Research Article

The PVSG/WHO versus the Rotterdam European clinical, molecular and pathological diagnostic criteria for the classification of myeloproliferative disorders and myeloproliferative neoplasms (MPD/MPN): From Dameshek to Georgii, Vainchenker and Michiels 1950-2018

Jan Jacques Michiels* and Hendrik De Raeve

Published: 04/17/2019 | Volume 2 – Issue 1 | Pages: 027-050

Abstract

The present article extends the PVSG-WHO criteria into a simplified set of Rotterdam and European Clinical, Molecular and Pathological (RCP/ECMP) criteria to diagnose and classify the myeloproliferative neoplasms (MPNs). The crude WHO criteria still miss the masked and early stages of ET and PV. Bone marrow histology has a near to 100% sensitivity and specificity to distinguish thrombocythemia in BCR/ABL positive CML and ET, and the myelodysplastic syndromes in RARS-T and 5q-minus syndrome from BCR/ABL negative thrombocythemias in myeloproliferative disorders (MPD). The presence of JAK2V617F mutation with increased erythrocytes above 6×1012/L and hematocrit (>0.51 males and >0.48 females) is diagnostic for PV obviating the need of red cell mass measurement. About half of WHO defined ET and PMF and 95% of PV patients are JAK2V617F positive. The combination of molecular marker screening JAK2V617F, JAK2 exon 12, MPL515 and CALR mutations and bone marrow pathology is 100% sensitive and specific for the diagnosis of latent, early and classical ECMP defined MPNs. The translation of WHO defined ET, PV and PMF into ECMP criteria have include the platelet count above 350 x109/l, mutation screening and bone marrow histology as inclusion criteria for thrombocythemia in various MPNs. According to ECMP criteria, ET comprises three distinct phenotypes of true ET, ET with features of early (“forme fruste” PV), and ET with a hypercellular erythrocythemic, megakaryocytic granulocytic myeloproliferation (EMGM or masked PV). The ECMP criteria clearly differentiate early erythrocythemic, prodromal and classical PV from congenital polycythemia and idiopathic or secondary erythrocytosis. The burden of JAK2V617F mutation in heterozygous ET and in homozygous PV is of major clinical and prognostic significance. JAK2 wild type MPL515 mutated normocellular ET and MF lack PV features in blood and bone marrow. JAK2/MPL wild type hypercellular ET associated with primary megakaryocytic granulocytic myeloproliferation (PMGM) is the third distinct CALR mutated MPN. The translation of WHO into ECMP criteria for the classification of MPNs have a major impact on prognosis assessment and best choice for first line non-leukemogenic approach to postpone potential leukemogenic myelopsuppressive agents as long as possible in ET, PV and PMGM patients..

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References

  1. Heuck G. Two cases of leukemia with peculiar blood resp. Bone marrow findings. Virch Archiv. 1879; 78: 475-496. http://tinyurl.com/y3nj4d9a
  2. Vaquez MH. On a special form of cyanosis accompanied by excessive and persistent hyperglobulism. Minutes of meetings of the Society of Biology. 1892; 44: 384-388.
  3. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951; 6: 372-375. Ref.: http://tinyurl.com/y3jaylqy
  4. Nowell PC, Hungerford DA. A minute chromosome in human chronic, granulocytic leukemia. Science. 1960; 142: 1497. http://tinyurl.com/y643rqmp
  5. Rowley J. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence Giemsa staining. Nature. 1973; 243: 290-291. Ref.: http://tinyurl.com/y6q2cge5
  6. De Klein A, Van Kessel AG, Grosveld GG, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia. Nature. 1982; 300: 765-767. Ref.: http://tinyurl.com/yyt56e7j
  7. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of BCR/ABL oncogene products. Science. 1990; 247: 1079-1082. Ref.: http://tinyurl.com/y27g6qbd
  8. Kelliber MA, McLaughin J, Witte ON, Rosenberg N. Induction of a chronic myelogenous-like syndrome in mice with v-abl and BCR/ABL. Proc Nat Sci. 1990; 87: 6649-6653. Ref.: http://tinyurl.com/yya3hopy
  9. Shephard PCA, Ganesan TS, Galton DAG. Haematological classification of the chronic myeloid leukemias. Baillière’s Clin Haematol. 1987; 1: 887-906. Ref.: http://tinyurl.com/y27glcpu
  10. Michiels JJ, Prins ME, Hagemeijer A, Brederoo P, Van der Meulen J, et al. Philadelphia chromosome-positive thrombocythemia and megakaryoblast leukemia. Am J Clin Pathol. 1987; 88: 645-652. Ref.: http://tinyurl.com/y4wyaeaa
  11. Dameshek W. Physiopathology and course of polycythemia vera as related to therapy. J Am Med Ass. 1950; 142: 790-797. Ref.: http://tinyurl.com/y2b5pqa2
