Abstract

Research Article

Primary myelofibrosis is not primary anymore since the discovery of MPL515 and CALR mutations as driver causes of mono-linear megakaryocytic and dual megakaryocytic granulocytic myeloproliferation and secondary myelofibrosis

Jan Jacques Michiels* and Hendrik De Raeve

Published: 15 April, 2019 | Volume 2 - Issue 1 | Pages: 018-026

Primary myelofibrosis (PMF) is a distinct clinicopathological myeloproliferatve disease (MPD) not preceded by any other MPD ET, PV, CML,... 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. Silverstein MN. Myeloproliferative diseases. Hematology review. Postgraduate Medicine. 1977; 61: 206-201.
  2. 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
  3. Tefferi A1, Lasho TL, Jimma T, Finke CM, Gangat N, et al. One thousand patients with primary myelofibrosis: the Mayo Clinici experience. Mayo Clinic Proc. 2012; 87: 25-33. Ref.: http://tinyurl.com/y4eyy6nw
  4. Klampf Tl, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. New Eng J Med December. 2013; 369: 2379-2387. Ref.: http://tinyurl.com/y3hc7vte
  5. Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, et al. Jak2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcome. Blood, 2014; 123: 1552-1565. Ref.: http://tinyurl.com/y4vyyotn
  6. Nangalia J, Massie CE, Baxter J, Nice FL, Gundem G, et al. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. N Engl J Med. 2013; 369: 2391-2405. Ref.: http://tinyurl.com/yx8otrz7
  7. Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014; 28: 1472-1477. Ref.: http://tinyurl.com/y6cpm8hn
  8. 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://tinyurl.com/y2fnhwwo
  9. Michiels JJ, Forstier K, Valster F, Potters V, Schelfout K, et al. Criteria for the Classification and Staging of Five Distinct JAK2, MPL and CALR Mutated Myeloproliferative Neoplasms. J Hematol Thromb Dis. 2014; 2-6. Ref.: http://tinyurl.com/yy3mze9e
  10. Michiels JJ, Berneman Z, Schroyens W, De Raeve H. Changing concepts and 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
  11. 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; 6: 16-53. Ref.: http://tinyurl.com/y65e9q4h
  12. 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://tinyurl.com/yy8n4ygs
  13. Pich 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.: http://tinyurl.com/yxgbmga6
  14. Pich A, Riera L, di Celle PF, Beggiato E, Benevolo G, Godio L. JAK2V617F, CALR and MPL mutations and bone marrow histology in patients with essential thrombocythemia. Acta Haematol. 2018; 140: 234-239. Ref.: http://tinyurl.com/y5faxo7k
  15. Michiels JJ, Valster F, Potter V, Schelfout K, Schroyens W, et al. Secondary myelofibrosis in the natural history of JAK2, MPL and CALR mutated myeloproliferative neoplasms. J Hematol Thrmb Dis. 2016; 4: 3. Ref.: http://tinyurl.com/yxdsyxkj
  16. 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, MPL,515 and Calreticulin Mutated Thrombocythemia in Myeloproliferative Neoplasms. Clin Res Hematol. 2018; 1: 1-7. Ref.: http://tinyurl.com/yycbcvnn
  17. 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 MutatedMyeloproliferative Neoplasms: The Role of Driver Mutation Analysis and Bone Marrow Histology. Int J Cancer Res Ther. 2018; 3: 1-12.
  18. Michiels JJ, Berneman Z, Schroyens W, J ten Kate FW, et al. European Clinical Laboratory, Molecular and Pathological (ECMP) criteria for prefibrotic JAK2V617F-Thrombocythemia and Polycythemia Vera versus MPL515 and CALR mutated Thrombocythemia and Myelofibrosis: From Dameshek to Michiels 1950-2018. Int J Bone Marrow Res. 2019; 2: 001-017. Ref.: http://tinyurl.com/yxvu6d8p

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