Abstract

Research Article

Bone marrow histology in CALR mutated thrombocythemia and myelofibrosis: Results from two cross sectional studies in 70 newly diagnosed JAK2/MPL wild type thrombocythemia patients

Jan Jacques Michiels*, Yonggoo Kim, Myungshin Kim, Francisca Valster, Vincent Potters, Zwi Berneman, Alain Gadisseur, Wilfried Schroyens and Hendrik De Raeve

Published: 21 June, 2019 | Volume 2 - Issue 1 | Pages: 064-078

The clinical phenotypes in 268 JAK2V617F mutated MPN patients in the Seoul study were PV in 101, ET in 95 and MF in 78 and 56 CALR mutated MPN consisted of PV in none, ET in 40 and MF in 16 cases. CALR mutated MPN patients were younger than JAK2V617F mutated MPN patients (mean ages 57.5 and 66 years), had lower values for values for leukocytes (8.6 vs 11.9x109/L) and higher values for platelets (898 vs 643x109/L respectively). Bone marrow histopathology in 268 JAK2V617F mutated MPN patients in the Seoul study was featured by an increased erythropoiesis and megakaryopoiesis (EM) in 13.5%, an increased erythropoiesis, megakaryopoiesis and granulopoiesis (EMG) in 31.3%, a normocellular megakaryocytic (M) proliferation in 29,1%, a megakaryocytic and granulocytic (MG) proliferation with a relative reduction of erythropoiesis in post-ET and Post-PV myelofibrosis in 26.2%. The bone marrow histology in 56 cases of CALR mutated MPN show a predominantly increased megakaryopoiesis (M) in two thirds and an increased megakaryopoiesis and granulopoiesis (MG) with a decreased erythropoiesis in one third.

Thirteen consecutive CALR MPN patients in the Belgian & Dutch cross sectional study presented with thrombocythemia associated with a typical PMGM bone marrow histology in 11 and myelofibrosis in 2 cases. All 11 thrombocythemia and 2 myelofibrosis CALR mutated MPN patients did not have constitutional symptoms and did not suffer from microvascular erythromelalgic disturbances, major thrombosis at platelet counts between 400 and 1000x109/L. There was an occurrence of hemorrhages at platelet counts above 1000x109/L in two CALR thrombocythemia cases.

Bone marrow histology of CALR mutated thrombocythemia in the Seoul and Belgian/Dutch study showed loose clusters of large megakaryocytes (M) with bulky, cloud-like nuclei with a normal or a minor reduction of erythropoiesis and no increase in reticulin fibers grade 0 or 1 (RF 0 or 1). CALR thrombocythemia patients show various degrees of increased bone marrow cellularity due to dual megakaryocytic and granulocytic (MG) proliferation featured by large megakaryocytes with roundish bulky nuclear forms and cloud-like clumsy nuclei, which are almost never seen in JAK2V617F ET and PV. Assessment of allele burden is an independent and most important factor for all molecular variants MPN disease burden. Overt myelofibrosis with advanced post PV and or ET myelofibrosis at the bone marrow level occurred in one third (30%) of 208 evaluable JAK2 MPN patients and in 8 (14%) of 56 CALR MPN patients in the Seoul study.

Read Full Article HTML DOI: 10.29328/journal.ijbmr.1001006 Cite this Article Read Full Article PDF

Keywords:

Myeloproliferative neoplasms; Essential thrombocythemia; Primary megakaryocytic granulocytic myeloproliferation; Myelofibrosis; Calreticulin mutation; JAK2 wild type; Bone marrow histology