  12. James C, Ugo V, Le Couedic PF, Staerk J, Delhommeau F, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera. Nature. 2005; 434: 1144-1148. Ref.: http://tinyurl.com/yxnm998a
  13. James C, Ugo V, Casadevall N, Constantinescu SN, Vainchenker W. A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects. Trends Mol Med. 2005; 11: 546-554. Ref.: http://tinyurl.com/y66ty8n8
  14. Thiele J, Zankovich R, Schneider G, Kremer B, Fischer R, et al. Primary (essential) thrombocythemia versus polycythemia rubra vera. A histomorphometric analysis of bone marrow features in trephine biopsies. Analyt Quat Cytol Histol. 1988; 10: 375-382. Ref.: http://tinyurl.com/y4oesnkw
  15. Thiele J, Schneider G, Hoeppner B, Wienhold S, Zankovich R, et al. Histomorphometry of bone marrow biopsies in chronic myeloproliferative disorders with associated thrombocythosis – features of significance for the diagnosis of primary (essential) thrombocythemia. Virch Arch A Path Anat. 1988; 413: 407-417. Ref.: http://tinyurl.com/y3lqtokm
  16. Thiele J, Zankovich R, Steinberg T, Kremer B, Fischer R, et al. Primary (essential) thrombocythemia versus hyperplastic stages of agnogenic myeloid metaplasia with thrombocytosis: a critical evaluation of clinical and histomorphological data. Acta Haematol. 1989; 81: 192-202. Ref.: http://tinyurl.com/y5vevoy7
  17. Thiele J, Zankovich R, Steinberg T, Fischer R, Diehl V. Agnogenic myeloid metaplasia (AMM) – correlation of bone marrow lesions with laboratory data: a longitudinal clinicopathological study on 114 patients. Hematol Oncol. 1989; 7: 327-343. Ref.: http://tinyurl.com/yyusm65l
  18. Georgii A, Vykoupil KF, Buhr Th, Choritz H, Doehler U, et al. Chronic myeloproliferative disorders in bone marrow biopsies. Path Res Pract. 1990; 186: 3-27. Ref.: http://tinyurl.com/y4v9x6t2
  19. Wasserman LR. The management of polycythemia vera. Br J Haematol. 1971; 21: 371-376. Ref.: http://tinyurl.com/y2vsn9h3
  20. Berlin NI. Diagnosis and classification of the polycythemias. Sem Hematol. 1975; 12: 339-351. Ref.: http://tinyurl.com/yyqkheob
  21. Laszlo J. Myeloproliferative disorders (MPD): myelofibrosis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD and hemorrhagic thrombocythemia. Semin Hematol. 1975; 12: 409-432. Ref.: http://tinyurl.com/y68mreem
  22. Murphy S, Iland H, Rosenthal D, Laszlo J. Essential thrombocythemia: An interim report from the Polycythemia Vera Study Group. Semin Hematol. 1986; 23: 177-182. Ref.: http://tinyurl.com/y4pwch4j
  23. 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. Sem Hematol. 1997; 34: 29-39. Ref.: http://tinyurl.com/y6fmr7pb
  24. Michiels JJ. Diagnostic criteria of the myeloproliferative4 disorders (MPD): essential thrombocythemia, polycythemia vera, and chronic megakaryocytic granulocytic metaplasia. Neth J Med. 1997; 51: 57-64. Ref.: http://tinyurl.com/y6s2az6b
  25. Jaffe S, Harris NL, Stein H. WHO classification of the chronic myeloproliferative diseases (CMPD) polycythemia vera, chronic idiopathic myelofibrosis, essential thrombocythemia and CMPD unclassifiable. Tumours of Haematopoiesis and Lymphoid Tissues. Lyon. 2001; 31-42.
  26. Michiels JJ, De Raeve H, Berneman Z, Van Bockstaele D, Hebeda K, et al. The 2001 World Health Organization (WHO) and updated European clinical and pathological (ECP) criteria for the diagnosis, classification and staging of the Ph1-chromosome negative chronic myeloproliferative disorders (MPD). Sem Thromb Hemostas. 2006; 32: 307-340.
  27. Thiele J, Kvasnicka HM, Diehl V, Fischer R, Michiels JJ. Clinicopathological diagnosis and differential criteria of thrombocythemias in various myeloproliferative disorders by histopathology, histochemistry and immunostaining from bone marrow biopsies. Leukemia and Lymphoma. 1999; 33: 207-218. Ref.: http://tinyurl.com/yy79mqsk
  28. Thiele J, Kvasnicka HM. Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classifications systems (PVSG-WHO) on 839 patients. Ann Hematol. 2003; 82: 148-152. Ref.: http://tinyurl.com/y3hryz69
  29. Florena AM, Tripodo C, Iannitto E, Porcasi R, Ingrao S, et al. Value of bone marrow biopsy for diagnosis of essential thrombocythemia. Haematologica. 2004; 89: 911-919. Ref.: http://tinyurl.com/y4b9f3qd
  30. Lengfelder E, Hochhaus A, Kronawitter U. Should a platelet count of 600 x109/l be used as a diagnostic criterion in essential thrombocythemia? An analysis of the natural course including early stages. Br J Haematol. 1998; 100: 15-23.
