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A. Mast Cells [6,8] navigator

  1. Mainly found in tissues, low numbers in blood of normal persons
  2. Usually found beneath epithelial surfaces and near blood vessels
  3. Long lived cells (weeks to months)
  4. Derived from CD34+ bone marrow progenitor cells
    1. Disbursed to tissue as precursor cells, probably related to basophils
    2. Mast cell precursors fully mature in specific tissues
    3. Development requires mast-cell growth factor, the ligand for the c-kit gene
  5. Preformed granules in cytoplasm, released on activation of cells
    1. Have immunoglobulin (Ig) Fc receptors, specific primarily for IgE
    2. Responsible for a variety of IgE dependent and some independent reactions
    3. Mast cell disease usually occurs in skin
    4. Also occurs in skeleton, bone marrow, gastrointestinal (GI) tract, central nervous system
  6. Mast Cell Granule Contents
    1. Histamine and metabolites
    2. Prostaglandin D2 and other arachidonic acid metabolites
    3. Tryptase
    4. Chymase (separate population of mast cells)
    5. Heparin
  7. Mast Cell Cytokine Production
    1. Interleukin (IL-) 1
    2. IL-2 and -3
    3. IL-4 and -5
    4. Granulocyte-macrophage colony stimulating factor (GM-CSF)
    5. Interferon gamma (IFNg)
    6. Tumor necrosis factor (TNF) alpha
  8. No humans with absence of mast cells have been reported
  9. Play key role in common allergic diseases in humans [1,2]
    1. Allergic rhinitis
    2. Allergic
    3. Asthma - mast cell infiltation into smooth muscle likely important in pathogenesis [9]
    4. Urticaria
    5. Eosinophilic bronchitis

B. Reactive Mastocytosis navigator

  1. May be seen in immediate or delayed type hypersensitivity reactions
  2. Found in some patients with benign and malignant tumors, particularly Hodgkin's Disease
  3. Secondary Marrow Mastocytosis
    1. Lymphoproliferative Syndromes - Waldenstrom's Macroglobulinemia, Lymphoma
    2. Stem Cell Diseases - acute myeloid leukemia, myeloproliferative syndromes, including sideroblastic anemia, chronic myelogenous leukemia
    3. Chronic Liver Disease
    4. Chronic Renal Disease
    5. Osteoporosis

C. Symptoms of Mast Cell Diseasenavigator

  1. Cutaneous
    1. Eczema
    2. Pruritis
    3. Dermogrphism
    4. Urticaria
    5. Flushing and diaphoresis
  2. Mediator Release [10]
    1. Flushing
    2. Headache
    3. Dyspnea
    4. Diarrhea
    5. Nausea and vomiting
    6. Palpitations
    7. Tachycardia
    8. Hypotension is not common
  3. Organ infiltration (see below)

D. Mastocytosis [5,6] navigator

  1. Due to mast cell hyperplasia
  2. Classification
    1. Cutaneous only
    2. Systemic - organ involvement, usually bone marrow, GI tract, skeletal
    3. Mastocytosis in association with hematologic involvement
    4. Lymphadenopathic mastocytosis with eosinophilia
    5. Mast cell leukemia
  3. Types of Cutaneous Mastocytosis
    1. Urticaria pigmentosa
    2. Solitary mastocytoma
    3. Diffuse mastocytosis
    4. Telangiectasia macularis eruptiva perstans
  4. Urticaria Pigmentosa
    1. Most common form of cutaneous mastocytosis
    2. Multiple lesions, symmetric and diffuse
    3. Macular, papular or nodular
    4. Usually red-brown hue
    5. Usually occurs in infants and young children
    6. Diagnosis by biopsy of lesional skin
  5. Solitary Mastocytoma
    1. <5% of cutaneous mastocytosis
    2. Usually at birth or within weeks
    3. Isolated brown nodules
  6. Diffuse Erythrodermic cutaneous mastocytosis
    1. Generalized infiltration of skin, soft or doughy thickening
    2. Red-brown or yellow hue
    3. May be associated with systemic disease

