Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.


Classification of Ph-Negative Chronic Myeloproliferative Disorders – Morphology as the Yardstick of Classification

Kvasnicka H.M. · Thiele J.

Author affiliations

Institute of Pathology, University of Cologne, Cologne, Germany

Corresponding Author

Hans Michael Kvasnicka, MD

Institute for Pathology, University of Cologne

Joseph-Stelzmann-Strasse 9

DE–50924 Cologne (Germany)

Tel. +49 221 47 86369, Fax +49 221 47 86360, E-Mail hm.kvasnicka@uni-koeln.de

Related Articles for ""

Pathobiology 2007;74:63–71

Do you have an account?

Login Information

Contact Information

I have read the Karger Terms and Conditions and agree.


Objective: Histopathology of bone marrow (BM) biopsies plays a crucial role in the interdisciplinary approach to diagnosis and classification of Ph-negative chronic myeloproliferative disorders. Based on careful clinicopathologic studies, BM features are critical determinants that help to predict overall prognosis, to detect complications such as progression to myelofibrosis and blast crisis, and to assess therapy-related changes. Methods and Results: A systematic evaluation of BM histopathology allows an objective identification of cases of (true) essential thrombocythemia and their separation from early prefibrotic stages of chronic idiopathic myelofibrosis. By follow-up examinations that include BM biopsies, the progression of the disease process is unveiled, which is especially important for patients with initial polycythemia vera and prefibrotic chronic idiopathic myelofibrosis that may require a different therapeutic approach than the full-blown stages. Conclusion: BM biopsy should be considered as major diagnostic tool for evaluation and follow-up of patients enrolled in prospective studies.

