Advertisement

Medical Oncology

, Volume 29, Issue 5, pp 3540–3546 | Cite as

Systemic mastocytosis: progressive evolution of an occult disease into fatal mast cell leukemia: unique findings on an unusual hematological neoplasm

  • T. GülenEmail author
  • B. Sander
  • G. Nilsson
  • J. Palmblad
  • K. Sotlar
  • H.-P. Horny
  • H. Hägglund
Original Paper

Abstract

Systemic mastocytosis (SM) may be associated with a clonal hematopoietic non-mast cell-lineage disease (AHNMD). SM and AHNMD even may be clonally related. This report contributes to a better understanding of the different morphological aspects of SM by demonstrating that various AHNMDs can be detected in one patient during the course of disease. Routinely processed biopsy specimens of bone marrow and spleen removed from a 63-year-old man were investigated including a broad panel of immunohistochemical stainings. KIT codon 816 mutation analysis was carried out by melting point analysis of nested PCR products amplified from DNA of pooled microdissected mast cells. The histomorphological features of the initial bone marrow showed diffuse infiltration by hairy cell leukemia (HCL). Occult SM was only detected retrospectively by demonstration of a slight diffuse increase in loosely scattered, spindle-shaped mast cells carrying the activating point mutation KIT D816V . In the second bone marrow, core biopsy removed about two years later HCL had been completely eradicated, while a diagnosis of SM-AHNMD with multifocal compact mast cell infiltrates associated with a myeloproliferative neoplasm (MPN) and significant increase in eosinophilic granulocytes was established. The third and last bone marrow biopsy specimen lacked the features of both MPN and HCL but showed progression into a secondary mast cell leukemia (MCL) with a focal sarcomatous component. To the best of the authors’ knowledge, this is the first description of a case of SM-AHNMD with coexisting hematological neoplasms of lymphatic and myeloid origin initially presenting as occult disease and terminating as secondary MCL.

Keywords

Mastocytosis SM-AHNMD Mast cell leukemia Eosinophilia c-Kit mutation Occult SM 

Notes

Acknowledgments

This study was supported by grants from the Swedish Research Council; the Swedish Cancer Society; the Center for Allergy Research, Karolinska Institute and through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institutet.

Conflict of interest

The authors report no conflict of interest.

