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Table of Contents
Vol. 74, No. 2, 2007
Issue release date: June 2007
Section title: Review
Pathobiology 2007;74:121–132
(DOI:10.1159/000101711)

Mastocytosis: State of the Art

Horny H.-P.a · Sotlar K.b · Valent P.c
aInstitute of Pathology, Ansbach, and bInstitute of Pathology, University of Tübingen, Tübingen, Germany; cDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
email Corresponding Author

Abstract

Mastocytosis is a neoplastic disease involving mast cells (MC) and their CD34+ progenitors. Symptoms in mastocytosis are caused by biological mediators released from MC and/or the infiltration of neoplastic MC in various organs, the skin and the bone marrow being predominantly involved. A WHO consensus classification for mastocytosis exists, which is widely accepted and includes three major categories: (1) Cutaneous mastocytosis (CM), a benign disease in which MC infiltration is confined to the skin, is preferentially seen in young children and exhibits a marked tendency to regress spontaneously. (2) Systemic mastocytosis (SM) which is commonly diagnosed in adults and includes four major subtypes: (i) indolent SM (ISM, the most common form involving mainly skin and bone marrow); (ii) a unique subcategory termed SM with an associated non-mast cell clonal hematological disease (SM-AHNMD); (iii) aggressive SM usually presenting without skin lesions, and (iv) MC leukemia, probably representing the rarest variant of human leukemias. (3) The extremely rare localized extracutaneous MC neoplasms, either presenting as malignancy (MC sarcoma) or as benign tumor termed extracutaneous mastocytoma. Diagnostic criteria for mastocytosis are available and are widely accepted. SM criteria include one major criterion (multifocal compact tissue infiltration by MC) and four minor criteria: (1) prominent spindling of MC; (2) atypical immunophenotype of MC with coexpression of CD2 and/or CD25 (antigens which have not been found to be expressed on normal/reactive MC); (3) activating (somatic) point mutations of the c-kit proto-oncogene usually involving exon 17, with the imatinib-resistant type D816V being most frequent, and (4) persistently elevated serum tryptase level (>20 ng/ml). To establish the diagnosis of SM, at least one major and one minor criterion, or at least three minor criteria, have to be fulfilled. The natural clinical course of mastocytosis is variable. Most patients, in particular those with CM and ISM, remain in an indolent stage over many years or even decades, while others, in particular those with aggressive SM, SM-AHNMD, or mast cell leukemia, show a progressive course, usually with a fatal outcome.

© 2007 S. Karger AG, Basel


  

Key Words

  • Mastocytosis
  • Bone marrow
  • Immunohistochemistry
  • Mast cell
  • Systemic mastocytosis