© 2007 S. Karger AG, Basel


  1. Dickstein JI, Vardiman JW: Hematopathologic findings in the myeloproliferative disorders. Semin Oncol 1995;22:355–373.
  2. Kutti J, Wadenvik H: Diagnostic and differential criteria of essential thrombocythemia and reactive thrombocytosis. Leuk Lymphoma 1996;22(suppl 1):41–45.
  3. Murphy S, Peterson P, Iland H, Laszlo J: Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol 1997;34:29–39.
  4. Murphy S: Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematol 1999;36:9–13.
  5. Pearson TC: Diagnosis and classification of erythrocytoses and thrombocytoses. Baillieres Clin Haematol 1998;11:695–720.
  6. Finazzi G, Barbui T: Treatment of essential thrombocythemia with special emphasis on leukemogenic risk. Ann Hematol 1999;78:389–392.
  7. Radaelli F, Mazza R, Curioni E, Ciani A, Pomati M, Maiolo AT: Acute megakaryocytic leukemia in essential thrombocythemia: an unusual evolution? Eur J Haematol 2002;69:108–111.
  8. Barbui T, Barosi G, Grossi A, Gugliotta L, Liberato LN, Marchetti M, Mazzucconi MG, Rodeghiero F, Tura S: Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004;89:215–232.
  9. Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, Barbui T: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132–1136.
  10. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005;353:33–45.
  11. Harrison CN, Green AR: Essential thrombocythemia. Hematol Oncol Clin North Am 2003;17:1175–1190.
  12. Finazzi G, Harrison C: Essential thrombocythemia. Semin Hematol 2005;42:230–238.
  13. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–1148.
  14. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054–1061.
  15. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779–1790.
  16. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D’Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG: Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387–397.
  17. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, Score J, Seear R, Chase AJ, Grand FH, White H, Zoi C, Loukopoulos D, Terpos E, Vervessou EC, Schultheis B, Emig M, Ernst T, Lengfelder E, Hehlmann R, Hochhaus A, Oscier D, Silver RT, Reiter A, Cross NC: Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106:2162–2168.
  18. Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, Zhao ZJ: Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280:22788–22792.
  19. Goerttler PS, Steimle C, Marz E, Johansson PL, Andreasson B, Griesshammer M, Gisslinger H, Heimpel H, Pahl HL: The Jak2V617F mutation, PRV-1 overexpression, and erythroid colony formation define a similar cohort of MPD patients. Blood 2005;106:2862–2864.
  20. Wolanskyj AP, Lasho TL, Schwager SM, McClure RF, Wadleigh M, Lee SJ, Gilliland DG, Tefferi A: JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol 2005;131:208–213.
  21. Goldman JM: A unifying mutation in chronic myeloproliferative disorders. N Engl J Med 2005;352:1744–1746.
  22. Kaushansky K: On the molecular origins of the chronic myeloproliferative disorders: it all makes sense. Blood 2005;105:4187–4190.
  23. Tefferi A, Gilliland DG: JAK2 in myeloproliferative disorders is not just another kinase. Cell Cycle 2005;4:1053–1056.
  24. Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 2006;355:2452–2466.
  25. Antonioli E, Guglielmelli P, Pancrazzi A, Bogani C, Verrucci M, Ponziani V, Longo G, Bosi A, Vannucchi AM: Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia 2005;19:1847–1849.
  26. Bock O, Neuse J, Hussein K, Brakensiek K, Buesche G, Buhr T, Wiese B, Kreipe H: Aberrant collagenase expression in chronic idiopathic myelofibrosis is related to the stage of disease but not to the JAK2 mutation status. Am J Pathol 2006;169:471–481.
  27. Vardiman JW, Pierre R, Thiele J, Imbert M: Chronic myeloproliferative disorders; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): WHO Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001, pp 16–59.
  28. Thiele J, Kvasnicka HM: Clinicopathological criteria for differential diagnosis of thrombocythemias in various myeloproliferative disorders. Semin Thromb Hemost 2006;32:219–230.
  29. Thiele J, Kvasnicka HM, Vardiman J: Bone marrow histopathology in the diagnosis of chronic myeloproliferative disorders: a forgotten pearl. Best Pract Res Clin Haematol 2006;19:413–437.
  30. Cervantes F, Alvarez-Larran A, Talarn C, Gomez M, Montserrat E: Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients. Br J Haematol 2002;118:786–790.
  31. Gianelli U, Vener C, Raviele PR, Moro A, Savi F, Annaloro C, Somalvico F, Radaelli F, Franco V, Deliliers GL: Essential thrombocythemia or chronic idiopathic myelofibrosis? A single-center study based on hematopoietic bone marrow histology. Leuk Lymphoma 2006;47:1774–1781.
  32. Thiele J, Kvasnicka HM, Fischer R: Histochemistry and morphometry on bone marrow biopsies in chronic myeloproliferative disorders – aids to diagnosis and classification. Ann Hematol 1999;78:495–506.
  33. Florena AM, Tripodo C, Iannitto E, Porcasi R, Ingrao S, Franco V: Value of bone marrow biopsy in the diagnosis of essential thrombocythemia. Haematologica 2004;89:911–919.
  34. Thiele J, Kvasnicka HM, Orazi A: Bone marrow histopathology in myeloproliferative disorders – current diagnostic approach. Semin Hematol 2005;42:184–195.