  31. Sacchi S, Vinci G, Gugliotta L, Rupoli S, Garganti L, et al. Diagnosis of essential thrombocythemia at platelet counts between 400 and 600×109/l. Gruppo Italiano Malattie Mieloproliferative Chroniche (GIMMC). Haematologica. 2000; 85: 492-495. Ref.: http://tinyurl.com/y3setqtg
  32. Michiels JJ, Ten Kate FWJ. Erythromelalgia in thrombocythemia of various myeloproliferative disorders. Am J Hematol. 1992; 39: 131-136. Ref.: http://tinyurl.com/yxr8gy7m
  33. Michiels JJ, Juvonen E. Proposal for revised diagnostic criteria of essential thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group. Semin Thromb Hemostas. 1997; 23: 339-347. Ref.: http://tinyurl.com/y6zb6dah
  34. Wasserman LR. Polycthemia vera, its course and treatment: relation to myeloid metaplasia and leukemia. Bull NY Acad Med. 1954; 30: 343-375. Ref.: http://tinyurl.com/y5448f94
  35. Wasserman LR, Berk PD, Berlin NI. Polycythemia vera and the myeloproliferative disorders. WB Saunders Philadelphia. 1995; ISBN 0-7216-4213-6.
  36. Michiels JJ, Barbui T, Fruchtman SM, Kutti J, Rain JD, et al. Diagnosis and treatment of polycythemia vera and possible future study designs of the PVSG. Leukemia Lymphoma. 2000; 36: 239-253. Ref.: http://tinyurl.com/y5tm3zbp
  37. Pearson TC, Wetherley-Mein G. The course and complications of idiopathic erythrocytosis. Clin Lab Haematol. 1979; 1: 189-196. Ref.: http://tinyurl.com/y5u7m9rd
  38. Najean Y, Triebel F, Dresch C. Pure erythrocytosis: reappraisal of a study of 51 patients. Am J Hematol. 1981; 10: 129-136. Ref.: http://tinyurl.com/yxtn5zx6
  39. Kurnick JE, Ward HP, Block MH. Bone marrow sections in the differential diagnosis of polycythemia. Arch Path. 1972; 94: 489-499. Ref.: http://tinyurl.com/y3m2mn8y
  40. Ellis JT, Silver RT, Coleman M, Geller SA. The bone marrow in polycythemia vera. Sem Hematol. 1975; 12: 433-444. Ref.: http://tinyurl.com/y5afjdyz
  41. Ellis JT, Peterson P. The bone marrow in polycythemia vera. Pathol Annu. 1979; 14: 383-403. Ref.: http://tinyurl.com/y3c6dvks
  42. Prchal JF, Axelrad AE. Bone marrow responses in polycythemia vera. N Eng J Med. 1974; 290: 1382. Ref.: http://tinyurl.com/y6axsstc
  43. Prchal JF, Axelrad A, Crookston JH. Erythroid colony formation in plasma culture from cells of peripheral blood in myeloproliferative disorders. Blood. 1974; 44: 912.
  44. Zanjani ED, Lutton JD, Hoffman R, Wasserman LR. Erythroid colony formation by polycythemia vera bone marrow in vitro. Dependence on erythropoietin. J Clin Invest. 1977; 59: 841-848. Ref.: http://tinyurl.com/y2xqsvpy
  45. Casadevall N, Lacombe C, Varet B. In vitro study of erythroid. Precursors in Vaquez’s disease (polycythemia vera). Evidence supporting 2 populations of elytroid. Stem cells in the bone marrow. Nouvelle Revue Francaise d’Hematologie. 1978; 20: 575-574. Ref. : http://tinyurl.com/yy3rfjc4
  46. 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://tinyurl.com/y3r2hp25
  47. Michiels JJ. Bone marrow histopathology and biological markers as specific clues to the differential diagnosis of essential thrombocythemia, polycythemia vera and prefibrotic or fibrotic myeloid metaplasia. Hematol J. 2004; 5: 93-102. Ref.: http://tinyurl.com/y2zlay6n
  48. Thiele J, Kvasnicka HM, Diehl V. Bone marrow features of diagnostic impact in erythrocytosis. Ann Haematol. 2005; 84: 362-367. Ref.: http://tinyurl.com/y47bqszj
  49. Thiele J, Kvasnicka HM, Diehl V. Initial (latent) polycythemia vera with thrombocytosis mimicking essential thrombocythemia. Acta Haematologica. 2005; 113: 213-219. Ref.: http://tinyurl.com/y5ktlbk7
  50. Thiele J, Kvasnicka HM, Zankovich R, Diehl V. The value of bone marrow histopathology for the differentiation between early stage polycythemia vera and secondary (reactive) polycythemias. Haematologica. 2001; 86: 368-374. Ref.: http://tinyurl.com/y584phsq
