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Skin Disease in Mastocytosis

  • Zita-Rose Manjaly Thomas
  • Karin Hartmann
Chapter

Abstract

The hallmark of mastocytosis is the pathological accumulation of mast cells in various tissues. The skin is the most frequently affected organ, followed by bone marrow. Cutaneous mast cell infiltration is usually associated with typical skin lesions. According to the morphology of the lesions, three subforms are distinguished, namely maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis and cutaneous mastocytoma. Maculopapular cutaneous mastocytosis is further subdivided into a monomorphic and a polymorphic variant. An important diagnostic feature of all subforms is a positive Darier’s sign. There are significant clinical differences in skin lesions based on the age of disease onset. Paediatric patients often show cutaneous mastocytoma or the polymorphic variant of maculopapular cutaneous mastocytosis, normally without systemic involvement, and a transient disease course with spontaneous remission after several years. By contrast, adults typically present with the monomorphic variant of maculopapular cutaneous mastocytosis, usually associated with systemic mastocytosis and a chronic or progressive course. Patients with skin lesions, regardless of whether bone marrow and other organs are involved, can experience mast cell mediator symptoms such as pruritus, anaphylaxis, flushing and diarrhoea. The current treatment mainly aims at reducing mediator symptoms using antihistamines and, if indicated, also adrenaline, corticosteroids, sodium cromoglycate, specific immunotherapy and omalizumab. Preliminary study results indicate that specific tyrosine kinase inhibitors will soon also become relevant in the treatment of skin involvement in mastocytosis.

Keywords

Childhood-onset mastocytosis Cutaneous mastocytosis Darier’s sign KIT mutation Mast cell Mastocytosis Mastocytosis in the skin Paediatric mastocytosis Tryptase Urticaria pigmentosa 