References

  1. 1.
    Valent P, Horny H-P, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Valent P, Akin C, Sperr WR, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res. 2003;27:635–41.PubMedCrossRefGoogle Scholar
  3. 3.
    Horny HP, Sotlar K, Valent P. Mastocytosis: state of the Art. Pathobiology. 2007;74:121–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37(6):435–53.PubMedCrossRefGoogle Scholar
  5. 5.
    Horny HP, Akin C, Metcalfe DD, Bennett JM, et al. Mastocytosis. In:Swerdlow SH, Campo E, Harris NL, et al., (eds.). World Health Organization (WHO) Classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research and Cancer (IARC); 2008. pp 54–63.Google Scholar
  6. 6.
    Horny HP, Valent P. Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res. 2001;25:543–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Horny HP, Sillaber C, Menke D, et al. Diagnostic value of immunostaining for tryptase in patients with mastocytosis. Am J Surg Pathol. 1998;22:1132–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Escribano L, Orfao A, Díaz-Agustin B, Villarrubia J, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood. 1998;91(8):2731–6.PubMedGoogle Scholar
  9. 9.
    Sperr WR, Escribano L, Jordan JH, et al. Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk Res. 2001;25:529–36.PubMedCrossRefGoogle Scholar
  10. 10.
    Morgado JM, Sánchez-Muñoz L, Teodósio CG, Jara-Acevedo M, et al. Immunophenotyping in systemic mastocytosis diagnosis: ‘CD25 positive’ alone is more informative than the ‘CD25 and/or CD2’ WHO criterion. Mod Pathol. 2012 Jan 6. doi: 10.1038/modpathol.2011.192. [Epub ahead of print].
  11. 11.
    Sotlar K, Escribano L, Landt O, et al. One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J Pathol. 2003;162:737–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Sotlar K, Marafioti T, Griesser H, 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;53:188–93.PubMedCrossRefGoogle Scholar
  13. 13.
    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;92:10560–4.PubMedCrossRefGoogle Scholar
  14. 14.
    Feger F, Ribadeau Dumas A, Leriche L, et al. Kit and c-kit mutations in mastocytosis: a short overview with special reference to novel molecular and diagnostic concepts. Int Arch Allergy Immunol. 2002;127:110–4.PubMedCrossRefGoogle Scholar
  15. 15.
    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;25:571–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Horny HP, Sotlar K, Sperr WR, et al. Systemic mastocytosis with associated clonal haematological non- mast cell lineage diseases: a histopathological challenge. J Clin Pathol. 2004;57:604–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Sotlar K, Bache A, Stellmacher F, et al. Systemic mastocytosis associated with chronic idiopathic myelofibrosis: a distinct subtype of systemic mastocytosis associated with a [corrected] clonal hematological non-mast [corrected] cell lineage disorder carrying the activating point mutations KITD816 V and JAK2V617F. J Mol Diagn. 2008;10(1):58–66.PubMedCrossRefGoogle Scholar
  18. 18.
    Sperr WR, Horny H-P, Lechner K, et al. Clinical and biologic diversity of leukemias occurring in patients with mastocytosis. Leuk Lymphoma. 2000;37:473–86.PubMedCrossRefGoogle Scholar
  19. 19.
    Hagen W, Schwarzmeier J, Walchshofer S, et al. A case of bone marrow mastocytosis associated with multiple myeloma. Ann Hematol. 1998;76(3–4):167–74.PubMedCrossRefGoogle Scholar
  20. 20.
    Tzankov A, Sotlar K, Muhlematter D, et al. Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involving FLT3. J Clin Pathol. 2008;61(8):958–61.PubMedCrossRefGoogle Scholar
  21. 21.
    Maric I, Robyn J, Metcalfe DD, et al. KIT D816 V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities. J Allergy Clin Immunol. 2007;120(3):680–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Böhm A, Födinger M, Wimazal F, et al. Eosinophilia in systemic mastocytosis: clinical and molecular correlates and prognostic significance. J Allergy Clin Immunol. 2007;120(1):192–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Gotlib J, Cools J, Malone JM, et al. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood. 2004;103:2879–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104:3038–45.PubMedCrossRefGoogle Scholar
  25. 25.
    Pardanani A. H.C. Flynn, S.F. Paternoster and B.M. Shearer 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;102:3093–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Bain B, Pierre R, Imbert M, et al. Chronic eosinophilic leukemia and hypereosinophilic syndrome. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors, World Health Organization (WHO) classification of tumours. Pathology & genetics. Tumours of haematopoietic and lymphoid tissues vol. 1; 2001. pp. 29–31.Google Scholar
  27. 27.
    Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201–14.PubMedCrossRefGoogle Scholar
  28. 28.
    Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood. 2003;101:4660–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Cortes J, Ault P, Koller C, et al. Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood. 2003;101:4714–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • T. Gülen
    • 1
    • 2
    • 6
    Email author
  • B. Sander
    • 3
    • 6
  • G. Nilsson
    • 2
    • 6
  • J. Palmblad
    • 4
  • K. Sotlar
    • 5
  • H.-P. Horny
    • 5
  • H. Hägglund
    • 4
    • 6
  1. 1.Department of Respiratory Medicine and Allergy, M53Karolinska University Hospital HuddingeStockholmSweden
  2. 2.Clinical Immunology and Allergy Research Unit, Department of MedicineKarolinska University Hospital Solna, Karolinska InstituteStockholmSweden
  3. 3.Department of PathologyKarolinska University Hospital HuddingeStockholmSweden
  4. 4.Department of HematologyKarolinska University Hospital HuddingeStockholmSweden
  5. 5.Institute of PathologyLudwig-Maximilians UniversityMunichGermany
  6. 6.Mastocytosis Center at Karolinska University Hospital and Karolinska InstituteStockholmSweden

Personalised recommendations