References

  1. Valent P, Sillaber C, Bettelheim P: The growth and differentiation of mast cells. Prog Growth Factor Res 1991;3:27–41.
  2. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, Metcalfe DD: 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 1995;96:2702–2710.
  3. Sperr WR, Jordan JH, Fiegl M, Escribano L, Dirnhofer S, Semper H, 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;128:136–141.
  4. Kirshenbaum AS, Goff JP, Kessler SW, Mican JM, Zsebo KM, Metcalfe DD: Effects of IL-3 and stem cell factor on the appearance of human basophils and mast cells from CD34+ pluripotent progenitor cells. J Immunol 1992;148:772–777.
  5. Rottem M, Okada T, Goff JP, Metcalfe DD: Mast cells cultured from peripheral blood of normal donors and patients with mastocytosis originate from a CD34+/FcεRI cell population. Blood 1994;84:2489–2496.
  6. Valent P, Spanblöchl E, Sperr WR, Sillaber CH, Agis H, Zsebo K, et al: 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 1992;80:2237–2245.
  7. Sperr WR, Escribano L, Jordan JH, Schernthaner GH, Kundi M, Horny H-P, Valent P: Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk Res 2001;25:529–536.
  8. Valent P, Horny H-P, Li CY, Longley JB, Metcalfe DD, Parwaresch RM, Bennett JM: Mastocytosis (mast cell disease). World Health Organization Classification of Tumours: Pathology and Genetics; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): Tumours of Haematopoietic and Lymphoid Tissues. Geneva, WHO, 2001, vol 1, pp 291–302.
  9. Valent P, Horny H-P, Escribano L, Longley JB, Li CY, Schwartz LB, et al: Diagnostic criteria and classification of mastocytosis: a consensus proposal. Conference Report of ‘Year 2000 Working Conference on Mastocytosis’. Leuk Res 2001;25:603–625.
  10. Valent P, Akin C, Sperr WR, Horny H-P, Metcalfe DD: Mast cell proliferative disorders: current view on variants recognized by the World Health Organization. Hematol Oncol Clin North Am 2003;17:1227–1241.
  11. Horny H-P, Valent P: Diagnosis of mastocytosis: General histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res 2001;25:543–551.
  12. Horny H-P, Lange K, Sotlar K, Valent P: Increase of bone marrow lymphocytes in systemic mastocytosis: reactive lymphocytosis or malignant lymphoma? Immuno-histochemical and molecular findings on routinely processed bone marrow biopsy specimens. J Clin Pathol 2003;56:575–578.
  13. Jordan JH, Sperr WR, Lechner K, Geissler K, Schernthaner G-H, Fritsche-Polanz R, et al: Stem cell factor-induced bone marrow mast cell hyperplasia mimicking systemic mastocytosis (SM): histopathologic and morphologic evaluation with special reference to novel SM criteria. Leuk Lymphoma 2002;43:575–582.
  14. Horny H-P, Sillaber C, Menke D, Kaiserling E, Wehrmann M, Stehberger B, et al: Diagnostic utility of staining for tryptase in patients with mastocytosis. Am J Surg Pathol 1998;22:1132–1140.
  15. Li C-Y: Diagnosis of mastocytosis: value of cytochemistry and immunohistochemistry. Leuk Res 2001;25:537–541.
  16. Sotlar K, Horny H-P, Simonitsch I, Krokowski M, Aichberger KJ, Mayerhofer M, Printz D, Fritsch G, Valent P: CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis in routinely processed bone marrow biopsy specimens. Am J Surg Pathol 2004;28:1319–1325.
  17. Jordan H, Walchshofer S, Jurecka W, Mosberger I, Sperr WR, Wolff K, et al: Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-xL. Hum Pathol 2001;32:545–552.
  18. Sotlar K, Escribano L, Landt O, Möhrle S, Herrero S, Torrelo A, Lass ,Horny H-P, Bültmann B: One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J Pathol 2003;162:737–746.
  19. Sotlar K, Marafioti T, Griesser H, Theil J, Aepinus C, Jaussi R, et al: Detection of c-kit mutation Asp-816-Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukemia. Mol Pathol 2000;53:188–193.
  20. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD: 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;92:10560–10564.
  21. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al: Somatic c-kit activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996;12:312–314.
  22. Longley BJ, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu S-Z, et al: Activating and dominant inactivating c-kit catalytic domain mutations in distinct forms of human mastocytosis. Proc Natl Acad Sci USA 1999;96:1609–1614.
  23. Feger F, Ribadeau Dumas A, Leriche L, Valent P, Arock M: Kit and c-kit mutations in mastocytosis: a short overview with special reference to novel molecular and diagnostic concepts. Int Arch Allergy Immunol 2002;127:110–114.