Abbreviations

ASM

Aggressive SM

DCM

Diffuse cutaneous mastocytosis

ECNM

European Competence Network on Mastocytosis

ISM

Indolent systemic mastocytosis

MCL

Mast cell leukaemia

MPCM

Maculopapular cutaneous mastocytosis

SM

Systemic Mastocytosis

SM-AHN

Systemic mastocytosis with an associated haematological neoplasm

TKI

Tyrosine kinase inhibitors

TMEP

Telangiectasia macularis eruptive perstans

UV

Ultraviolet

WHO

World Health Organization

References

  1. 1.
    Horny HP, Akin C, Arber D, et al. Mastocytosis. In: World Health Organization (WHO) classification of tumours. Pathology & genetics. Tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2016.Google Scholar
  2. 2.
    Valent P, Akin C, Hartmann K, et al. Advances in the classification and treatment of mastocytosis: current status and outlook toward the future. Cancer Res. 2017;77(6):1261–70.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Metcalfe DD, Mekori YA. Pathogenesis and pathology of mastocytosis. Annu Rev Pathol. 2017;12:487–514.PubMedCrossRefGoogle Scholar
  4. 4.
    Hartmann K, Escribano L, Grattan C, et al. Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016;137(1):35–45.PubMedCrossRefGoogle Scholar
  5. 5.
    Galen BT, Rose MG. Darier's sign in mastocytosis. Blood. 2014;123(8):1127.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Nettleship E, Tay W. Rare forms of urticaria. Br Med J. 1869;2:323–30.CrossRefGoogle Scholar
  7. 7.
    Branford WA. Edward Nettleship (1845–1913) and the description of urticaria pigmentosa. Int J Dermatol. 1994;33(3):214–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Sagher F, Even-Paz Z. Mastocytosis and the mast cell. New York: Karger; 1967.Google Scholar
  9. 9.
    Nagata H, Worobec AS, Oh CK, et al. 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 USA. 1995;92(23):10560–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Bodemer C, Hermine O, Palmerini F, et al. Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol. 2010;130(3):804–15.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Arock M, Sotlar K, Akin C, et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015;29(6):1223–32.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Soucie E, Brenet F, Dubreuil P. Molecular basis of mast cell disease. Mol Immunol. 2015;63(1):55–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Hartmann K, Wardelmann E, Ma Y, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology. 2005;129(3):1042–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Halpern AL, Torphy RJ, McCarter MD, Sciotto CG, Glode LM, Robinson WA. A familial germline mutation in KIT associated with achalasia, mastocytosis and gastrointestinal stromal tumors shows response to kinase inhibitors. Cancer Genet. 2019;233–234:1–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Munoz-Gonzalez JI, Jara-Acevedo M, Alvarez-Twose I, et al. Impact of somatic and germline mutations on the outcome of systemic mastocytosis. Blood Adv. 2018;2(21):2814–28.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Wang HJ, Lin ZM, Zhang J, Yin JH, Yang Y. A new germline mutation in KIT associated with diffuse cutaneous mastocytosis in a Chinese family. Clin Exp Dermatol. 2014;39(2):146–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Tang X, Boxer M, Drummond A, Ogston P, Hodgins M, Burden AD. A germline mutation in KIT in familial diffuse cutaneous mastocytosis. J Med Genet. 2004;41(6):e88.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hartmann K, Horny HP, Valent P. Cutaneous mastocytosis. In: WHO classificiaton of skin tumours. Lyon: IARC Press; 2018.Google Scholar
  19. 19.
    Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129(11):1420–7.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Wiechers T, Rabenhorst A, Schick T, et al. Large maculopapular cutaneous lesions are associated with favorable outcome in childhood-onset mastocytosis. J Allergy Clin Immunol. 2015;136(6):1581–1590.e3.PubMedCrossRefGoogle Scholar
  21. 21.
    Marrouche N, Grattan C. TMEP or not TMEP: that is the question. J Am Acad Dermatol. 2014;70(3):581–2.PubMedCrossRefGoogle Scholar
  22. 22.
    Brockow K, Akin C, Huber M, Metcalfe DD. Assessment of the extent of cutaneous involvement in children and adults with mastocytosis: relationship to symptomatology, tryptase levels, and bone marrow pathology. J Am Acad Dermatol. 2003;48(4):508–16.PubMedCrossRefGoogle Scholar
  23. 23.
    Berezowska S, Flaig MJ, Rueff F, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol. 2014;27(1):19–29.PubMedCrossRefGoogle Scholar
  24. 24.
    Valent P, Oude Elberink JNG, Gorska A, et al. The data registry of the European Competence Network on Mastocytosis (ECNM): set up, projects, and perspectives. J Allergy Clin Immunol Pract. 2019;7(1):81–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Brockow K, Scott LM, Worobec AS, et al. Regression of urticaria pigmentosa in adult patients with systemic mastocytosis: correlation with clinical patterns of disease. Arch Dermatol. 2002;138(6):785–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Lange M, Niedoszytko M, Renke J, Glen J, Nedoszytko B. Clinical aspects of paediatric mastocytosis: a review of 101 cases. J Eur Acad Dermatol Venereol. 2013;27(1):97–102.PubMedCrossRefGoogle Scholar
  27. 27.