  51. Thiele J, Kvasnicka HM, Muehlhausen K, Walter S, Zankovich R, et al. Polycythemia rubra vera versus secondary polycythemias. A clinicopathological evaluation of distinctive features in 199 patients. Pathology Res Pract. 2001; 197: 77-84. Ref.: http://tinyurl.com/y69jrm5p
  52. Tefferi A, 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. Blood. 2007. 110: 1092-1097. Ref.: http://tinyurl.com/y6kkf6ew
  53. Sirhan S, Fairbanks VG, Tefferi A. Red cell mass and plasma volume measurements in polycythemia. Cancer. 2005; 104: 213-215. Ref.: http://tinyurl.com/y642u8m9
  54. Johansson PL, Safia-Kutti S, Kutti J. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythemia vera and apparent polycythaemia. Br J Haematol. 2005; 129: 701-705. Ref.: http://tinyurl.com/y32628n5
  55. Westwood NB, Pearson TC. Diagnostic applications of haematopoietic progenitor culture techniques in polycythaemias and thrombocythaemias. Leukemia Lymphoma. 1996; 22: 95-103. Ref.: http://tinyurl.com/y4sdzk9l
  56. Juvonen E, Ikkala E, Oksanen K, Tapani R. Megakaryocyte and erythroid colony formation in essential thrombocythaemia and reactive thrombocytosis: diagnostic value and correlation to complication. Br J Haematol. 1993; 83: 192-197. Ref.: http://tinyurl.com/y6ez6b6k
  57. Shih LY, Lee CT. Identification of masked polycythemia vera from patients with idiopathic thrombocytosis by endogenous elytroid colony assay. Blood. 1994; 83: 744-748. Ref.: http://tinyurl.com/yxkfc9af
  58. Liu E, Jelinek J, Pastore YD, Guan Y, Prchal JF. Discrimination of polycythemias and thrombocytoses by novel simple, accurate clonality assays and comparison with PRV-1expression and BFU-e responses to erythropoietin. Blood. 2003; 101: 3294-3301. Ref.: http://tinyurl.com/y2he6wkm
  59. Dobo I, Donnard M, Giridon F, Mossuz P, Boiret N, et al. Standardization and comparison of endogenous erythroid colony assays performed with bone marrow or blood progenitors for the diagnosis of polycythemia vera. Hematol J. 2004; 5: 161-167. Ref.: http://tinyurl.com/y54dzoju
  60. Mossuz P, Giridon F, Latger-Cannard V, Dobo I, Boiret N, et al. Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis. Haematologica. 2004; 89: 1194-1198. Ref.: http://tinyurl.com/y32v63gk
  61. Johansson P, Andreason B, Safai-Kutti S, Wennstrom L, Palmqvist L, et al. The presence of a significant association between elevated PRV-1 mRNA expression and low plasma erythropoietin concentration in essential thrombocythemia. Eur J Haematol. 2003; 70: 358-362. Ref.: http://tinyurl.com/y2vxuu2z
  62. Temerinac S, Klippel S, Strunck E, Röder S, Lübbert M, et al. Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is over expressed in polycythemia rubra vera. Blood. 2000; 95: 2569-2576. Ref.: http://tinyurl.com/y2zrkrqp
  63. Pahl HL. Polycythaemia vera: will new markers help us answer old questions? Acta Haematol. 2002; 108: 120-131. Ref.: http://tinyurl.com/y5w3ccpo
  64. Goertler PS, Steimle C, Maerz E, Johanson PL, Andreasson B, Griesshammer M, et al. The JAK2 V617F mutation, PRV-1 over expression and EEC formation define a similar cohort of MPD patients. Blood. 2005; 106: 2862-2864. Ref.: http://tinyurl.com/y6bkgtal
  65. Griesshammer M, Klippel S, Strunk E, Temeric S, Mohr U, et al. PRV-1 mRNA expression discriminates two types of essential thrombocythemia. Ann Hematol. 2004; 83: 364-370. Ref.: http://tinyurl.com/y5el3guo
  66. Messinezy M, Westwood NB, El-Hemaida I, Marsden JT, Sherwood RS, et al. Serum erythropoietin values in erythrocytoses and in primary thrombocythaemia. Br J Haematol. 2002; 117: 47-53. Ref.: http://tinyurl.com/yytm66zv
  67. Jantunen R, Juvonen E, Ikkala E, Oksanen K, Antilla P, et al. Development of erythrocytosis in the course of essential thrombocythemia. Ann Hematol. 1999; 78: 219-222. Ref.: http://tinyurl.com/y5hljytl
  68. De Stefano V, Teofili L, Leone G, Michiels JJ. Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis. Sem Thromb Hemostas. 1997; 23: 411-418. Ref.: http://tinyurl.com/y6d2n38q
