Research Article

European Clinical Laboratory, Molecular and Pathological (ECMP) criteria for prefibrotic JAK2V617F-Thrombocythemia and Polycythemia Vera versus MPL515- and CALR-Thrombocythemia and Myelofibrosis: From Dameshek to Michiels 1950-2018

Jan Jacques Michiels*, Zwi Berneman, Wilfried Schroyens, Fibo W J ten Kate, King Lam and Hendrik De Raeve

Published: 03/01/2019 | Volume 2 - Issue 1 | Pages: 001-017

Abstract

The broad spectrum of heterozygous versus homozygous JAK2V617F mutated MPN consists ET, ET with early features of PV (prodromal PV), classical PV, masked PV, advanced PV and post-PV myelofibrosis. Combined use of bone marrow histology and increased erythrocyte counts above 5.8x1012/L can replace increased red cell mass at time of presentation as the pathognomonic clue for the correct diagnosis of hetero/homozygous or homozygous mutated PV. Erythrocyte counts are in the normal range below 5.8x1012/L in heterozygous JAK2V617F mutated ET and prodromal PV but above 5.8x1012/L in heterozygous-homozygous or homozygous mutated PV. The bone marrow cellularity and morphology in pre-fibrotic ET, prodromal PV and PV carrying the JAK2V617F mutation are overlapping showing clustered increase of large mature pleomorphic megakaryocytes (M) with no increase of cellularity (<60%) in ET. The bone marrow is hypercellular (60%-80%) due to increased erythropoiesis megakaryopoiesis (EM) in prodromal and classical PV and trilinear hypercellular (80%-100% due increased megakaryopoiesis, erythropoiesis and granulopoiesis (EMG) in advanced PV and masked PV. Bone marrow cellularity ranging from normal (<60%) in ET to increased erythropoiesis (EM) in prodromal PV to hypercellular (80-100%) in advanced PV and masked PV largely depends on increasing JAK2V617F mutation load from low to high on top of other biological MPN variables like constitutional symptoms during long-term follow-up. MPL515 mutated ET is featured by an increase of clustered small and giant megakaryocytes with hyper-lobulated staghorn-like nuclei in a normal cellular bone marrow. The third entity of pronounced JAK2/MPL wild type ET associated with primary megakaryocytic granulocytic myeloproliferation (PMGM) without PV features proved to be caused by calreticulin (CALR) mutation. CALR mutated thrombocythemia is characterized by dual proliferation of megakaryocytic and granulocytic bone marrow proliferation of dense clustered large to giant immature dysmorphic megakaryocytes with bulky (bulbous) hyperchromatic nuclei, which are not seen in MPL515-mutated Thrombocythemia and JAK2V617F-Thrombocythemia, prodromal PV and classical PV.

