Clinical Reviews in Allergy & Immunology

, Volume 38, Issue 2–3, pp 125–134 | Cite as

Contemporary Challenges in Mastocytosis

  • H. David Pettigrew
  • Suzanne S. Teuber
  • James S. Kong
  • M. Eric Gershwin
Article

Abstract

Mastocytosis denotes a wide range of disorders characterized by having abnormal growth and accumulation of mast cells. Mast cells contain histamine and other inflammatory mediators, which have diverse actions within the body, and play crucial roles in acquired and innate immunity. The diverse actions of these inflammatory mediators can lead to puzzling symptoms in individuals with mastocytosis. These symptoms can include flushing, pruritis, nausea, vomiting, abdominal pain, diarrhea, vascular instability, and headache. These clinical features generally divide into cutaneous and systemic manifestations, giving rise to the two divisions of mastocytosis: cutaneous mastocytosis (CM) and systemic mastocytosis. CM has a highly favorable clinical prognosis. Systemic mastocytosis has a range of severity, with the milder forms often remaining chronic conditions, while the severe forms have rapid complex courses with poor prognoses. Generally, treatment is aimed at avoiding mast cell degranulation, inhibiting the actions of the constitutive mediators released by mast cells and, in severe cases, cytoreductive and polychemotherapeutic agents. Behavioral intervention includes avoidance of triggers, such as heat, cold, pressure, exercise, sunlight, and strong emotions. Treatment for released histamine and other inflammatory mediators includes H1 antihistamines, H2 antihistamines, proton pump inhibitors, anti-leukotriene agents, and injectible epinephrine (for possible anaphylaxis). For severe cases, treatment includes cytoreductive agents (interferon alpha, glucocorticoids, and cladribine) and polychemotherapeutic agents (daunomycin, etoposide, and 6-mercaptopurine). For very specific and severe cases, tyrosine kinase inhibitors, imatinib and midostaurine, have shown promise.