  24. Longley BJ, Reguera MJ, Ma Y: Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. Leuk Res 2001;25:571–576.
  25. Akin C, Brockow K, D’Ambrosio C, Kirshenbaum AS, Ma Y, Longley BJ, Metcalfe DD: Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol 2003;31:686–692.
  26. Kemmer K, Corless CL, Fletcher JA, McGreevey L, Haley A, Griffith D, Cummings OW, Wait C, Town A, Heinrich MC: Kit mutations are common in testicular seminomas. Am J Pathol 2004;164:305–313.
  27. Bernd HW, Sotlar K, Lorenzen J, Osieka R, Fabry U, Valent P, Horny H-P: Acute myeloid leukaemia with t(8;21) associated with ‘occult’ mastocytosis. Report of an unusual case and review of the literature. J Clin Pathol 2004;57:324–328.
  28. Wang YY, Zhou GB, Yin T, Chen B, Shi JY, Liang WX, Jin XL, You JH, Shen ZX, Chen J, Xiong SM, Chen GQ, Xu F, Liu YW, Chen Z, Chen SJ: AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA 2005;102:1104–1109.
  29. Schnittger S, Kohl TM, Haferlach T, Kern W, Hiddemann W, Spiekermann K, Schoch C: KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 2006;107:1791–1799.
  30. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD: A novel form of mastocytosis associated with a transmembrane c-Kit mutation and response to imatinib. Blood 2004;103:3222–3225.
  31. Sperr WR, Stehberger B, Wimazal F, Baghestanian M, Schwartz LB, Kundi M, et al: Serum tryptase measurements in patients with myelodysplastic syndromes. Leuk Lymphoma 2002;43:1097–1105.
  32. Wolff K, Komar M, Petzelbauer P: Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res 2001;25:519–528.
  33. Hartmann K, Henz BM: Cutaneous mastocytosis – clinical heterogeneity. Int Arch Allergy Immunol 2002;127:143–146.
  34. Escribano L, Orfao A, Diaz-Agustin B, Villarrubia J, Cervero C, Lopez A, et al: Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implication. Blood 1998;91:2731–2736.
  35. Valent P, Akin C, Sperr WR, Escribano L, Arock M, Horny HP, Bennett JM, Metcalfe DD: Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res 2003;27:635–641.
  36. Hauswirth A, Sperr WR, Ghannadan M, Schernthaner G-H, Jordan JH, Fritsche-Planz R, et al: A case of smouldering mastocytosis with peripheral blood eosinophilia and lymphadenopathy. Leuk Res 2002;26:601–606.
  37. Horny H-P, Sotlar K, Sperr WR, Valent P: systemic mastocytosis with associated clonal haematological non-mast cell lineage disease (SM-AHNMD): a histopathological challenge. J Clin Pathol 2004;57:604–608.
  38. Horny H-P, Ruck M, Wehrmann M, Kaiserling E: Blood findings in generalized mastocytosis: evidence of frequent simultaneous occurrence of myeloproliferative disorders. Br J Haematol 1990;76:186–193.
  39. Sperr WR, Horny H-P, Lechner K, Valent P: Clinical and biologic diversity of leukemias occurring in patients with mastocytosis. Leuk Lymphoma 2000;37:473–486.
  40. Tefferi A, Pardanani A: Clinical, genetic, and therapeutic insights into systemic mast cell disease. Curr Opin Hematol 2004;11:58–64.
  41. Akin C, Kirshenbaum AS, Semere T, Worobec AS, Scott LM, Mwetcalfe DD: Analysis of the surface expression of c-kit and the c-kit Asp816Val activating mutationin T cells, B cells, and myelomonocytic cells in patients with mastocytosis. Exp Hematol 2000;28:140–147.
  42. Travis WD, Li CY, Hogaland HC, Travis LB, Banks PM: Mast cell leukemia: report of a case and review of the literature. Mayo Clin Proc 1986;61:957–966.
  43. Horny H-P, Parwaresch MR, Kaiserling E, Muller K, Olbermann M, Mainzer K, Lennert K: Mast cell sarcoma of the larynx. J Clin Pathol 1986;39:596–602.
  44. Kojima M, Nakamura S, Itoh H, Ohno Y, Masawa N, Joshita T, Suchi T: Mast cell sarcoma with tissue eosinophilia arising in the ascending colon. Modern Pathology 1999;12:739–743.
  45. Guenther PP, Huebner A, Sobottka SB, Neumeister V, Weissbach G, Todt H, Parwaresch MR: Temporary response of localized intracranial mast cell sarcoma to combination chemotherapy. J Pediatr Hematol Oncol 2001;23:134–138.
  46. Akin C, Scott LM, Metcalfe DD: Slowly progressing mastocytosis with high mast cell burden and no evidence of a non-mast cell hematologic disorder: an example of a smoldering case? Leuk Res 2001;25:635–638.
  47. Jordan JH, Fritsche-Polanz R, Sperr WR, Mitterbauer G, Födinger M, Schernthaner GH, et al: A case of smouldering mastocytosis with high mast cell burden, monoclonal myeloid cells, and c-kit mutation Asp-816-Val. Leuk Res 2001;25:627–634.
  48. Akin C, Metcalfe DD: Occult bone marrow mastocytosis presenting as recurrent systemic anaphylaxis. J Allergy Clin Immunol 2003;111:S206.

