Skip to main content
SpringerLink
Log in

Myeloproliferative Neoplasien

Histopathologische und molekularpathologische Diagnostik

Myeloproliferative neoplasms

Histopathological and molecular pathological diagnosis

  • Schwerpunkt
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Zu den myeloproliferativen Neoplasien (chronische myeloproliferative Erkrankungen nach früherer Nomenklatur) zählen die chronische myeloische Leukämie, die Polycythämia vera, die essenzielle Thrombozythämie, die primäre Myelofibrose, die chronische Eosinophilenleukämie, die chronische Neutrophilenleukämie und die systemische Mastozytose. Allen ist gemeinsam, dass eine oder mehrere hämatopoetische Differenzierungslinien exzessiv vermehrt sind und dass sie mit unterschiedlichen Wahrscheinlichkeiten in eine Blastenkrise oder Knochenmarkfibrose übergehen können. Ferner sind bei allen Tyrosinkinasen und assoziierte Signalwege von Mutationen betroffen (BCR-ABL, JAK2V617F, MPLW515L/K, KITD816V und FIP1L1-PDGFRA), welche die gesteigerte Proliferation auslösen. Diese Mutationen sind diagnostisch wie therapeutisch von großer Bedeutung, da sie reaktive Myeloproliferationen ausschließen, mit unterschiedlicher Spezifität zur Subtypisierung beitragen und zumindest z. T. medikamentös gezielt zu hemmen sind. Die molekularen Mechanismen der blastären und fibrotischen Progression sind noch unbekannt.

Abstract

Myeloproliferative neoplasms (chronic myeloproliferative disorders according to former nomenclature) comprise chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic eosinophilic leukemia, chronic neutrophilic leukemia and systemic mastocytosis. All disorders have excessive proliferation of one or more hematopoietic lineages in common and progress with different probability to blast crisis or fibrosis. A further common feature is provided by the activating mutation of tyrosin kinases and associated pathways of signal transduction (BCR-ABL, JAK2V617F, MPLW515L/K, KITD816V and FIP1L1-PDGFRA) causative for the abnormal proliferation. With regard to diagnosis and therapy these mutations are of utmost importance because they enable the exclusion of reactive processes, contribute with varying specificity to subtyping of MPN and are at least partly sensitive to targeted therapy. The molecular mechanisms of blastic and fibrotic progression are not yet understood.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Literatur

  1. Beer PA, Delhommeau F, LeCouédic JP et al (2010) Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood 115:2891–2900

    Article  PubMed  CAS  Google Scholar 

  2. Bock O, Muth M, Theophile K et al (2009) Identification of new target molecules PTK2, TGFBR2 and CD9 overexpressed during advanced bone marrow remodelling in primary myelofibrosis. Br J Haematol 146:510–520

    Article  PubMed  CAS  Google Scholar 

  3. Brousseau M, Parot-Schinkel E, Moles MP et al (2010) Practical application and clinical impact of the WHO histopathological criteria on bone marrow biopsy for the diagnosis of essential thrombocythemia versus prefibrotic primary myelofibrosis. Histopathology 56:758–767

    Article  PubMed  Google Scholar 

  4. Buhr T, Hebeda K, Kaloutsi V et al (2012) European Bone Marrow Working Group trial on reproducibility of WHO criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis. Haematologica 97:360–365

    Article  PubMed  Google Scholar 

  5. Burkhardt R, Bartl R, Jäger K et al (1986) Working classification of chronic myeloproliferative disorders based on histological, haematological, and clinical findings. J Clin Pathol 39:237–252

    Article  PubMed  CAS  Google Scholar 

  6. Bellanné-Chantelot C, Chaumarel I, Labopin M et al (2006) Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 1081:346–352

    Article  Google Scholar 

  7. Campbell PJ, Green AR (2006) The myeloproliferative disorders. N Engl J Med 355:2452–2466

    Article  PubMed  CAS  Google Scholar 

  8. Cervantes F, Dupriez B, Pereira A et al (2009) New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 113:2895–2901

    Article  PubMed  CAS  Google Scholar 

  9. Cools J, DeAngelo DJ, Gotlib J et al (2003) 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 348:1201–1214

    Article  PubMed  CAS  Google Scholar 

  10. Dameshek W (1951) Some speculations on the myeloproliferative syndromes. Blood 6:372–375

    PubMed  CAS  Google Scholar 

  11. Delhommeau F, Dupont S, Della Valle V et al (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301

    Article  PubMed  Google Scholar 

  12. Dupriez B, Morel P, Demory JL et al (1996) Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 88:1013–1018

    PubMed  CAS  Google Scholar 

  13. Elliott MA, Verstovsek S, Dingli D et al (2007) Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofibrosis. Leuk Res 31:1503–1509