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References

  1. Michiels JJ. Physiopathology, etiologic factors, diagnosis and course of polycythemia vera as related to therapy according to William Dameshek 1940-1950. Turkish J Hematol. 2013; 30: 102-110. Ref.: https://goo.gl/VWF3Td
  2. Michiels JJ, Ten Kate FWJ, Vuzevski VD, Abels J. Histopathology of erythromelalgia in thrombocythemia. Histopathology. 1984; 8: 669-678. Ref.: https://goo.gl/t79oZi
  3. Michiels JJ, Abels J, Steketee J, van Vliet HHDM, Vuzevski VD. Erythromelalgia caused by platelet mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med. 1985; 102: 466-471. Ref.: https://goo.gl/SctHNS
  4. Michiels JJ, Koudstaal PJJ, Mulder AH, Van Vliet HHDM. Transient neurologic and ocular manifestations in primary thrombocythemia. Neurology. 1993; 43: 1107-1110. Ref.: https://goo.gl/cYQy8p
  5. Michiels JJ, Juvonen E. Proposal for revised diagnostic criteria of essential thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group (TVSG). Semin Thromb Hemostas. 1997; 23: 339-347. Ref.: https://goo.gl/9igXoi
  6. Michiels JJ, Thiele J. Clinical and pathological criteria for the diagnosis of essential thrombocthemia, polycythemia vera, and idiopathic myelofibrosis (agnogenic myeloid metaplasia). Int J Hematol. 2002; 76: 133-145. Ref.: https://goo.gl/nZkVe3
  7. Michiels JJ, De Raeve H, Hebeda K, Lam KH, Berneman Z, et al. WHO bone marrow features and European clinical molecular and pathlogical (EMCP) criteria for the diagnosis and classification of myeloproliferative disorders. Leuk Res. 2007; 31: 1031-1038. Ref.: https://goo.gl/xNUgyu
  8. Laszlo J. Myeloproliferative disorders (MPD): myelofibrosis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD, and primary hemorrhagic thrombocythemia. Semin Haematol. 1975; 12: 409-432. Ref.: https://goo.gl/8pu88V
  9. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951; 6: 372-375. Ref.: https://goo.gl/VVzyAJ
  10. Berlin MI. Diagnosis and classification of the polycythemias. Semin Hematol. 1975; 12: 339-351. Ref.: https://goo.gl/U5Yaad
  11. Ellis JT, Silver RT, Coleman M, Geller SA. The bone marrow in polycythemia vera. Semin Hematol. 1986; 12: 433-444. Ref.: https://goo.gl/fNNG28
  12. Kurnick JE, Ward HP, Block MH. Bone marrow sections in the differential diagnosis of polycythemia. Arch Pathol. 1972; 94: 489-499. Ref.: https://goo.gl/8vjxEJ
  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.: https://goo.gl/VbWuP2
  14. Michiels JJ, Barbui T, Finazzi G, Fruchtman SM, Kutti J, et al. Diagnosis and treatment of polycythemia vera and possible future study designs of the PVSG. Leukemia Lymphoma. 2000; 36: 239-253. Ref.: https://goo.gl/JA8arG
  15. Michiels JJ. Bone marrow histopathology and biological markers as specific clues to differential diagnosis of essential thrombocythemia, polycythemia vera and prefibrotic or fibrotic agnogenic myeloid metaplasia. The Hematol J. 2004; 5: 93-102. Ref.: https://goo.gl/C7nKXe
  16. Michiels JJ, Kvasnicka HM, Thiele J. Myeloproliferative Disorders. Current perspectives on diagnostic criteria, histopathology and treatment in essential thrombocythemia, polycythemia vera, and chronic idiopathic myelofibrosis. ISBN 3-9808075-6-8, 2005. Ref.: https://goo.gl/UvMStz
  17. Thiele J, Kvasnicka HM, Facchetti F, Franco V, Van Der Walt J, et al. European consensus for grading bone marrow fibrosis and assessment of cellularity in myeloproliferative diaorders. Haematologica. 2005; 90: 1128-1132. Ref.: https://goo.gl/AEWjiW
  18. Baxter EJ1, Scott LM, Campbell PJ, East C, Fourouclas N, et al. Acquired mutation of tyrosine kinase in human myeloproliferative disorders. Lancet. 2005; 365: 1054-1061. Ref.: https://goo.gl/JRaA1r
  19. Messinezy M, Westwood NB, Woodcock SP, Strong RM, Pearson TC. Low serum erythropoietin - a strong diagnostic criterion of primary polycythaemia even at normal haemoglobin levels. Clin Lab Haematol. 1995; 17: 217-220. Ref.: https://goo.gl/4QfJiu
  20. Messinezy M1, Westwood NB, El-Hemaidi I, Marsden JT, Sherwood RS, et al. Serum erythropoietine values in erythrocytoses and in primary thrombocythemia. Br J Haematol. 2002; 117: 47-53. Ref.: https://goo.gl/b3vQaJ
  21. Mossuz P1, Girodon F, Donnard M, Latger-Cannard V, Dobo I, et al. Diagnostic value of serum erythropoietine in patients with absolute erythrocytosis. Haematologica. 2004; 89: 1194-1198. Ref.: https://goo.gl/ezvfQq
  22. Dameshek W, Henstell HH. The diagnosis of polycythemia. Ann Intern Med. 1940: 13: 1360-1387. Ref.: https://goo.gl/9UY1MD
  23. Dameshek W. Physiopathology and course of polycythemia vera as related to therapy. JAMA. 1950; 142: 790-797. Ref.: https://goo.gl/sNRiJJ
  24. Thiele et al. 2008 WHO criteria for polycthemia vera, primary myelofibrosis and essential thrombocythemia. In: Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of Haematopoietic and Lympoid Tissues. Lyon France IARC Press. 2008; 40-50.
  25. Thiele J, Zankovich R, Schneider G, Kremer B, Fischer R, et al. Primary (essential) thrombocythemia versus polycythemia rubra vera. A histmorphometric analysis of bone marrow features in trephine biopsies. Anal Quant Cytol Histol. 1988; 10: 375-382. Ref.: https://goo.gl/MLursT
  26. Georgii A, Vykoupil KF, Buhr H, Choritz H, Doehler U, et al. Chronic myeloproliferative disorders in bone marrow biopsies. Path Res Pracxt. 1990; 186: 3-27. Ref.: https://goo.gl/mU4E5g