    Meni C, Bruneau J, Georgin-Lavialle S, et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015;172(3):642–51.PubMedCrossRefGoogle Scholar
  28. 28.
    Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy. 2008;63(2):226–32.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Oropeza AR, Bindslev-Jensen C, Broesby-Olsen S, et al. Patterns of anaphylaxis after diagnostic workup: a follow-up study of 226 patients with suspected anaphylaxis. Allergy. 2017;72(12):1944–52.PubMedCrossRefGoogle Scholar
  30. 30.
    Ludolph-Hauser D, Rueff F, Fries C, Schopf P, Przybilla B. Constitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet. 2001;357(9253):361–2.PubMedCrossRefGoogle Scholar
  31. 31.
    Pardanani A, Shah S, Mannelli F, et al. Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models. Blood Adv. 2018;2(21):2964–72.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Sperr WR, Jordan JH, Fiegl M, et al. Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease. Int Arch Allergy Immunol. 2002;128(2):136–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Carter MC, Clayton ST, Komarow HD, et al. Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. J Allergy Clin Immunol. 2015;136(6):1673–1679.e3.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kristensen T, Vestergaard H, Bindslev-Jensen C, et al. Prospective evaluation of the diagnostic value of sensitive KIT D816V mutation analysis of blood in adults with suspected systemic mastocytosis. Allergy. 2017;72(11):1737–43.PubMedCrossRefGoogle Scholar
  35. 35.
    Erben P, Schwaab J, Metzgeroth G, et al. The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol. 2014;93(1):81–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Kristensen T, Vestergaard H, Moller MB. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn. 2011;13(2):180–8.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Carter MC, Metcalfe DD, Clark AS, Wayne AS, Maric I. Abnormal bone marrow histopathology in paediatric mastocytosis. Br J Haematol. 2015;168(6):865–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Rossini M, Zanotti R, Bonadonna P, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone. 2011;49(4):880–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Rabenhorst A, Christopeit B, Leja S, et al. Serum levels of bone cytokines are increased in indolent systemic mastocytosis associated with osteopenia or osteoporosis. J Allergy Clin Immunol. 2013;132(5):1234–1237.e7.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Czarnetzki BM, Behrendt H. Urticaria pigmentosa: clinical picture and response to oral disodium cromoglycate. Br J Dermatol. 1981;105(5):563–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Broesby-Olsen S, Vestergaard H, Mortz CG, et al. Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations. Allergy. 2018;73(1):230–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Carter MC, Robyn JA, Bressler PB, Walker JC, Shapiro GG, Metcalfe DD. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol. 2007;119(6):1550–1.PubMedCrossRefGoogle Scholar
  43. 43.
    Hermans MAW, Arends NJT, Gerth van Wijk R, et al. Management around invasive procedures in mastocytosis: an update. Ann Allergy Asthma Immunol. 2017;119(4):304–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Hartmann K, Metcalfe DD. Pediatric mastocytosis. Hematol Oncol Clin North Am. 2000;14(3):625–40.PubMedCrossRefGoogle Scholar
  45. 45.
    Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374(26):2530–41.PubMedCrossRefGoogle Scholar
  46. 46.
    Krauth MT, Mirkina I, Herrmann H, Baumgartner C, Kneidinger M, Valent P. Midostaurin (PKC412) inhibits immunoglobulin E-dependent activation and mediator release in human blood basophils and mast cells. Clin Exp Allergy. 2009;39(11):1711–20.PubMedCrossRefGoogle Scholar
  47. 47.
    Peter B, Winter GE, Blatt K, et al. Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth. Leukemia. 2016;30(2):464–72.PubMedCrossRefGoogle Scholar
  48. 48.
    van Anrooij B, Oude Elberink JNG, Span LFR, et al. Midostaurin in patients with indolent systemic mastocytosis: an open-label phase 2 trial. J Allergy Clin Immunol. 2018;142(3):1006–1008.e7.PubMedCrossRefGoogle Scholar
  49. 49.
    Alvarez-Twose I, Gonzalez P, Morgado JM, et al. Complete response after imatinib mesylate therapy in a patient with well-differentiated systemic mastocytosis. J Clin Oncol. 2012;30(12):e126–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Alvarez-Twose I, Matito A, Morgado JM, et al. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget. 2017;8(40):68950–63.PubMedCrossRefGoogle Scholar
  51. 51.
    Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113(23):5727–36.PubMedCrossRefGoogle Scholar
  52. 52.
    Alvarez-Twose I, Vano-Galvan S, Sanchez-Munoz L, et al. Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis. Allergy. 2012;67(6):813–21.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Zita-Rose Manjaly Thomas
    • 1
    • 2
  • Karin Hartmann
    • 3
  1. 1.Division of Allergy, Department of DermatologyUniversity Hospital BaselBaselSwitzerland
  2. 2.Department of BiomedicineUniversity of BaselBaselSwitzerland
  3. 3.Division of Allergy, Department of DermatologyUniversity of BaselBaselSwitzerland

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