References

  1. Dameshek W. Physiopathology and coarse of polycythemia vera as related to therapy. JAMA. 1950; 142: 790-797. Ref.: http://bit.ly/2MYKF4n
  2. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951; 6: 372-375. Ref.: http://bit.ly/2KDmirl
  3. Wasserman LR. The management of polycythaemia vera. Br J Haematol.1971; 21: 371-376 Ref.: http://bit.ly/2L8bHUH
  4. Laszlo J. Myeloproliferative disorders (MPD): myelofibrosis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD and hemorrhagic thrombocythemia. Semin Hematol. 1975; 12: 409-432. Ref.: http://bit.ly/2KxFiHo
  5. Berlin NI. Diagnosis and classification of the polycythemias. Sem Hematol. 1975; 12: 339-351. Ref.: http://bit.ly/2RtZrPx
  6. 2001 WHO classification of the chronic myeloproliferative diseases (CMPD) polycythemia vera, chronic idiopathic myelofibrosis essential thrombocythemia and cMPD unclassifiable. In: Jaffe SS, Harris NL, Stern A, Vardiman JW eds. WHO classification of Tumours of haematopoiesis and lymphoid tissues. Lyon, France IARC. 2001; 31-42.
  7. 2008 WHO criteria for polycthemia vera, primary myelofibrosis and essential thrombocythemia. Thiele et al In: Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon France IARC Press. 2008; 40-50.
  8. Michiels JJ1, Prins ME, Hagermeijer A, Brederoo P, van der Meulen J, et al. Philadelphia chromosome positive essential thrombocythemia and megakaryoblast leukemia. Am J Clin Pathol. 1987; 88: 645-752. Ref.: http://bit.ly/2J4b0sz
  9. Georgii A, Vykoupil KF, Buhr T, Choritz H, Döhler U, et al. Chronic myeloproliferative disorders in bone marrow biopsies. Path Res Pract. 1990; 186: 3-27. Ref.: http://bit.ly/2L8d7hZ
  10. Georgii A, Buhr T, Buesche G, Kreft A, Choritz H. Classification and staging of Ph-negative myeloproliferative disorders by histopathology from bone marrow biopsies. Leukemia Lymphoma. 1996; 22: Suppl 1: 15-29. Ref.: http://bit.ly/2WWFB0q
  11. Michiels JJ. Diagnostic criteria of the myeloproliferative disorders (MPD): essential thrombocythemia (ET), polycythemia vera (PV) and chronic megakaryocytic granulocytic metaplasia (CMGM). Neth J Med. 1997; 51: 57-64. Ref.: http://bit.ly/2Y88Y12
  12. Michiels JJ, Juvonen E. Proposal for revised diagnostic criteria of essential thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group. Sem Thromb Hemostas. 1997; 23: 339-347. Ref.: http://bit.ly/2J0Du6C
  13. Michiels JJ, Kutti J, Stark P, Bazzan M, Gugliotta L, et al. Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thromboythemia, polycythemia vera and essential megakaryocytic granulocytic myeloproliferation and myelofibrosis. Neth J Med. 1999; 54: 46-62. Ref.: http://bit.ly/2ZCIzbX
  14. 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. Ref.: http://bit.ly/2XAjmln
  15. Michiels JJ, Kvasnicka HM, Thiele J. Doctor’s Brochure 2004, Myeloproliferative Disorders Essential Thrombocythemia, Polycythemia Vera and Chronic idiopathic Myelofibrosis. MPD: Ref.: http://bit.ly/2Ru0TRZ
  16. Michiels JJ, Hendrik De Raeve, Berneman Z, Van Bockstaele D, Hebeda K, et al. The 2001 World Health Organization and updated European Clinical and Pathological criteria for the diagnosis classification and staging of the Philadelphia-negative chronic myeloproliferative disorders. Sem Thromb Hemostas. 2006; 32: 307-340. Ref.: http://bit.ly/2IyarIC
  17. Michiels JJ, Berneman Z, Van Bockstaele D, Van Der Planken M, De Raeve H, et al. Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding complications and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications. Sem Thromb Hemostas. 2006; 32: 174-207. Ref.: http://bit.ly/2YaX6eU
  18. Michiels JJ, Piche A, De Raeve H, Campr V, Schwarz J. WHO clinical molecular and pathological (WHO-CMP) features of congenital MPLS505N and the acquired MPLW515L/K mutated essential thrombocythemia and myelofibrosis. J Hematol Thromb Dis. 2014; 2: 6. Ref.: http://bit.ly/2L7N3na
  19. Michiels JJ. Myeloproliferative and thrombotic burden and treatment outcome in thrombocthemia and polycythemia patients. World J Crit Care Med. 2015; 4: 230-239. Ref.: http://bit.ly/2KyB4iX
  20. Michiels JJ, Berneman Z, Schroyens W, De Raeve H. Changing concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: From Dameshek 1950 to Vainchenker 2005 and beyond. Acta Haematol. 2015; 133: 36-51. Ref.: http://bit.ly/2Y4mVgz