  69. Chait Y, Condat B, Cazals-Hatem D, Rufat P, Atmani S, et al. Relevance of the criteria commonly used to diagnose myeloproliferative disorders in patients with splanchnic vein thrombosis. Br J Haematol. 2005; 129: 553-560. Ref.:  http://tinyurl.com/y552tgae
  70. Brière J. Budd-Chiari syndrome and portal vein thrombosis associated with myeloprioliferative disorders: diagnosis and management. Sem Thromb Hemostas. 2006; 32: 208-218. Ref.: http://tinyurl.com/yxaz3nfc
  71. Smalberg JH, Murad SD, Braakman E, Valk PJ, Janssen LA, et al. Myeloproliferative disease in the pathogenesis and survival of Budd-Chiari syndrome. Haematologica. 2006; 91: 1712-1713. Ref.: http://tinyurl.com/yyeelyr3
  72. Patel RK, Lea NC, Heneghan A, Westwood N, et al. Prevalence of the activating JAK2 troikas mutation V617F in the Budd-Chiari Syndrome. Gastroenterology. 2006; 130: 2031-2038. Ref.: http://tinyurl.com/y38kh7l5
  73. Colaizzo D, Amitrano L, Tiscia L, Scenna G, Grandone E, et al. The JAK2 V617F mutation frequently occurs in patients with portal vein and mesenteric vein thrombosis. J Thromb Haemostas. 2007; 5: 55-61. Ref.: http://tinyurl.com/y5pongum
  74. De Stefano V, Fiorini A, Rossi E, Farina G, Reddiconto G, et al. Prevalence of the JAK2V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemostas. 2007; 4: 708-714. Ref.: http://tinyurl.com/y5emhuk5
  75. Pragmanini M, Barosi G, Berrgamaschi G, Fianelli U, Fabris F, et al. Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis. Hepatology. 2006; 44: 1528-1534. Ref.: http://tinyurl.com/y4xbdctc
  76. Boissinot M, Lippert E, Girodon F, Dobo I, Fouassier M, et al. Latent myeloproliferative disorder revealed by the JAK2V617F mutation and endogenous megakaryocytic colonies in patients with splanchnic vein thrombosis. Blood. 2006; 108: 3323-3324. Ref.: http://tinyurl.com/y24xpvmt
  77. Vainchenker W, Delhommeau F, Villeval JL. Molecular pathogenesis of the myeloproliferative diseases. Hematology Education, EHA. 2007; 1: 239-246.
  78. Delhommeau F, Pisani DF, James C, Casadevall N, Constatinescu S, et al. Oncogenic mechanism in myeloproliferative disorders. Cell Mol Life Sci. 2006; 63: 2939-2953. Ref.: http://tinyurl.com/y2zaghxz
  79. Villeval JL, James C, Pisani DF, Casadevall N, Vainchenker W. New insights into the pathogenesis of JAK2V617F-positive myeloproliferative disorders and consequences for the management of patients. Sem Thromb Hemostas. 2006; 32: 341-351. Ref.: http://tinyurl.com/y5f64xjw
  80. 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://tinyurl.com/y6anppg8
  81. Passamonti F, Rumi E, Pietra D, Della Porta MG, Boveri E,  et al. Relation between JAK2 V617F mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood. 2006; 107: 3676-3682. Ref.: http://tinyurl.com/yyxpyaxc
  82. Scott LM, Scott MA, Campbell PJ, Green AR. Progenitors homozygous for the V617F JAK2 mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood. 2006; 108: 2435-2437. Ref.: http://tinyurl.com/y2sa4gky
  83. Dupont S, Massé A, James C, et al. The JAK2V617F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Blood. 2007. 110: 1013-1021. Ref.: http://tinyurl.com/y249xmgs
  84. Tefferi A, Lasho TL, Schwager SM, Strand JS, Elliott M, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia. Cancer. 2006; 106: 631-635. Ref.: http://tinyurl.com/y5ov7wnn
  85. Chen Z, Notohamiprodjo M, Guan XX, Paietta E, Blackwell S, et al. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes & Cancer. 1998; 22: 321-324. Ref.: http://tinyurl.com/y4jwbh5p
  86. Naifeld V, Montella L, Scalise A, Fruchtman S. Exploring polycythemia vera with fluorescence in situ hybridization: additional cryptic 9p is the most frequent abnormality detected. Br J Haematol. 2002; 119: 558-566. Ref.: http://tinyurl.com/y3uaz2lt
  87. Campbell PJ, Baxter EJ, Beer PhA, Scott LM, Bench AJ, et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and the role in leukemic transformation. Blood. 2006; 18: 3548-3555. Ref.: http://tinyurl.com/y56udcd2