  27. Piche A, Riera L, Beggiato E, Nicolino B, Godio L, et al. JAK2V617F mutation and allele burden are associated with distinct clinical and morphological subtypes in patients with essential thrombocythemia. J Clin Pathol. 2012; 65: 953-954. Ref.: https://goo.gl/UrE18X
  28. Thiele, 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. Ref.: https://goo.gl/tv1drc
  29. Tefferi A1, Thiele J, Orazi A, Kvasnicka HM, Barbui T, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007; 110: 1092-1097. Ref.: https://goo.gl/HRpXUq
  30. Buhr T, Hebeda K, Kaloutsi V, Porwit A, Van der Walt J, et al. European Bone Marrow Working group trial to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis. Haematologica. 2012; 97: 360-365. Ref.: https://goo.gl/3tXFk5
  31. Michiels JJ, Commandeur S, Hoogenboom GJ, Wegman JJ, Scholten L, et al. JAK2V617F positive early stage myeloproliferative disease (essential thrombocythemia) as the cause of portal vein thrombosis in two middle-aged women: therapeutic implications in view of the literature. Ann Hematol. 2007; 86: 793-800. Ref.: https://goo.gl/CCwbSU
  32. James C1, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, et al including Constantinescu S, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia var. Nature. 2005; 434: 1144-1148. Ref.: https://goo.gl/qHQJYj
  33. 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.: https://goo.gl/5vUrwS
  34. Michiels JJ, De Raeve H, Berneman Z, Van Bockstaele D, Hebeda K, et al. The 2001 WHO and updated European Clinical and Pathological (ECP) criteria for the diagnosis, classification, and staging of the Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD). Sem Thromb Hemostas. 2006; 32: 307-340. Ref.: https://goo.gl/XNy2Qe
  35. Michiels JJ, Berneman Z, Van Bockstaele, 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. Semin Thromb Hemostas. 2006; 32: 174-207. Ref.: https://goo.gl/8WHXgk
  36. Villeval JL, James C, Pisani D, Casadevall N, Vainchenker W. New insights into pathogenesis of JAK2V617F-positive myeloproliferative disorders and consequences for the management of patients. Sem Thromb Hemostas. 2006; 32: 341-351. Ref.: https://goo.gl/KzCMz2
  37. Thiele J, Kvasnicka HM, Diehl V. Initial (latent) polycythemia vera with thrombocytosis mimicking essential thrombocythemia. Acta Haematol. 2005; 113: 213-219. Ref.: https://goo.gl/ZjSa5L
  38. Gale RE, Allen AJR, Nash MJ, Linch DC. Log-term serial analysis of X-chromosome inactivation patterns andJAK2 V617F mutant levels in patients with essential thrombocythemia show that minor mutant-positive clones can remain stable for many years. Blood. 2007; 109: 1241-1243. Ref.: https://goo.gl/wBiyPZ
  39. Campbell PJ1, Scott LM, Buck G, Wheatley K, East CL, et al. Definition of essential thrombocythemia and relation of essential thrombocythemia to polycythemia vera based on JAK2 V617F mutation: a prospective study. Lancet. 2005; 366: 1945-1953. Ref.: https://goo.gl/nfWb6b
  40. Vannucchi AM1, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, et al. Clinical profile of homozygous JAK2V617F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007; 110: 840-846. Ref.: https://goo.gl/SC6fAj
  41. Antonioli E1, Guglielmelli P, Poli G, Bogani C, Pancrazzi A,, et al. Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica. 2008; 93: 41-48. Ref.: https://goo.gl/5EXWA5
  42. Vannucchi AM1, Antonioli E, Guglielmelli P, Pancrazzi A, Guerini V, et al. Charateristics and clinical correlates of MPL515W>L/K mutation in essential thrombocythemia. Blood. 2008; 112: 844-847. Ref.: https://goo.gl/2bmSWK
  43. Beer PA1, Campbell PJ, Scott LM, Bench AJ, Erber WN, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood. 2008; 112: 141-149. Ref.: https://goo.gl/hVpnbo
  44. Klampf T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, et al. Somatic mutations od calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013; 369: 2379-2390. Ref.: https://goo.gl/eWxPi3
  45. Georgii A, Buhr H, Buesche G, Kreft A, Chorotz H. Classification and staging of Ph-negative chronic myeloproliferative diseases. Leuk Lymphoma. 1996; 22(suppl 1): 15-29. Ref.: https://goo.gl/vBXsjq
  46. Georgii A, Buesche G, Kreft A. The histopathology of chronic myeloproliferative diseases. Bailliere’s Clin Haematol. 1998; 11: 721-749. Ref.: https://goo.gl/a5Fzas
  47. Michiels JJ, Valster F, Wielenga J, Schelfout K, De Raeve H. European vs 2015 World Health Organization clinical molecular and pathological (WHO-CMP) classification of myeloproliferative neoplasms. World J Hematol. 2015; 4: 16-53. Ref.: https://goo.gl/iaCLC6
  48. 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.: https://goo.gl/CJRMmt
  49. 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.: https://goo.gl/wJH2oJ
  50. Michiels JJ, De Rave 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 (CLMP) criteria for the diagnosis of myeloproliferative neoplasms: from Dameshek to Vainchenker, Green and Kralovics. EMJ. 2017a; 2: 72-81. Ref.: https://goo.gl/3QED5Z
  51. De Raeve H, Michiels JJ, Valster F, Potters V, Kim Y, et al. Novel clinical, laboratory, mollecular and pathological (2018 CLMP) criteria for the differential diagnosis of three distinct myeloprproliferative neoplasms: the role of driver mutation analysis and bone marrow histology. Int J Cancer Res Ther. 2018; 3: 1-13.
  52. 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 CALR mutated thrombocythemia in myeloproliferative neoplasms. Clin Res Hematol. 2018; 1: 1-7. Ref.: https://goo.gl/hq1ZCN