  35. Thiele J, Kvasnicka HM, Diehl V: Standardization of bone marrow features – does it work in hematopathology for histological discrimination of different disease patterns? Histol Histopathol 2005;20:633–644.
  36. Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A: European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 2005;90:1128–1132.
  37. Thiele J, Kvasnicka HM, Zankovich R, Diehl V: The value of bone marrow histology in differentiating between early stage polycythemia vera and secondary (reactive) polycythemias. Haematologica 2001;86:368–374.
  38. Thiele J, Kvasnicka HM: Diagnostic differentiation of essential thrombocythaemia from thrombocythaemias associated with chronic idiopathic myelofibrosis by discriminate analysis of bone marrow features – a clinicopathological study on 272 patients. Histol Histopathol 2003;18:93–102.
  39. Spivak JL: Polycythemia vera: myths, mechanisms, and management. Blood 2002;100:4272–4290.
  40. Thiele J, Kvasnicka HM: Diagnostic impact of bone marrow histopathology in polycythemia vera. Histol Histopathol 2005;20:317–328.
  41. Pierre R, Imbert M, Thiele J, Vardiman JW, Brunning RD, Flandrin G: Polycythaemia vera; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): WHO Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001, pp 32–38.
  42. Tefferi A: Current management of polycythemia vera. Leuk Lymphoma 2002;43:1–7.
  43. Thiele J, Kvasnicka HM, Muehlhausen K, Walter S, Zankovich R, Diehl V: Polycythemia rubra vera versus secondary polycythemias. A clinicopathological evaluation of distinctive features in 199 patients. Pathol Res Pract 2001;197:77–84.
  44. Ellis JT, Silver RT, Coleman M, Geller SA: The bone marrow in polycythemia vera. Semin Hematol 1975;12:433–444.
  45. Ellis JT, Peterson P, Geller SA, Rappaport H: Studies of the bone marrow in polycythemia vera and the evolution of myelofibrosis and second hematologic malignancies. Semin Hematol 1986;23:144–155.
  46. Thiele J, Kvasnicka HM, Zankovich R, Diehl V: Relevance of bone marrow features in the differential diagnosis between essential thrombocythemia and early stage idiopathic myelofibrosis. Haematologica 2000;85:1126–1134.
  47. Michiels JJ, Thiele J: Clinical and pathological criteria for the diagnosis of essential thrombocythemia, polycythemia vera, and idiopathic myelofibrosis (agnogenic myeloid metaplasia). Int J Hematol 2002;76:133–145.
  48. Kreft A, Buche G, Ghalibafian M, Buhr T, Fischer T, Kirkpatrick CJ: The incidence of myelofibrosis in essential thrombocythaemia, polycythaemia vera and chronic idiopathic myelofibrosis: a retrospective evaluation of sequential bone marrow biopsies. Acta Haematol 2005;113:137–143.
  49. Thiele J, Kvasnicka HM: Myelofibrosis in chronic myeloproliferative disorders – dynamics and clinical impact. Histol Histopathol 2006;21:1367–1378.
  50. Thiele J, Kvasnicka HM, Werden C, Zankovich R, Diehl V, Fischer R: Idiopathic primary osteo-myelofibrosis: a clinico-pathological study on 208 patients with special emphasis on evolution of disease features, differentiation from essential thrombocythemia and variables of prognostic impact. Leuk Lymphoma 1996;22:303–317.
  51. Thiele J, Kvasnicka HM, Boeltken B, Zankovich R, Diehl V, Fischer R: Initial (prefibrotic) stages of idiopathic (primary) myelofibrosis – a clinicopathological study. Leukemia 1999;13:1741–1748.
  52. Thiele J, Kvasnicka HM, Diehl V, Fischer R, Michiels J: Clinicopathological diagnosis and differential criteria of thrombocythemias in various myeloproliferative disorders by histopathology, histochemistry and immunostaining from bone marrow biopsies. Leuk Lymphoma 1999;33:207–218.
  53. Thiele J, Kvasnicka HM: Prefibrotic chronic idiopathic myelofibrosis – a diagnostic enigma? Acta Haematol 2004;111:155–159.
  54. Thiele J, Kvasnicka HM, Diehl V: Bone marrow features of diagnostic impact in erythrocytosis. Ann Hematol 2005;84:362–367.
  55. Thiele J, Kvasnicka HM, Diehl V: Initial (latent) polycythemia vera with thrombocytosis mimicking essential thrombocythemia. Acta Haematol 2005;113:213–219.
  56. Ruggeri M, Tosetto A, Frezzato M, Rodeghiero F: The rate of progression to polycythemia vera or essential thrombocythemia in patients with erythrocytosis or thrombocytosis. Ann Intern Med 2003;139:470–475.
  57. Thiele J, Kvasnicka HM: Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients. Ann Hematol 2003;82:148–152.
  58. Kvasnicka HM, Thiele J: The impact of clinicopathological studies on staging and survival in essential thrombocythemia, chronic idiopathic myelofibrosis, and polycythemia rubra vera. Semin Thromb Hemost 2006;32:362–371.
  59. Thiele J, Kvasnicka HM, Schmitt-Graeff A, Zankovich R, Diehl V: Follow-up examinations including sequential bone marrow biopsies in essential thrombocythemia: a retrospective clinicopathological study of 120 patients. Am J Hematol 2002;70:283–291.
  60. Imbert M, Pierre R, Thiele J, Vardiman JW, Brunning RD, Flandrin G: Essential thrombocythaemia; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): WHO Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001, pp 39–41.
  61. Thiele J, Kvasnicka HM, Fuchs N, Brunnbauer K, Volkwein N, Schmitt-Graeff A: Anagrelide-induced bone marrow changes during therapy of chronic myeloproliferative disorders with thrombocytosis – an immunohistochemical and morphometric study of sequential trephine biopsies. Haematologica 2003;88:1130–1138.