  88. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. New Eng J Med. 2007; 356: 459-468. Ref.: http://tinyurl.com/yycdnksg
  89. Zhou W, Toombs CF, Zou T, Guo J, Robinson MO. Transgenic mice overexpression human c-mpl ligand exhibit chronic thrombocytosis and display enhanced recovery from 5-fluoruracil or antiplatelet serum treatment. Blood. 1997; 89: 1551-1559. Ref.: http://tinyurl.com/y2sc452s
  90. Pikman Y, Lee BH, Mercher Th, McDowell E, Ebert BL, et al. MPLW515L is a novel somatic activation mutation in myelofibrosis with myeloid metaplasia. PLOS Med. 2006; 3: e270. Ref.: http://tinyurl.com/yyby9jua
  91. Pardanani A, Levine RL, Lasho TL, Pikman Y, Mesa RA, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006; 108: 3472-3476. Ref.: http://tinyurl.com/yyn35ppv
  92. Michiels JJ, Abels J, Steketee J, vanVliet HHDM, Vuzevski VD. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med. 1985; 102: 466-471. Ref.:  http://tinyurl.com/y6luwa68
  93. Michiels JJ, Koudstaal P, Mulder AH, van Vliet HHDM. Transient neurologic and ocular manifestations in primary thombocythemia. Neurology. 1993; 43: 1107-1110. Ref.: http://tinyurl.com/y3s6c22s
  94. Michiels JJ, van Genderen PJJ, Lindemans J, van Vliet HHDM. Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia. Leukemia & Lymphoma. 1996; 22: 47-56. Ref.: http://tinyurl.com/y68eq38g
  95. 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 females: therapeutic implications in view of the literature. An Hematol. 2007; 86: 793-800. Ref.: http://tinyurl.com/y377uo55
  96. Schlemper RJ, van der Maas APC, Eikenboom JCJ. Familial essential thrombocythemia: clinical charateristics of 11 cases in one family. Ann Hematol. 1994; 68: 153-158. Ref.: http://tinyurl.com/y24a7qfh
  97. Wiestner A, Schlemper RJ, van der Maas APC, Skoda RC. An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythemia. Nat Genet. 1998; 18: 49-52. Ref.: http://tinyurl.com/y68ns5pz
  98. Kralovics R, Buser AS, Teo SS, Coers J, Tchelli A, et al. Comparison of molecular markers in a cohort of patients with chronic myeloproliferative disorders. Blood. 2003; 102: 1869-1871. Ref.: http://tinyurl.com/y4mj7esj
  99. Ding J, Komatsu H, Wakita A, Kato-Uranishi M, Ito M, et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes the receptor for thrombopoietin. Blood. 2004; 103: 4198-4200. Ref.: http://tinyurl.com/y2nlrob5
  100. 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 and Lymphoma. 1996; 22: 15-29. Ref.: http://tinyurl.com/y6jy8pf7
  101. Georgii A, Buesche G, Kreft A. The histopathology of chronic myeloproliferative diseases. Bailière’s Clin Haematol. 1998; 11:721-749. http://tinyurl.com/y6s3o9ay
  102. Thiele J, Kvasnicka HM, Werden C, Zankovich R, Diehl Fischer R. Idiopathic primary osteomyelofibrosis: A clinico-pathological study on 208 patients with special emphasis on evolution of disease features, differentiation from essential thrombocythemia and variables of prognostic impact. Leukemia and Lymphoma. 1996; 22: 303-317. Ref.: http://tinyurl.com/y3ats2fq
  103. Thiele J, Kvasnicka HM, Diehl V, Fischer R, Michiels JJ. Clinicopathological diagnosis and differential criteria of thrombocythemias in various myeloproliferative disorders by histopathology, histochemistry and immunostaining from bone marrow biopsies. Leukemia and Lymphoma. 1999; 33: 207-218. Ref.: http://tinyurl.com/yy79mqsk
  104. 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. Ref.: http://tinyurl.com/y4y65hqm
  105. Thiele J, Kvasnicka HM. Clinicopathological criteria for the differential diagnosis of thrombocythemia in various myeloproliferative disorders. Sem Thromb Hemostas. 2006; 32: 219-230. Ref.: http://tinyurl.com/y63uwo4e
  106. Thiele J, Kvasnicka HM. A critical reappraisal of the WHO classification of the chronic myeloproliferative disorders. Leukemia and Lymphoma. 2006; 47: 381-396. Ref.: http://tinyurl.com/y55rx9bo
