Criteria for Systemic Mastocytosis
(need the major + 1 minor or 3 minor criteria for diagnosis)
• Major:
– Characteristic multifocal dense infiltrates of mast cells in bone marrow biopsy
• Minor:
– Morphology of mast cells: Spindle shaped
– Detection of a codon 816 c-kit mutation
– Flow cytometric co-expression of CD117, CD2 and CD25
by the bone marrow mast cell population
– Serum tryptase >20 ng/ml
Signs and symptoms of mastocytosis
Skin: Episodic flushing, itching, hyperpigmented maculopapular lesions (UP)
Cardiovascular: Episodic tachycardia, hypotension, lightheadedness
Gastrointestinal: Abdominal cramping, diarrhea, heartburn, nausea, vomiting,
peptic ulcer, hepatomegaly, ascites
Musculoskeletal: Osteoporosis, osteosclerosis, diffuse soft-tissue pain
Hematologic: Splenomegaly, lymphadenopathy, signs and symptoms of the
associated hematologic disorder, if present
Constitutional: Fatigue, headache
When to suspect systemic mastocytosis
1. Adult patient with urticaria pigmentosa
2. Child with late onset of skin lesions (>2 years of age) and hepatosplenomegaly,
unexplained CBC abnormality or unexplained pathologic lymphadenopathy
3. Patients with recurrent unexplained anaphylaxis: Syncopal or pre-syncopal
episodes associated with other signs of mast cell mediator release
4. Patients with premature osteoporosis, or pathologic fractures
When to consider referral
1. Patients with aggressive variants who are candidates for investigational or
cytoreductive therapies
2. Patients with anaphylaxis and low tryptase levels (expected to have low mast
cell burden and thus need more sensitive diagnostic evaluation such as flow
cytometry)
3. Any time you need an expert opinion and the patient is willing and stable
enough to travel
Treatment of mastocytosis
Symptomatic
H1 antihistamines: e.g. Fexofenadine, Cetirizine, Hydroxyzine, Diphenhydramine
H2 antihistamines: e.g. Ranitidine, Famotidine
Antileukotrienes: e.g. Montelukast, Zileuton
Mast cell stabilizer: Gastrocrom
Epinephrine (Epi-Pen) as needed for anaphylactoid attacks
Glucocorticoids: e.g. Prednisone
PUVA
Cytoreductive
Consider in aggressive categories associated with decreased life expectancy
Consider a second opinion from a referral center
Refer to a Hematology/Oncology specialist
IFN-α (SQ injection)
2-CDA (Cladribine) (IV)
Imatinib in selected cases (D816V c-kit mutation negative; most patients are not
candidates)
Investigational therapy (new kinase inhibitors: PKC412)
Associated hematologic disorder (myeloproliferative, MDS, leukemias,
lymphomas): Treat accordingly
Mast cell activators of clinical relevance
• IgE-dependent
– Allergen
• IgE-independent
–
– Bacterial components
• Peptidoglycan: TLR2/6
• LPS: TLR4
• fMLP
– C3a, C5a
– Cysteinyl leukotrienes
– Cytokines/chemokines
• SCF, NGF
– Neuropeptides
– Drugs
• Opioids, muscle relaxants, radiocontrast material, adenosine
– Physical stimuli
• Heat, cold, pressure, exercise
– Hormones
• -MSH
Mast cell activation disorders
1. Primary
a. Anaphylaxis with an associated clonal mast cell disorder (systemic
mastocytosis)
b. Monoclonal mast cell activation syndrome
2. Secondary
a. Allergic diseases
b. Mast cell activation associated with chronic inflammatory or neoplastic
disorders
c. Physical urticarias
d. Chronic autoimmune urticaria
3. Idiopathic
a. anaphylaxis
b. angioedema
c. urticaria
d. mast cell activation disorder