    Article  PubMed  CAS  Google Scholar 

  14. Ernst T, Hochhaus A (2012) Chronic myeloid leukemia: clinical impact of BCR-ABL1 mutations and other lesions associated with disease progression. Semin Oncol 39:58–66

    Article  PubMed  CAS  Google Scholar 

  15. Foa P, Iurlo A, Saglio G et al (1991) Chronic neutrophilic leukaemia associated with polycythemia vera: pathogenetic implications and therapeutic approach. Br J Haematol 78:286–288

    Article  PubMed  CAS  Google Scholar 

  16. Gangat N, Caramazza D, Vaidya R et al (2011) DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 29:392–397

    Article  PubMed  Google Scholar 

  17. Georgii A, Buhr T, Buesche G et al (1996) Classification and staging of Ph-negative myeloproliferative disorders by histopathology from bone marrow biopsies. Leuk Lymphoma 22(Suppl 1):15–29

    Article  PubMed  Google Scholar 

  18. Hagemeijer A, Plas DC van der, Soekarman D et al (1990) The Philadelphia translocation in CML and ALL: recent investigations, new detection methods. Nouv Rev Fr Hematol 32:83–86

    PubMed  CAS  Google Scholar 

  19. Haq AU (1990) Transformation of polycythemia vera to Ph-positive chronic myelogenous leukemia. Am J Hematol 35:110–113

    Article  PubMed  CAS  Google Scholar 

  20. Harrison CN, Bareford D, Butt N et al (2010) Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 149:352–375

    Article  PubMed  CAS  Google Scholar 

  21. Harrison CN, Campbell PJ, Buck G et al (2005) Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 353:33–45

    Article  PubMed  CAS  Google Scholar 

  22. Higuchi T, Oba R, Endo M et al (1999) Transition of polycythemia vera to chronic neutrophilic leukemia. Leuk Lymphoma 33:203–206

    PubMed  CAS  Google Scholar 

  23. Hoppin EC, Lewis JP (1975) Polycythemia rubra vera progressing to Ph-positive chronic myelogenous leukemia. Ann Intern Med 83:820–823

    PubMed  CAS  Google Scholar 

  24. Hussein K, Bock O, Ballmaier M et al (2007) Familial polycythemia vera with non-germline JAK2(V617 F) mutation sparing the abnormal and clonal granulopoiesis. Leukemia 21:2566–2568

    Article  PubMed  CAS  Google Scholar 

  25. Hussein K, Bock O, Seegers A et al (2007) Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disease with coexisting BCR-ABL translocation and JAK2V617F mutation. Blood 109:4106–4107

    Article  PubMed  CAS  Google Scholar 

  26. Hussein K, Bock O, Theophile K et al (2008) Chronic myeloproliferative diseases with concurrent BCR-ABL junction and JAK2V617F mutation. Leukemia 22:1059–1062

    Article  PubMed  CAS  Google Scholar 

  27. Hussein K, Bock O, Theophile K et al (2009) JAK2(V617F) allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis. Exp Hematol 37:1186–1193

    Article  PubMed  CAS  Google Scholar 

  28. Hussein K, Theophile K, Buhr T et al (2009) Different lineage involvement in myelodysplastic/myeloproliferative disease with combined MPLW515L and JAK2V617F mutation. Br J Haematol 145:673–675

    Article  PubMed  CAS  Google Scholar 

  29. Iurlo A, Foa P, Maiolo AT et al (1990) Polycythemia vera terminating in chronic neutrophilic leukemia: report of a case. Am J Hematol 35:139–140

    Article  PubMed  CAS  Google Scholar 

  30. James C, Ugo V, Le Couédic JP et al (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148

    Article  PubMed  CAS  Google Scholar 

  31. Jantunen E, Nousiainen T (1991) Ph-positive chronic myelogenous leukemia evolving after polycythemia vera. Am J Hematol 37:212

    Article  PubMed  CAS  Google Scholar 

  32. Kreipe H, Hussein K, Göhring G, Schlegelberger B (2011) Progression of myeloproliferative neoplasms to myelofibrosis and acute leukaemia. J Hematopathol 4:61–68