    External Resources

  49. Sotlar K, Saeger W, Stellmacher F, Stahmer J, Jäckle S, Valent P, Horny H-P: ‘Occult’ mastocytosis with activating c-kit point mutation evolving into systemic mastocytosis associated with plasma cell myeloma and secondary amyloidosis. J Clin Pathol 2006;59:875–878.
  50. Valent P, Samorapoompichit P, Sperr WR, Horny H-P, Lechner K: Myelomastocytic leukemia: myeloid neoplasm characterized by partial differentiation of mast cell-lineage cells. Hematol J 2002;3:90–94.
  51. Sperr WR, Jordan JH, Baghestanian M, Kiener H, Samorapoompichit P, Semper H, et al: Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia. Blood 2001;98:2200–2209.
  52. Horny H-P, Sotlar K, Stellmacher F, Krokowski M, Agis H, Schwartz LB, Valent P: The tryptase-positive compact round cell infiltrate of the bone marrow (TROCI-bm): a novel histopathological finding requiring the application of lineage specific markers. J Clin Pathol 2006;59:98–302.
  53. Valent P, Akin C, Sperr WR, Horny H-P, Arock M, Lechner K, Bennett JM, Metcalfe DD: Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003;122:1–23.
  54. Worobec AS: Treatment of systemic mast cell disorders. Hematol Oncol North Am 2000;14:659–687.
  55. Escribano L, Akin C, Castells M, Orfao A, Metcalfe DD: Mastocytosis: current concepts in diagnosis and treatment. Ann Hematol 2002;81:677–690.
  56. Casassus P, Caillat-Vigneron N, Martin A, Simon J, Gallais V, Beaudry P, et al: Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol 2002;119:1090–1097.
  57. Butterfield JH: Response of severe systemic mastocytosis to interferon-α. Br J Dermatol 1998;138:489–495.
  58. Hauswirth AW, Simonitsch-Klupp I, Uffmann M, Koller E, Sperr WR, Lechner K, Valent P: Response to therapy with interferon-alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res 2004;28:249–257.
  59. Tefferi A, Li CY, Butterfield JH, Hoagland HC: Treatment of systemic mast-cell disease with cladribine. N Engl J Med 2001;344:307–309.
  60. Tefferi A: Treatment of systemic mast cell disease: beyond interferon. Leuk Res 2004;28:223–224.
  61. Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM, et al: CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 2003;102:3093–3096.
  62. Gotlib J, Berube C, Growney JD, et al: Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood 2005;106:2865–2870.