  107. Thiele J, Kvasnicka HM. Hematologic findings in chronic idiopathic myelofibrosis. Sem Oncol. 2005; 32: 380-304.
  108. Kvasnicka HM, Thiele J. The impact of clinicopathological studies on staging and survival in ET, PV and IMF. Sem Thromb Hemostas. 2006; 32: 362-371. Ref.: http://tinyurl.com/y56qnsts
  109. Barosi G, Ambrosetti A, Finelli C, et al. The Italian consensus on diagnostic criteria for myelofibrosis with myeloid metaplasia. Br J Haematol. 1999; 104: 730- 737. Ref.: http://tinyurl.com/y4rtft54
  110. Barosi G, Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol. 199; 17: 2954-2970. Ref.: http://tinyurl.com/y2yjf2zo
  111. 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://tinyurl.com/y2czw485
  112. Michiels JJ, De Raeve H, Hebeda K, Lam KH, Berneman Z, et al. WHO bone marrow features and European clinical molecular and pathlogical criteria for the diagnosis and classification of myeloproliferative disorders. Leuk Res. 2007; 31: 1031-1038. Ref.: http://tinyurl.com/yyzdsylv
  113. Gianelli U, Vener C, Ravielle PR, Moro A, Savi F, et al. Essential thrombocythemia or chronic myelofibrosis? A single-center study based on hematopoietic bone marrow histology. Leuk Lymph. 2006; 47: 1774-1781. Ref.: http://tinyurl.com/yyw3m36e
  114. Kreft A, Buche G, Ghalibafian M, Buhr T, Fischer T, et al. The incidence of myelofibrosis in essential thrombocythemia, polycythemia vera and chronic idiopathic myelofibrosis: a retrospective evaluation of sequential bone marrow biopsies. Acta Haematol. 2005; 113: 137-143. Ref.: http://tinyurl.com/y5yhsnmh
  115. Thiele J, Kvasnicka HM, Schmitt-Graeff A, Zankovich R, Diehl V. Follow-up examinations including sequential bone marrow biopsies in essential thrombocythemia (ET): a retrospective clinicopathological study of 120 patients. Am J Hematol. 2002; 70: 283-291. Ref.: http://tinyurl.com/yye9q8z5
  116. 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. Ref.: http://tinyurl.com/y4q6enlj
  117. Wolansky A, Schwager SM, McClure RF, Larson DR, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006; 81: 159-166. Ref.: http://tinyurl.com/yyfrdndl
  118. Michiels JJ, Berneman ZW, Schroyens W, Kutti J, Swolin B, et al. Philadelphia (Ph) chromosome positive thrombocythemia without features of chronic myeloid leukemia in peripheral blood: natural history and diagnostic differentiation from Ph-negative essential thrombocythemia. Ann Hematol. 2004; 83: 504-512. Ref.: http://tinyurl.com/yyvjp23w
  119. Schmitt-Graeff A, Thiele J, Zuk I, Kvasnicka HM. Essential thrombocythemia with ringed sideroblasts: a heterogenous spectrum of diseases, but not a distinct entity. Haematologica. 2002; 87: 392-399. Ref.: http://tinyurl.com/y4xcorpl
  120. Shaw GR. Ringed sideroblasts with thrombocytosis: an uncommon mixed myelodysplastic/myeloproliferative disease of older adults. Br J Haematol. 2005; 131: 180-184. Ref.: http://tinyurl.com/y2zev2we
  121. Szpurka H, Tiu R, Murugesan G, Aboudola S, His ED, et al. Refractory anemia with ringed sideroblasts associated with matked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2V617F mutation. Blood. 2006; 108: 2173-2181. Ref.: http://tinyurl.com/y2clq4e2
  122. Gatterman N, Billiet J, Kronenwett R, Zipperer E, Germing U, et al. High frequency of the JAK2 V617F mutation in patients with thrombocytosis (platelet count >600 x109/l) and ringed sideroblasts more than 15% considered as MDS/MPD, unclassifiable. Blood. 2007; 109: 1334-1335. Ref.: http://tinyurl.com/y24wxwvc
  123. Campbell P, Scott LM, Buck G, Wheatley K, East CL, et al. Definition of essential thrombocythemia and relation of essential thrombocythemia to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet. 2005; 366: 1945-1953. Ref.: http://tinyurl.com/y3xzxh56
  124. Campbell P, Green AR. The myeloproliferative disorders. New Eng J Med. 2006; 355: 2452-2466. Ref.: http://tinyurl.com/y4ymfgtq
  125. Juvonen E, Ikkala EE, Fyrrquist F Ruutu T. Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin. Blood. 1991; 78: 3066-3069. Ref.: http://tinyurl.com/y45nwdoc
  126. De La Chapelle A, Träskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci. 1993; 90: 4495-4499. Ref.: http://tinyurl.com/y3fxnxua
  127. James C, Delhommeau F, Marzac C, Teyssandier I, Couédic JP, et al. Detection of JAK2 V617F as a first intention diagnostic test for erythrocytosis. Leukemia 2006: 20: 350-353. Ref.: http://tinyurl.com/y4lpcrvp
  128. Tefferi A, Pardanani A. Mutation screening for JAK2V617F: when to order the test and how to interpret the results. Leukemia Res. 2006; 30: 739-744. Ref.: http://tinyurl.com/yylj489j
  129. Adamson JW. The erythropoietin/hematocrit relationship in normal and polycythemic man: implicatons of marrow regulation. Blood. 1968; 32: 597-609. Ref.: http://tinyurl.com/y2wxoxcb