    Article  Google Scholar 

  33. Kreipe H, Jaquet K, Felgner J et al (1991) Clonal granulocytes and bone marrow cells in the cellular phase of agnogenic myeloid metaplasia. Blood 78:1814–1817

    PubMed  CAS  Google Scholar 

  34. Kreipe HH, Beham-Schmid C, Dirnhofer S et al (2011) Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification. [e-Letter], Blood http://bloodjournal.hematologylibrary.org/content/117/21/5710.long/reply#bloodjournal_el_3427). Zugegriffen: 23. Dez. 2011

  35. Lugassy G, Farhi R(1989) Chronic neutrophilic leukemia associated with polycythemia vera. Am J Hematol 31:300–301

    Article  PubMed  CAS  Google Scholar 

  36. Mirza I, Frantz C, Clarke G et al (2007) Transformation of polycythemia vera to chronic myelogenous leukemia. Arch Pathol Lab Med 131:1719–1724

    PubMed  CAS  Google Scholar 

  37. Muth M, Engelhardt BM, Kröger N et al (2011) Thrombospondin-1 (TSP-1) in primary myelofibrosis (PMF)—a megakaryocyte-derived biomarker which largely discriminates PMF from essential thrombocythemia. Ann Hematol 90:33–40

    Article  PubMed  CAS  Google Scholar 

  38. Pardanani A, Lasho TL, Finke CM et al (2010) IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia 24:1146–1151

    Article  PubMed  CAS  Google Scholar 

  39. Pardanani A, Lasho TL, Finke CM, Tefferi A (2011) Infrequent occurrence of MPL exon 10 mutations in polycythemia vera and post-polycythemia vera myelofibrosis. Am J Hematol 86:701–702

    Article  PubMed  CAS  Google Scholar 

  40. Pietra D, Li S, Brisci A et al (2008) Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617 F)-negative myeloproliferative disorders. Blood 111:1686–1689

    Article  PubMed  CAS  Google Scholar 

  41. Primo D, Sanchez ML, Espinosa AB et al (2006) Lineage involvement in chronic myeloid leukaemia: comparison between MBCR/ABL and mBCR/ABL cases. Br J Haematol 132:736–739

    Article  PubMed  CAS  Google Scholar 

  42. Skoda RC (2010) Hereditary myeloproliferative disorders. Haematologica 95:6–8

    Article  PubMed  CAS  Google Scholar 

  43. Spivak JL, Silver RT (2008) The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis: an alternative proposal. Blood 112:231–239

    Article  PubMed  CAS  Google Scholar 

  44. Swerdlow SH, Campo E, Harris NL et al (2008) WHO classification of tumours of haemtopoietic and lymphoid tissues. Lyon, IARC, Lyon

  45. Tan PT, Wei AH (2011) The epigenomics revolution in myelodysplasia: a clinico-pathological perspective. Pathology 43:536–546

    Article  PubMed  CAS  Google Scholar 

  46. Tefferi A, Vainchenker W (2011) Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 29:573–582

    Article  PubMed  CAS  Google Scholar 

  47. Theocharides A, Boissinot M, Girodon F et al (2007) Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 110:375–379

    Article  PubMed  CAS  Google Scholar 

  48. Thiele J, Kvasnicka HM, Facchetti F et al (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90:1128–1132

    PubMed  Google Scholar 

  49. Thiele J, Kvasnicka HM, Müllauer L et al (2011) Essential thromobcythemia versus early primary myelofibrosis—a multicenter study to validate WHO classification. Blood 117:5710–5718

    Article  PubMed  CAS  Google Scholar 

  50. Thoennissen NH, Krug UO, Lee DH et al (2010) Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms. Blood 115:2882–2890

    Article  PubMed  CAS  Google Scholar 

  51. Verstovsek S, Kantarjian HM, Estrov Z et al (2012) Long term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood

  52. Wilkins BS, Erber WN, Bareford D et al (2008) Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. Blood 111:60–70

    Article  PubMed  CAS  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor gibt für sich und seine Koautoren an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland

    K. Hussein, G. Büsche, J. Schlue, U. Lehmann &  H. Kreipe

Authors
  1. K. Hussein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Büsche
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Schlue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. U. Lehmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Kreipe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Kreipe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hussein, K., Büsche, G., Schlue, J. et al. Myeloproliferative Neoplasien. Pathologe 33, 508–517 (2012). https://doi.org/10.1007/s00292-012-1651-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-012-1651-3

Schlüsselwörter

Keywords

Search

Navigation