  

Author Contacts

Hans-Peter Horny, MD
Institut für Pathologie, Klinikum Ansbach
Escherichstrasse 6
DE–91522 Ansbach (Germany)
Tel. +49 981 488 830, Fax +49 981 4888 310, E-Mail horny@pathologie-ansbach.com

  

Article Information

Number of Print Pages : 12
Number of Figures : 4, Number of Tables : 3, Number of References : 62

  

Publication Details

Pathobiology

Vol. 74, No. 2, Year 2007 (Cover Date: June 2007)

Journal Editor: Yasui, W. (Hiroshima)
ISSN: 1015–2008 (print), 1423–0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Mastocytosis is a neoplastic disease involving mast cells (MC) and their CD34+ progenitors. Symptoms in mastocytosis are caused by biological mediators released from MC and/or the infiltration of neoplastic MC in various organs, the skin and the bone marrow being predominantly involved. A WHO consensus classification for mastocytosis exists, which is widely accepted and includes three major categories: (1) Cutaneous mastocytosis (CM), a benign disease in which MC infiltration is confined to the skin, is preferentially seen in young children and exhibits a marked tendency to regress spontaneously. (2) Systemic mastocytosis (SM) which is commonly diagnosed in adults and includes four major subtypes: (i) indolent SM (ISM, the most common form involving mainly skin and bone marrow); (ii) a unique subcategory termed SM with an associated non-mast cell clonal hematological disease (SM-AHNMD); (iii) aggressive SM usually presenting without skin lesions, and (iv) MC leukemia, probably representing the rarest variant of human leukemias. (3) The extremely rare localized extracutaneous MC neoplasms, either presenting as malignancy (MC sarcoma) or as benign tumor termed extracutaneous mastocytoma. Diagnostic criteria for mastocytosis are available and are widely accepted. SM criteria include one major criterion (multifocal compact tissue infiltration by MC) and four minor criteria: (1) prominent spindling of MC; (2) atypical immunophenotype of MC with coexpression of CD2 and/or CD25 (antigens which have not been found to be expressed on normal/reactive MC); (3) activating (somatic) point mutations of the c-kit proto-oncogene usually involving exon 17, with the imatinib-resistant type D816V being most frequent, and (4) persistently elevated serum tryptase level (>20 ng/ml). To establish the diagnosis of SM, at least one major and one minor criterion, or at least three minor criteria, have to be fulfilled. The natural clinical course of mastocytosis is variable. Most patients, in particular those with CM and ISM, remain in an indolent stage over many years or even decades, while others, in particular those with aggressive SM, SM-AHNMD, or mast cell leukemia, show a progressive course, usually with a fatal outcome.

© 2007 S. Karger AG, Basel


  

Author Contacts

Hans-Peter Horny, MD
Institut für Pathologie, Klinikum Ansbach
Escherichstrasse 6
DE–91522 Ansbach (Germany)
Tel. +49 981 488 830, Fax +49 981 4888 310, E-Mail horny@pathologie-ansbach.com

  

Article Information

Number of Print Pages : 12
Number of Figures : 4, Number of Tables : 3, Number of References : 62

  

Publication Details

Pathobiology

Vol. 74, No. 2, Year 2007 (Cover Date: June 2007)

Journal Editor: Yasui, W. (Hiroshima)
ISSN: 1015–2008 (print), 1423–0291 (Online)

For additional information: http://www.karger.com/PAT


Article / Publication Details

First-Page Preview
Abstract of Review

Received: 11/30/2006
Accepted: 1/18/2007
Published online: 6/25/2007
Issue release date: June 2007