  130. Napier JAF, Janowsky-Wieczorck A. Erythropoietin measurements in the differential diagnosis of polycythemia. Br J Haematol. 1981; 48: 393-401. Ref.: http://tinyurl.com/y3tdvk3e
  131. Cotes PM, Dore CJ, Tin JA, Lewis SM, Messinezy M, et al. Determination of serum immunoreactive erythropoietin in the investigation of erythrocytosis. N Eng J Med. 1986; 315: 283-287. Ref.: http://tinyurl.com/yyz5ruu2
  132. Birgegard G, Wide L. Serum erythropoietin in the diagnosis of polycythemia and after phlebotomy treatment. Br J Haematol. 1992; 81: 603-606. Ref.: http://tinyurl.com/yy8mgudn
  133. Messinezy M, Westwood NB, Woodstock 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.: http://tinyurl.com/y45p6syc
  134. Tefferi A. The diagnosis of polycythemia vera: new tests and old dictums. Best Practice & Research Clin Haematol. 2006; 19: 455-469. Ref.: http://tinyurl.com/y5v32o5b
  135. Andreasson B, Löfvenberg E, Westin J. Management of patients with polycythemia vera: results of a survey among Swedish haematologists. Eur J Haematol. 2005; 74: 489-495. Ref.: http://tinyurl.com/y5rwvlzb
  136. Le Bousse-Kerdiles MC, Martyré MC. Dual implication of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid metaplasia with myelofibrosis. Ann Hematol. 1999; 78: 437-444. Ref.: http://tinyurl.com/y6fw95c2
  137. Bauermeister DE. Quantification of bone marrow reticulin. Am J Clin Pathol. 1971; 56: 24-31. Ref.: http://tinyurl.com/yyn6h6gc
  138. Manoharan A, Smart RC, Pitney WR. Prognostic factors in myelofibrosis. Pathology. 1982; 14: 445-461. Ref.: http://tinyurl.com/y3xrseho
  139. Thiele J, Kvasnicka HM, Facchetti F, Franco V, Van Der Walt J, et al. European consensus for grading of bone marrow fibrosis and assessment of cellularity in myeloproliferative disorders. Haematologica. 2005; 90: 1128-1132. Ref.: http://tinyurl.com/y59wzkm7
  140. Moliterno AR, Williams DM, Rogers O, Spivak JL. Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2V617F and MPL expression. Blood. 2005; 106: 3520. Ref.: http://tinyurl.com/y6e5o6ec
  141. Bock O, Busche G, Koop C, Schroter S, Buhr T, et al. Detection of the single hotspot mutation in the JH2 pseudokinase domain of Janus kinase 2 in bone marrow trephine biopsies derived from myeloproliferative disorders. J Mol Diagn. 2006; 8: 170-177. Ref.: http://tinyurl.com/yydugqrw
  142. Bock O, Neuse J, Hussein K, Brakensiek K Buesche G, et al. Aberrant collagenase expression in chronic idiopathic myelofibrosis (CIMF) is related to the stage of disease but not to the JAK2 mutation status. Am J Pathol. 2006; 169: 471-481. Ref.: http://tinyurl.com/y26t9f9b
  143. Horn Th, Kremer M, Dechow T, Pfeifer WM, Geist B, et al. Detection of the activating JAK2 V617F mutation in paraffin-embedded trephine bone marrow biopsies of patients with chronic myeloproliferative diseases. J Mol Diagn. 2006; 3: 299-304. Ref.: http://tinyurl.com/y38u894j
  144. Michiels JJ, Kvasnicka HM, Thiele J. Myeloproliferative disorders. 2005 Verlag ME-Uwe Grunwald, Munich, Germany. ISBN. 3-9808075-6-8.
  145. Xu X, Zhang Q, Xing S, Li Q, Krantz A, et al. JAK2V617F: prevalence in a large Chinese hospital population. Blood. 2007; 109: 339-342. Ref.: http://tinyurl.com/y294tc8h
  146. Sidon EL Housni H, Dessars B, Heiman P. The JAK2V617F mutation is detectable at very low level in peripheral blood. Leukemia. 2006; 20: 1662. Ref.: http://tinyurl.com/yylj942p
  147. Passamonti F, Rumi E, Pietra D, Lazzarino M, Cazzola M. JAK2 (V617F) mutation in healthy individuals. Br J Haematol. 2007: 136: 677-679. Ref.: http://tinyurl.com/yxpguqjt
  148. Michiels JJ, De Raeve H, Berneman Z, Van Bockstaele D, Hebeda K, et al. The 2001 World Health Organization (WHO) and updated European clinical and pathological (ECP) criteria for the diagnosis, classification and staging of the Ph1-chromosome negative chronic myeloproliferative disorders (MPD). Sem Thromb Hemostas. 2006; 32: 307-340.
  149. Michiels JJ, Berneman Z, Van Bockstaele D, De Raeve H, Schroyens W. Current diagnostic criteria for the chronic myeloproliferative disorders (MPD) essential thrombocythemia (ET), polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF). Pathologie Biologie. 2007; 55: 92-104. Ref.: http://tinyurl.com/yxrorx7s
  150. Michiels JJ, Berneman Z, Schroyens W, De Raeve H. Changing concepts on the 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://tinyurl.com/y34d62ot
  151. 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://tinyurl.com/yycbcvnn
  152. De Raeve H, Michiels JJ, Valster F, Potters V, Kim  Y, et al. Novel Clinical, Laboratory, Molecular and Pathological (2018 CLMP) Criteriafor the Differential Diagnosis of three Distinct JAK2, CALR and MPL MutatedMyeloproliferative Neoplasms: The Role of Driver Mutation Analysis and Bone Marrow Histology. Int J Cancer Res Ther. 2018; 3: 1-12.