  21. Michiels JJ, Valster F, Wielenga J, Schelfout K, De Raeve H. European vs 2015 World Health Organization clinical molecular and pathological classification of myeloproliferative neoplasms. World J Hematol. 2015; 4: 16-53. Ref.: http://bit.ly/2ZC2szZ
  22. Michiels JJ, Medinger M, De Raeve H, Schroyens W, Schelfout K, et al. Increased erythrocyte count on top of bone marrow histology, but not by EPO level or JAK2V617F mutation load discriminates between JAK2V617F mutated essential thrombocythemia and polycythemia vera. J Hematol Thromb Dis. 2015; SI.001. Ref.: http://bit.ly/2IY5zM3
  23. Michiels JJ, Tevet M, Trifa A, Niculescu-Mizil E, Lupa A, et al. 2016 WHO Clinical Molecular and Pathological Criteria for Classification and Staging of Myeloproliferative Neoplasms (MPN) Caused by MPN Driver Mutations in the JAK2, MPL and CALR Genes in the Context of New 2016 WHO Classification: Prognostic and Therapeutic Implications. MAEDICA. 2016; 11: 5-25. Ref.: http://bit.ly/2IY688D
  24. Michiels JJ, De Raeve H, Valster F, Potters V, Kim Y, et al. Extension of 2016 World Health Organization (WHO) classification and a new set of clinical, laboratory, molecular and pathological criteria for the diagnosis of myeloproliferative neoplasms: from Dameshek to Vainchenker, Green and Kralovics. EMJ. 2017; 2: 72-81. Ref.: http://bit.ly/31NrRbV
  25. De Raeve H, Fostier K, Valster F, Potters V, Kim Y, et al. Bone Marrow Histology is a Pathognomonic Clue to Each of the JAK2V617F, MPL515 and Calreticulin Mutated Thrombocythemia in Myeloproliferative Neoplasms. Clin Res Hematol. 2018: 1: 1-7. Ref.: http://bit.ly/2IwU3Ih
  26. De Raeve H, Michiels JJ, Valster F, Potters V, Kim Y, et al. Novel Clinical, Laboratory, Molecular and Pathological (2018 CLMP) Criteria for the Differential Diagnosis of three Distinct JAK2, CALR and MPL Mutated Myeloproliferative Neoplasms: The Role of Driver Mutation Analysis and Bone Marrow Histology. Int J Cancer Res Ther. 2018; 3: 1-12. Ref.: http://bit.ly/2IvwsHY
  27. James C, Delhommeau F, Marzac C, Teyssandier I, Le Couédic JP, et al. Detection of JAK2 V617F as a first intention diagnostic test for erythrocytosis. Leukemia. 2006; 20: 350-353. Ref.: http://bit.ly/2WS1QEA
  28. Vainchenker W, Constantinescu SN. A unique activating mutation in JAK2 V617F is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases. Hematology (Am Soc Hematol Educ Progr). 2005; 195-200. Ref.: http://bit.ly/2IZ9JmF
  29. Klampf T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, et al. Somatic mutations of calreticulin myeloproliferative neoplasms. N Engl J Med. 2013; 369: 2379-2387. Ref.: http://bit.ly/2Rr7iNI
  30. Kim Y, Park J, Jo I, Lee GD, Kim, et al. Genetic-pathologic characterization of myeloproiferative neoplasms. Exp Mol Med. 2016; 48: 247. Ref.: http://bit.ly/2Ix46go
  31. Michiels JJ, De Raeve H, Schwarz J, Campr V, Kim Y, et al.. Bone Marrow Histology Characteristics in MPL515 Mutated Thrombocythemia with Various Degrees of Myelofibrosis: A Cross Sectional Follow-up Study in Eight Cases. J Hematol Thrombo Dis. 2018; 6: 2. Ref.: http://bit.ly/2Xn3fHC
  32. Michiels JJ, Berneman Z, Gadisseur A, De Raeve HD, Schroyens W, et al. Myelofibrosis is a Secondary Event in JAK2 Trilinear Myeloproliferative Neoplasm (MPN) and in CALR and MPL Thrombocythemia: Implications for Novel Treatment Options of Prefibrotic MPN. J Hematol Thromembolic Dis. 2017; 5: 5. Ref.: http://bit.ly/2N4aMHa
  33. Michiels JJ, De Raeve H. The PVSG/WHO versus the Rotterdam European clinical, molecular and pathological diagnostic criteria for the classifi cation of myeloproliferative disorders and myeloproliferative neoplasms (MPD/MPN): From Dameshek toGeorgii, Vainchenker and Michiels 1950-2018. Int J Bone Marrow Res. 2019; 2: 027-050. Ref.: http://bit.ly/2IvOIBc
  34. Michiels JJ, Berneman Z, Schroyens W, J ten Kate FW, Lam K, et al. European Clinical Laboratory, Molecular and Pathological (ECMP) criteria for prefi brotic JAK2V617F-Thrombocythemia and Polycythemia Vera versus MPL51- and CALR-Thrombocythemia and Myelofi brosis: From Dameshek to Michiels 1950-2018. Int J Bone Marrow Res. 2019; 2: 001-017. Ref.: http://bit.ly/31SeYxp

Figures:

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More

Help ?