Number of Print Pages: 12
Number of Figures: 4
Number of Tables: 3

ISSN: 1015-2008 (Print)
eISSN: 1423-0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Valent P, Sillaber C, Bettelheim P: The growth and differentiation of mast cells. Prog Growth Factor Res 1991;3:27–41.
  2. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, Metcalfe DD: 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 1995;96:2702–2710.
  3. Sperr WR, Jordan JH, Fiegl M, Escribano L, Dirnhofer S, Semper H, 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;128:136–141.
  4. Kirshenbaum AS, Goff JP, Kessler SW, Mican JM, Zsebo KM, Metcalfe DD: Effects of IL-3 and stem cell factor on the appearance of human basophils and mast cells from CD34+ pluripotent progenitor cells. J Immunol 1992;148:772–777.
  5. Rottem M, Okada T, Goff JP, Metcalfe DD: Mast cells cultured from peripheral blood of normal donors and patients with mastocytosis originate from a CD34+/FcεRI cell population. Blood 1994;84:2489–2496.
  6. Valent P, Spanblöchl E, Sperr WR, Sillaber CH, Agis H, Zsebo K, et al: 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 1992;80:2237–2245.
  7. Sperr WR, Escribano L, Jordan JH, Schernthaner GH, Kundi M, Horny H-P, Valent P: Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk Res 2001;25:529–536.
  8. Valent P, Horny H-P, Li CY, Longley JB, Metcalfe DD, Parwaresch RM, Bennett JM: Mastocytosis (mast cell disease). World Health Organization Classification of Tumours: Pathology and Genetics; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): Tumours of Haematopoietic and Lymphoid Tissues. Geneva, WHO, 2001, vol 1, pp 291–302.
  9. Valent P, Horny H-P, Escribano L, Longley JB, Li CY, Schwartz LB, et al: Diagnostic criteria and classification of mastocytosis: a consensus proposal. Conference Report of ‘Year 2000 Working Conference on Mastocytosis’. Leuk Res 2001;25:603–625.
  10. Valent P, Akin C, Sperr WR, Horny H-P, Metcalfe DD: Mast cell proliferative disorders: current view on variants recognized by the World Health Organization. Hematol Oncol Clin North Am 2003;17:1227–1241.
  11. Horny H-P, Valent P: Diagnosis of mastocytosis: General histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res 2001;25:543–551.
  12. Horny H-P, Lange K, Sotlar K, Valent P: Increase of bone marrow lymphocytes in systemic mastocytosis: reactive lymphocytosis or malignant lymphoma? Immuno-histochemical and molecular findings on routinely processed bone marrow biopsy specimens. J Clin Pathol 2003;56:575–578.
  13. Jordan JH, Sperr WR, Lechner K, Geissler K, Schernthaner G-H, Fritsche-Polanz R, et al: Stem cell factor-induced bone marrow mast cell hyperplasia mimicking systemic mastocytosis (SM): histopathologic and morphologic evaluation with special reference to novel SM criteria. Leuk Lymphoma 2002;43:575–582.
  14. Horny H-P, Sillaber C, Menke D, Kaiserling E, Wehrmann M, Stehberger B, et al: Diagnostic utility of staining for tryptase in patients with mastocytosis. Am J Surg Pathol 1998;22:1132–1140.
  15. Li C-Y: Diagnosis of mastocytosis: value of cytochemistry and immunohistochemistry. Leuk Res 2001;25:537–541.
  16. Sotlar K, Horny H-P, Simonitsch I, Krokowski M, Aichberger KJ, Mayerhofer M, Printz D, Fritsch G, Valent P: CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis in routinely processed bone marrow biopsy specimens. Am J Surg Pathol 2004;28:1319–1325.
  17. Jordan H, Walchshofer S, Jurecka W, Mosberger I, Sperr WR, Wolff K, et al: Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-xL. Hum Pathol 2001;32:545–552.
  18. Sotlar K, Escribano L, Landt O, Möhrle S, Herrero S, Torrelo A, Lass ,Horny H-P, Bültmann B: One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J Pathol 2003;162:737–746.
  19. Sotlar K, Marafioti T, Griesser H, Theil J, Aepinus C, Jaussi R, et al: Detection of c-kit mutation Asp-816-Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukemia. Mol Pathol 2000;53:188–193.
  20. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD: 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;92:10560–10564.
  21. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al: Somatic c-kit activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996;12:312–314.
  22. Longley BJ, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu S-Z, et al: Activating and dominant inactivating c-kit catalytic domain mutations in distinct forms of human mastocytosis. Proc Natl Acad Sci USA 1999;96:1609–1614.
  23. Feger F, Ribadeau Dumas A, Leriche L, Valent P, Arock M: Kit and c-kit mutations in mastocytosis: a short overview with special reference to novel molecular and diagnostic concepts. Int Arch Allergy Immunol 2002;127:110–114.