Keywords

Mastocytosis IgE Tryptase 

References

  1. 1.
    Nettleship E, Tay W (1869) Rare forms of urticaria. Br Med J 2:323–330CrossRefGoogle Scholar
  2. 2.
    Unna PG (1894) Die spezifische farbung der mastzellenkornung. Monatsh Prakt Dermatol 19:367–368Google Scholar
  3. 3.
    Ellis JM (1949) Urticaria pigmentosa: a report of a case with autopsy. AMA Arch Pathol 48:426–435Google Scholar
  4. 4.
    Metcalfe DD (2008) Mast cells and mastocytosis. Blood 112(4):946–956CrossRefPubMedGoogle Scholar
  5. 5.
    Jorpes J (1939) The site of formation of heparin. In: Jorpes JE (ed) Heparin: its chemistry, physiology, and application in medicine. Oxford University Press, Oxford, pp 30–39Google Scholar
  6. 6.
    Riley JF (1953) Histamine in tissue mast cells. Science 118(3064):332CrossRefPubMedGoogle Scholar
  7. 7.
    Valent P, Sillaber C, Bettelheim P (1991) The growth and differentiation of mast cells. Prog Growth Factor Res 3(1):27–41CrossRefPubMedGoogle Scholar
  8. 8.
    Kirshenbaum AS et al (1999) Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13). Blood 94(7):2333–2342PubMedGoogle Scholar
  9. 9.
    Kirshenbaum AS et al (1991) Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol 146(5):1410–1415PubMedGoogle Scholar
  10. 10.
    Saavedra-Delgado AM, Turpin S, Metcalfe DD (1984) Typical and atypical mast cells of the rat gastrointestinal system: distribution and correlation with tissue histamine. Agents Actions 14(1):1–7CrossRefPubMedGoogle Scholar
  11. 11.
    Metcalfe DD, Baram D, Mekori YA (1997) Mast cells. Physiol Rev 77(4):1033–1079PubMedGoogle Scholar
  12. 12.
    Kirshenbaum AS et al (1992) Effect of IL-3 and stem cell factor on the appearance of human basophils and mast cells from CD34+ pluripotent progenitor cells. J Immunol 148(3):772–777PubMedGoogle Scholar
  13. 13.
    Valent P et al (1992) Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood 80(9):2237–2245PubMedGoogle Scholar
  14. 14.
    Sperr WR et al (2001) Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk Res 25(7):529–536CrossRefPubMedGoogle Scholar
  15. 15.
    Furitsu T et al (1993) Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest 92(4):1736–1744CrossRefPubMedGoogle Scholar
  16. 16.
    Longley BJ et al (1996) Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 12(3):312–314CrossRefPubMedGoogle Scholar
  17. 17.
    Nagata H et al (1995) Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A 92(23):10560–10564CrossRefPubMedGoogle Scholar
  18. 18.
    Echtenacher B, Mannel DN, Hultner L (1996) Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381(6577):75–77CrossRefPubMedGoogle Scholar
  19. 19.
    Varadaradjalou S et al (2003) Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. Eur J Immunol 33(4):899–906CrossRefPubMedGoogle Scholar
  20. 20.
    Kulka M et al (2004) Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol 114(1):174–182CrossRefPubMedGoogle Scholar
  21. 21.
    Metcalfe DD (1991) Classification and diagnosis of mastocytosis: current status. J Invest Dermatol 96(3):2S–4SCrossRefGoogle Scholar
  22. 22.
    Valent P et al (2001) Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 25(7):603–625CrossRefPubMedGoogle Scholar
  23. 23.
    Kong JS et al (2006) Mastocytosis: the great masquerader. Clin Rev Allergy Immunol 30(1):53–60CrossRefPubMedGoogle Scholar
  24. 24.
    Horny HP, Sotlar K, Valent P (2007) Mastocytosis: state of the art. Pathobiology 74(2):121–132CrossRefPubMedGoogle Scholar
  25. 25.
    Hartmann K, Metcalfe DD (2000) Pediatric mastocytosis. Hematol Oncol Clin North Am 14(3):625–640CrossRefPubMedGoogle Scholar
  26. 26.
    Wolff K, Komar M, Petzelbauer P (2001) Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res 25(7):519–528CrossRefPubMedGoogle Scholar
  27. 27.
    Hartmann K, Henz BM (2002) Cutaneous mastocytosis—clinical heterogeneity. Int Arch Allergy Immunol 127(2):143–146CrossRefPubMedGoogle Scholar
  28. 28.
    Roupe G, Granerus G, Olafson JH (1983) Urticaria pigmentosa or systemic mastocytosis? J Am Acad Dermatol 8(1):137CrossRefPubMedGoogle Scholar
  29. 29.
    Brockow K (2004) Urticaria pigmentosa. Immunol Allergy Clin North Am 24(2):287–316 viiCrossRefPubMedGoogle Scholar
  30. 30.
    Topar G et al (1998) Urticaria pigmentosa: a clinical, hematopathologic, and serologic study of 30 adults. Am J Clin Pathol 109(3):279–285PubMedGoogle Scholar
  31. 31.
    Findlay GH, Schulz EJ, Pepler WJ (1960) Diffuse cutaneous mastocytosis. S Afr Med J 34:353–356PubMedGoogle Scholar
  32. 32.
    Waxtein LM et al (2000) Diffuse cutaneous mastocytosis with bone marrow infiltration in a child: a case report. Pediatr Dermatol 17(3):198–201CrossRefPubMedGoogle Scholar
  33. 33.
    Willemze R et al (1980) Diffuse cutaneous mastocytosis with multiple cutaneous mastocytomas. Report of a case with clinical, histopathological and ultrastructural aspects. Br J Dermatol 102(5):601–607CrossRefPubMedGoogle Scholar
  34. 34.
    Scheck O et al (1987) Solitary mastocytoma of the eyelid. A case report with special reference to the immunocytology of human tissue mast cells, and a review of the literature. Virchows Arch A Pathol Anat Histopathol 412(1):31–36CrossRefPubMedGoogle Scholar
  35. 35.
    Sperr WR et al (2002) Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease. Int Arch Allergy Immunol 128(2):136–141CrossRefPubMedGoogle Scholar
  36. 36.
    Schwartz LB (2006) Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am 26(3):451–463CrossRefPubMedGoogle Scholar
  37. 37.
    Schwartz LB et al (1995) The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest 96(6):2702–2710CrossRefPubMedGoogle Scholar
  38. 38.
    Schwartz LB et al (1987) Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med 316(26):1622–1626PubMedGoogle Scholar
  39. 39.
    Schwartz LB (1994) Tryptase: a clinical indicator of mast cell-dependent events. Allergy Proc 15(3):119–123CrossRefPubMedGoogle Scholar
  40. 40.