  62. Harrison CN: Essential thrombocythaemia: challenges and evidence-based management. Br J Haematol 2005;130:153–165.
  63. Fenaux P, Simon M, Caulier MT, Lai JL, Goudemand J, Bauters F: Clinical course of essential thrombocythemia in 147 cases. Cancer 1990;66:549–556.
  64. Annaloro C, Lambertenghi Deliliers G, Oriani A, Pozzoli E, Lambertenghi Deliliers D, Radaelli F, Faccini P: Prognostic significance of bone marrow biopsy in essential thrombocythemia. Haematologica 1999;84:17–21.
  65. Barbui T, Finazzi G: When and how to treat essential thrombocythemia. N Engl J Med 2005;353:85–86.
  66. Thiele J, Kvasnicka HM: A critical reappraisal of the WHO classification of the chronic myeloproliferative disorders. Leuk Lymphoma 2006;47:381–396.
  67. Barosi G: Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol 1999;17:2954–2970.
  68. Barosi G, Ambrosetti A, Finelli C, Grossi A, Leoni P, Liberato NL, Petti MC, Pogliani E, Ricetti M, Rupoli S, Visani G, Tura S: The Italian Consensus Conference on diagnostic criteria for myelofibrosis with myeloid metaplasia. Br J Haematol 1999;104:730–737.
  69. Buhr T, Georgii A, Schuppan O, Amor A, Kaloutsi V: Histologic findings in bone marrow biopsies of patients with thrombocythemic cell counts. Ann Hematol 1992;64:286–291.
  70. Thiele J, Windecker R, Kvasnicka HM, Titius BR, Zankovich R, Fischer R: Erythropoiesis in primary (idiopathic) osteomyelofibrosis: quantification, PCNA reactivity, and prognostic impact. Am J Hematol 1994;46:36–42.
  71. Buhr T, Georgii A, Choritz H: Myelofibrosis in chronic myeloproliferative disorders. Incidence among subtypes according to the Hannover Classification. Pathol Res Pract 1993;189:121–132.
  72. Georgii A, Buesche G, Kreft A: The histopathology of chronic myeloproliferative diseases. Baillieres Clin Haematol 1998;11:721–749.
  73. Georgii A, Buhr T, Buesche G, Kreft A, Choritz H: Classification and staging of Ph-negative myeloproliferative disorders by histopathology from bone marrow biopsies. Leuk Lymphoma 1996;22(suppl 1):15–29.
  74. Georgii A, Vykoupil KF, Buhr T, Choritz H, Doehler U, Kaloutsi V, Werner M: Chronic myeloproliferative disorders in bone marrow biopsies. Pathol Res Pract 1990;186:3–27.
  75. Thiele J, Imbert M, Pierre R, Vardiman JW, Brunning RD, Flandrin G: Chronic idiopathic myelofibrosis; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): WHO Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001, pp 35–38.
  76. Buhr T, Choritz H, Georgii A: The impact of megakaryocyte proliferation of the evolution of myelofibrosis. Histological follow-up study in 186 patients with chronic myeloid leukaemia. Virchows Arch A Pathol Anat Histopathol 1992;420:473–478.
  77. Thiele J, Kvasnicka HM: Hematopathologic findings in chronic idiopathic myelofibrosis. Semin Oncol 2005;32:380–394.
  78. Thiele J, Kvasnicka HM, Schmitt-Graeff A, Diehl V: Bone marrow histopathology following cytoreductive therapy in chronic idiopathic myelofibrosis. Histopathology 2003;43:470–479.
  79. Buhr T, Buesche G, Choritz H, Langer F, Kreipe H: Evolution of myelofibrosis in chronic idiopathic myelofibrosis as evidenced in sequential bone marrow biopsy specimens. Am J Clin Pathol 2003;119:152–158.
  80. Thiele J, Kvasnicka HM, Schmitt-Graeff A, Diehl V: Dynamics of fibrosis in chronic idiopathic (primary) myelofibrosis during therapy: a follow-up study on 309 patients. Leuk Lymphoma 2003;44:949–953.
  81. Thiele J, Kvasnicka HM, Schmitt-Graeff A: Acute panmyelosis with myelofibrosis. Leuk Lymphoma 2004;45:681–687.
  82. Bain BJ: The relationship between the myelodysplastic syndromes and the myeloproliferative disorders. Leuk Lymphoma 1999;34:443–449.
  83. Thiele J, Titius BR, Kopsidis C, Fischer R: Atypical micromegakaryocytes, promegakaryoblasts and megakaryoblasts: a critical evaluation by immunohistochemistry, cytochemistry and morphometry of bone marrow trephines in chronic myeloid leukemia and myelodysplastic syndromes. Virchows Arch B Cell Pathol Incl Mol Pathol 1992;62:275–282.
  84. Kvasnicka HM, Thiele J, Regn C, Zankovich R, Diehl V, Fischer R: Prognostic impact of apoptosis and proliferation in idiopathic (primary) myelofibrosis. Ann Hematol 1999;78:65–72.
  85. Kvasnicka HM, Thiele J, Werden C, Zankovich R, Diehl V, Fischer R: Prognostic factors in idiopathic (primary) osteomyelofibrosis. Cancer 1997;80:708–719.
  86. Strasser-Weippl K, Steurer M, Kees M, Augustin F, Tzankov A, Dirnhofer S, Fiegl M, Simonitsch-Klupp I, Zojer N, Gisslinger H, Ludwig H: Age and hemoglobin level emerge as most important clinical prognostic parameters in patients with osteomyelofibrosis: introduction of a simplified prognostic score. Leuk Lymphoma 2006;47:441–450.

Article / Publication Details

First-Page Preview
Abstract of Review

Received: March 05, 2007
Accepted: March 27, 2007
Published online: June 25, 2007
Issue release date: June 2007

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 0

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

For additional information: https://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.
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 government 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.