  24. Longley BJ, Reguera MJ, Ma Y: Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. Leuk Res 2001;25:571–576.
  25. Akin C, Brockow K, D’Ambrosio C, Kirshenbaum AS, Ma Y, Longley BJ, Metcalfe DD: Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol 2003;31:686–692.
  26. Kemmer K, Corless CL, Fletcher JA, McGreevey L, Haley A, Griffith D, Cummings OW, Wait C, Town A, Heinrich MC: Kit mutations are common in testicular seminomas. Am J Pathol 2004;164:305–313.
  27. Bernd HW, Sotlar K, Lorenzen J, Osieka R, Fabry U, Valent P, Horny H-P: Acute myeloid leukaemia with t(8;21) associated with ‘occult’ mastocytosis. Report of an unusual case and review of the literature. J Clin Pathol 2004;57:324–328.
  28. Wang YY, Zhou GB, Yin T, Chen B, Shi JY, Liang WX, Jin XL, You JH, Shen ZX, Chen J, Xiong SM, Chen GQ, Xu F, Liu YW, Chen Z, Chen SJ: AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA 2005;102:1104–1109.
  29. Schnittger S, Kohl TM, Haferlach T, Kern W, Hiddemann W, Spiekermann K, Schoch C: KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 2006;107:1791–1799.
  30. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD: A novel form of mastocytosis associated with a transmembrane c-Kit mutation and response to imatinib. Blood 2004;103:3222–3225.
  31. Sperr WR, Stehberger B, Wimazal F, Baghestanian M, Schwartz LB, Kundi M, et al: Serum tryptase measurements in patients with myelodysplastic syndromes. Leuk Lymphoma 2002;43:1097–1105.
  32. Wolff K, Komar M, Petzelbauer P: Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res 2001;25:519–528.
  33. Hartmann K, Henz BM: Cutaneous mastocytosis – clinical heterogeneity. Int Arch Allergy Immunol 2002;127:143–146.
  34. Escribano L, Orfao A, Diaz-Agustin B, Villarrubia J, Cervero C, Lopez A, et al: Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implication. Blood 1998;91:2731–2736.
  35. Valent P, Akin C, Sperr WR, Escribano L, Arock M, Horny HP, Bennett JM, Metcalfe DD: Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res 2003;27:635–641.
  36. Hauswirth A, Sperr WR, Ghannadan M, Schernthaner G-H, Jordan JH, Fritsche-Planz R, et al: A case of smouldering mastocytosis with peripheral blood eosinophilia and lymphadenopathy. Leuk Res 2002;26:601–606.
  37. Horny H-P, Sotlar K, Sperr WR, Valent P: systemic mastocytosis with associated clonal haematological non-mast cell lineage disease (SM-AHNMD): a histopathological challenge. J Clin Pathol 2004;57:604–608.
  38. Horny H-P, Ruck M, Wehrmann M, Kaiserling E: Blood findings in generalized mastocytosis: evidence of frequent simultaneous occurrence of myeloproliferative disorders. Br J Haematol 1990;76:186–193.
  39. Sperr WR, Horny H-P, Lechner K, Valent P: Clinical and biologic diversity of leukemias occurring in patients with mastocytosis. Leuk Lymphoma 2000;37:473–486.
  40. Tefferi A, Pardanani A: Clinical, genetic, and therapeutic insights into systemic mast cell disease. Curr Opin Hematol 2004;11:58–64.
  41. Akin C, Kirshenbaum AS, Semere T, Worobec AS, Scott LM, Mwetcalfe DD: Analysis of the surface expression of c-kit and the c-kit Asp816Val activating mutationin T cells, B cells, and myelomonocytic cells in patients with mastocytosis. Exp Hematol 2000;28:140–147.
  42. Travis WD, Li CY, Hogaland HC, Travis LB, Banks PM: Mast cell leukemia: report of a case and review of the literature. Mayo Clin Proc 1986;61:957–966.
  43. Horny H-P, Parwaresch MR, Kaiserling E, Muller K, Olbermann M, Mainzer K, Lennert K: Mast cell sarcoma of the larynx. J Clin Pathol 1986;39:596–602.
  44. Kojima M, Nakamura S, Itoh H, Ohno Y, Masawa N, Joshita T, Suchi T: Mast cell sarcoma with tissue eosinophilia arising in the ascending colon. Modern Pathology 1999;12:739–743.
  45. Guenther PP, Huebner A, Sobottka SB, Neumeister V, Weissbach G, Todt H, Parwaresch MR: Temporary response of localized intracranial mast cell sarcoma to combination chemotherapy. J Pediatr Hematol Oncol 2001;23:134–138.
  46. Akin C, Scott LM, Metcalfe DD: Slowly progressing mastocytosis with high mast cell burden and no evidence of a non-mast cell hematologic disorder: an example of a smoldering case? Leuk Res 2001;25:635–638.
  47. Jordan JH, Fritsche-Polanz R, Sperr WR, Mitterbauer G, Födinger M, Schernthaner GH, et al: A case of smouldering mastocytosis with high mast cell burden, monoclonal myeloid cells, and c-kit mutation Asp-816-Val. Leuk Res 2001;25:627–634.
  48. Akin C, Metcalfe DD: Occult bone marrow mastocytosis presenting as recurrent systemic anaphylaxis. J Allergy Clin Immunol 2003;111:S206.