    Akin C, Metcalfe DD (2004) Systemic mastocytosis. Annu Rev Med 55:419–432CrossRefPubMedGoogle Scholar
  41. 41.
    Stevens EC, Rosenthal NS (2001) Bone marrow mast cell morphologic features and hematopoietic dyspoiesis in systemic mast cell disease. Am J Clin Pathol 116(2):177–182CrossRefPubMedGoogle Scholar
  42. 42.
    Pardanani A et al (2003) Differential expression of CD2 on neoplastic mast cells in patients with systemic mast cell disease with and without an associated clonal haematological disorder. Br J Haematol 120(4):691–694CrossRefPubMedGoogle Scholar
  43. 43.
    Jordan JH et al (2001) Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L). Hum Pathol 32(5):545–552CrossRefPubMedGoogle Scholar
  44. 44.
    Longley BJ Jr et al (1999) Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A 96(4):1609–1614CrossRefPubMedGoogle Scholar
  45. 45.
    Akin C et al (2000) Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis. Exp Hematol 28(2):140–147CrossRefPubMedGoogle Scholar
  46. 46.
    Feger F et al (2002) Kit and c-kit mutations in mastocytosis: a short overview with special reference to novel molecular and diagnostic concepts. Int Arch Allergy Immunol 127(2):110–114CrossRefPubMedGoogle Scholar
  47. 47.
    Kemmer K et al (2004) KIT mutations are common in testicular seminomas. Am J Pathol 164(1):305–313PubMedGoogle Scholar
  48. 48.
    Horny HP et al (2003) Increase of bone marrow lymphocytes in systemic mastocytosis: reactive lymphocytosis or malignant lymphoma? Immunohistochemical and molecular findings on routinely processed bone marrow biopsy specimens. J Clin Pathol 56(8):575–578CrossRefPubMedGoogle Scholar
  49. 49.
    Sagher F, Cohen C, Schorr S (1952) Concomitant bone changes in urticaria pigmentosa. J Invest Dermatol 18(6):425–432PubMedGoogle Scholar
  50. 50.
    Escribano L et al (1998) Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood 91(8):2731–2736PubMedGoogle Scholar
  51. 51.
    Horny HP et al (2004) Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: a histopathological challenge. J Clin Pathol 57(6):604–608CrossRefPubMedGoogle Scholar
  52. 52.
    Horny HP et al (1990) Blood findings in generalized mastocytosis: evidence of frequent simultaneous occurrence of myeloproliferative disorders. Br J Haematol 76(2):186–193CrossRefPubMedGoogle Scholar
  53. 53.
    Sperr WR et al (2000) Clinical and biologic diversity of leukemias occurring in patients with mastocytosis. Leuk Lymphoma 37(5–6):473–486PubMedGoogle Scholar
  54. 54.
    Travis WD et al (1986) Mast cell leukemia: report of a case and review of the literature. Mayo Clin Proc 61(12):957–966PubMedGoogle Scholar
  55. 55.
    Worobec AS (2000) Treatment of systemic mast cell disorders. Hematol Oncol Clin North Am 14(3):659–687 viiCrossRefPubMedGoogle Scholar
  56. 56.
    Guenther PP et al (2001) Temporary response of localized intracranial mast cell sarcoma to combination chemotherapy. J Pediatr Hematol Oncol 23(2):134–138CrossRefPubMedGoogle Scholar
  57. 57.
    Horny HP et al (1986) Mast cell sarcoma of the larynx. J Clin Pathol 39(6):596–602CrossRefPubMedGoogle Scholar
  58. 58.
    Kojima M et al (1999) Mast cell sarcoma with tissue eosinophilia arising in the ascending colon. Mod Pathol 12(7):739–743PubMedGoogle Scholar
  59. 59.
    Wolff K (2002) Treatment of cutaneous mastocytosis. Int Arch Allergy Immunol 127(2):156–159CrossRefPubMedGoogle Scholar
  60. 60.
    Castells M, Akin C (2008) Treatment and prognosis of mastocytosis (cutaneous and systemic). Up to Date; www.utdol.com, accessed 9 Apr 2009
  61. 61.
    Valent P et al (2007) Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 37(6):435–453CrossRefPubMedGoogle Scholar
  62. 62.
    Wilson TM, Metcalfe DD, Robyn J (2006) Treament of systemic mastocytosis. Immunol Allergy Clin Nort Am 26(3):549-573CrossRefGoogle Scholar
  63. 63.
    Pardanani A, Akin C, Valent P (2006) Pathogenesis, clinical features, and treatment advances in mastocytosis. Best Pract Res Clin Haematol 19(3):595-615CrossRefPubMedGoogle Scholar
  64. 64.
    Gonzalez de Olano D et al (2008) Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytois presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol 121(2):519-526CrossRefPubMedGoogle Scholar
  65. 65.
    Kluin-Nelemans HC et al (1992) Response to interferon alfa-2b in a patient with systemic mastocytosis. N Engl J Med 326(9):619–623PubMedCrossRefGoogle Scholar
  66. 66.
    Tefferi A et al (2001) Treatment of systemic mast-cell disease with cladribine. N Engl J Med 344(4):307–309CrossRefPubMedGoogle Scholar
  67. 67.
    Kluin-Nelemans HC et al (2003) Cladribine therapy for systemic mastocytosis. Blood 102(13):4270–4276CrossRefPubMedGoogle Scholar
  68. 68.
    Valent P et al (2003) Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 122(5):695–717CrossRefPubMedGoogle Scholar
  69. 69.
    Pardanani A et al (2003) Imatinib for systemic mast-cell disease. Lancet 362(9383):535–536CrossRefPubMedGoogle Scholar
  70. 70.
    Akin C et al (2004) A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood 103(8):3222–3225CrossRefPubMedGoogle Scholar
  71. 71.
    Ma Y et al (2002) The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 99(5):1741–1744CrossRefPubMedGoogle Scholar
  72. 72.
    Akin C et al (2003) Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol 31(8):686–692CrossRefPubMedGoogle Scholar
  73. 73.
    Musto P et al (2004) Inefficacy of imatinib-mesylate in sporadic, aggressive systemic mastocytosis. Leuk Res 28(4):421–422CrossRefPubMedGoogle Scholar
  74. 74.
    Gotlib J et al (2005) Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood 106(8):2865–2870CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • H. David Pettigrew
    • 1
  • Suzanne S. Teuber
    • 1
  • James S. Kong
    • 1
  • M. Eric Gershwin
    • 1
  1. 1.Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California at Davis School of MedicineDavisUSA

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