E. Systemic Mastocytosis navigator

  1. May develop from localized disease, usually in adults, not children
  2. About 30% of cases occur with hematologic disorder, usually of myeloid origin [11]
  3. Symptoms [3,10]
    1. Likely due to histamine (and prostaglandin) excess
    2. Flushing, dizziness, headache, palpitations nearly always
    3. Hives, pruritis; dyspnea can occur, but frank bronchospasm is rare
    4. Abdominal pain and cramping, nausea, vomiting
    5. Hypersplenism may occur [3]
    6. Hypersecretion of gastric acid may be seen
    7. Hypotension and/or bradycardia - may manifest as syncope
    8. May progress to circulatory collapse and shock
  4. Many patients have idiosyncratic response to aspirin with hypotension and flushing
    1. Thought to be due to release of large quantities of prostaglandins
    2. Calcitonin Gene Related Peptide (CGRP) and calcitonin may also paly a role [4,5]
  5. Laboratory Evaluation
    1. Eosinophilia ~25% of patients
    2. ESR normal, may have mildly elevated liver function tests
    3. Diagnosis is suggested by documenting increased urinary histamines [6]
    4. Serum histamine levels may also be elevated (normal levels 0.11-0.50 ng/mL)
    5. Serum tryptase levels are typically elevated
    6. Mast cell numbers increased on skin biopsy ("urticaria pigmentosa")
    7. Bone marrow must confirm diagnosis and rule out neoplastic conditions
    8. Immunohistochemistry with CD117 markers confirm bone marrow diagnosis
    9. Mutations in c-kit may be present
  6. Therapy
    1. Anti-H1 histamines: high doses
    2. Adjunctive Histamine H2-blockers (probably additive with H1 blockers)
    3. Cyclooxygenase (prostaglandin) inhibitors - NSAIDs
    4. Glucocorticoids in severe cases
    5. c-kit inhibitor imatinib
  7. Imatinib (Gleevec®) [12]
    1. Activating mutations in c-kit receptor implicated in mast cell disease
    2. 50% response in 10 patients with systmic mast cell disease (100mg or 400mg qd dose)
    3. 2 patients had complete clinical and histological remission
    4. Patients with c-kit mutations did not respond to the treatment
  8. Prognosis
    1. Majority of patients have slow progression
    2. Better prognosis in absence of associated hematologic disorder
    3. Mast cell leukemia has a poorer prognosis
    4. Progressive involvement of internal organs has worse prognosis

References navigator

  1. Kay AB. 2001. NEJM. 344(1):30 abstract
  2. Kay AB. 2001. NEJM. 344(2):109 abstract
  3. Sawalha AH, Bronze MS, Saint S, et al. 2003. NEJM. 349(23):2253 (Case Discussion) abstract
  4. Yocum MW, Butterfield JH, Gharib H. 1994. Mayo Clin Proc. 69:987 abstract
  5. Butterfield JH, Kao PC, Klee GG, Yocum MW. 1995. Mayo Clin Proc. 70(5):481 abstract
  6. Golkar L and Bernhard JD. 1997. Lancet. 349:1379 abstract
  7. Leung DYM, Diaz LA, DeLeo V, Soter NA. 1997. JAMA. 278(22):1914 abstract
  8. Busse WW and Lemanske RF. 2001. NEJM. 344(5):350 abstract
  9. Brightling CE, Bradding P, Symon FA, et al. 2002. NEJM. 346(22):1699 abstract
  10. Koide T, Nakajima T, Makifuchi T, Fukuhara N. 2002. Lancet. 359(9323):2084 abstract
  11. Pardanani A, Baek JY, Li CY, et al. 2002. Mayo Clin Proc. 77:1169 abstract
  12. Pardanani A, Elliott M, Reeder T, et al. 2003. Lancet. 362(9383):535 abstract