    External Resources

  49. Sotlar K, Saeger W, Stellmacher F, Stahmer J, Jäckle S, Valent P, Horny H-P: ‘Occult’ mastocytosis with activating c-kit point mutation evolving into systemic mastocytosis associated with plasma cell myeloma and secondary amyloidosis. J Clin Pathol 2006;59:875–878.
  50. Valent P, Samorapoompichit P, Sperr WR, Horny H-P, Lechner K: Myelomastocytic leukemia: myeloid neoplasm characterized by partial differentiation of mast cell-lineage cells. Hematol J 2002;3:90–94.
  51. Sperr WR, Jordan JH, Baghestanian M, Kiener H, Samorapoompichit P, Semper H, et al: Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia. Blood 2001;98:2200–2209.
  52. Horny H-P, Sotlar K, Stellmacher F, Krokowski M, Agis H, Schwartz LB, Valent P: The tryptase-positive compact round cell infiltrate of the bone marrow (TROCI-bm): a novel histopathological finding requiring the application of lineage specific markers. J Clin Pathol 2006;59:98–302.
  53. Valent P, Akin C, Sperr WR, Horny H-P, Arock M, Lechner K, Bennett JM, Metcalfe DD: Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003;122:1–23.
  54. Worobec AS: Treatment of systemic mast cell disorders. Hematol Oncol North Am 2000;14:659–687.
  55. Escribano L, Akin C, Castells M, Orfao A, Metcalfe DD: Mastocytosis: current concepts in diagnosis and treatment. Ann Hematol 2002;81:677–690.
  56. Casassus P, Caillat-Vigneron N, Martin A, Simon J, Gallais V, Beaudry P, et al: Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol 2002;119:1090–1097.
  57. Butterfield JH: Response of severe systemic mastocytosis to interferon-α. Br J Dermatol 1998;138:489–495.
  58. Hauswirth AW, Simonitsch-Klupp I, Uffmann M, Koller E, Sperr WR, Lechner K, Valent P: Response to therapy with interferon-alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res 2004;28:249–257.
  59. Tefferi A, Li CY, Butterfield JH, Hoagland HC: Treatment of systemic mast-cell disease with cladribine. N Engl J Med 2001;344:307–309.
  60. Tefferi A: Treatment of systemic mast cell disease: beyond interferon. Leuk Res 2004;28:223–224.
  61. Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM, et al: CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 2003;102:3093–3096.
  62. Gotlib J, Berube C, Growney JD, et al: Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood 2005;106:2865–2870.