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Annals of Hematology

, Volume 97, Issue 9, pp 1581–1590 | Cite as

The WHO diagnostic criteria for polycythemia vera—role of red cell mass versus hemoglobin/hematocrit level and morphology

  • Ljubomir Jakovic
  • Mirjana Gotic
  • Heinz Gisslinger
  • Ivan Soldatovic
  • Dijana Sefer
  • Mila Tirnanic
  • Danijela Lekovic
  • Maja Perunicic Jovanovic
  • Martin Schalling
  • Bettina Gisslinger
  • Christine Beham-Schmid
  • Ingrid Simonitsch-Klupp
  • Jürgen Thiele
Original Article

Abstract

Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65 years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n = 143)/Hct (n = 45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements.

Keywords

Polycythemia vera Red cell mass Clinical criteria Bone marrow morphology Masked polycythemia vera WHO classification 2016 

Notes

Acknowledgments

This study was conducted under the aegis of CEMPO (Central European Myeloproliferative Organization) which provided the necessary conditions to make it possible.

Authors’ contributions

M.G., L.J., J.T., and H.G. designed the research, contributed patients, participated in data analysis and interpretation, and wrote the paper. I.S. performed the statistical analysis, D.S. the EEC assays, and M.T. the RCM measurements. J.T., L.J., Ch.B.-Sch., and I.S.-K reviewed all bone marrow biopsies. All other authors either contributed patients or participated in reviewing bone marrow morphology.

Compliance with ethical standards

This study was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice. The clinical study protocol was approved by the Institutional Ethical Committee of the Clinical Center of Serbia, No. 195/11, Date 24.11.2016.

All patients provided written informed consent in accordance with the Declaration of Helsinki prior to study participation.

Conflict of interest

None of the authors have any conflict of interest to disclose with regard to the current manuscript. All of the authors read and approved the final draft.

References

  1. 1.
    Spivak JL (2002) Polycythemia vera: myths, mechanisms and management. Blood 100(13):4272–4290CrossRefPubMedGoogle Scholar
  2. 2.
    Johansson PL, Safai-Kutti S, Kutti J (2005) An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemiavera and apparent polycythaemia. Br J Haematol 129(5):701–705CrossRefPubMedGoogle Scholar
  3. 3.
    Tefferi A (2005) The rise and fall of red cell mass measurement in polycythemia vera. Curr Hematol Rep 4(4):213–217PubMedGoogle Scholar
  4. 4.
    Cassinat B, Laguillier C, Gardin C, de Beco V, Burcheri S, Fenaux P, Chomienne C, Kiladjian JJ, PV-Nord Group (2008) Classification of myeloproliferative disorders in the JAK2 era: is there a role for the red cell mass? Leukemia 22(2):352–453CrossRefGoogle Scholar
  5. 5.
    Alvarez-Larran A, Ancochea A, Angona A, Carme P, Garcia-Pallarols F, Martinez-Aviles L, Bellosillo B, Besses C (2012) Red cell mass measurement in patients with clinically suspected diagnosis of polycythemia vera or essential thrombocythemia. Haematologica 97(11):1704–1707CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Silver RT, Chow W, Orazi A, Arles SP, Goldsmith SJ (2013) Evaluation of WHO criteria for diagnosis of polycythemia vera: a prospective analysis. Blood 122(11):1881–1886CrossRefPubMedGoogle Scholar
  7. 7.
    McMullinMF WBS, Harrison CN (2016) Management of polycythaemiavera: a critical review of current data. Br J Haematol 172(3):337–349CrossRefGoogle Scholar
  8. 8.
    Barbui T, Thiele J, Gisslinger H, Carobbio A, Vannucchi AM, Tefferi A (2017) Diagnostic impact of the 2016 revised WHO criteria for polycythemia vera. Am J Hematol 92(5):417–419CrossRefPubMedGoogle Scholar
  9. 9.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20):2391–2405CrossRefPubMedGoogle Scholar
  10. 10.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (eds) (2017) WHO classification of tumours of haematopoietic and lymphoid tissues. (revised 4th edition). International Agency for Research on Cancer, LyonGoogle Scholar
  11. 11.
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD (2009) The 2008 revision of the WHO classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114(5):937–951CrossRefPubMedGoogle Scholar
  12. 12.
    Spivak JL (2017) Myeloproliferative neoplasms. N Engl J Med 376(22):2168–2181CrossRefPubMedGoogle Scholar
  13. 13.
    Barbui T, Thiele J, Gisslinger H, Finazzi G, Carobbio A, Rumi E, Luigia Randi M, Betozzi I, Vannucchi AM, Pieri L, Carrai V, Gisslinger B, Mullauer L, Ruggeri M, Rambaldi A, Tefferi A (2014) Masked polycythemia vera (mPV): results of an international study. Am J Hematol 89(1):52–54CrossRefPubMedGoogle Scholar
  14. 14.
    Barbui T, Thiele J, Carobbio A, Gisslinger H, Finazzi G, Rumi E, Luigia Randi M, Vannucchi AM, Gisslinger B, Mullauer L, Ruggeri M, Rambaldi A, Tefferi A (2014) Masked polycythemia vera diagnosed according to WHO and BCSH classification. Am J Hematol 89(2):199–202CrossRefPubMedGoogle Scholar
  15. 15.
    Tefferi A, Barbui T (2017) Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification and management. Am J Hematol 92(1):94–108CrossRefPubMedGoogle Scholar
  16. 16.
    Thiele J, Kvasnicka HM (2005) Diagnostic impact of bone marrow histopathology in polycythemia vera (PV). Histol Histopathol 20(1):317–328PubMedGoogle Scholar
  17. 17.
    Kvasnicka HM (2013) WHO classification of myeloproliferative neoplasms (MPN): a critical update. Curr Hematol Malig Rep 8(4):333–341CrossRefPubMedGoogle Scholar
  18. 18.
    Madelung AB, Bondo H, Stamp I, Loevgreen P, Nielsen SL, Falensteen A, Knudsen H, Ehinger M, Dahl-Sorensen MNB, Svendsen KD, Lange T, Ralfkiaer E, Nielsen K, Hasselbalch HC, Thiele J (2013) World Health Organization-defined classification of myeloproliferative neoplasms: morphological reproducibility and clinical correlations—the Danish experience. Am J Hematol 88(12):1012–1016CrossRefPubMedGoogle Scholar
  19. 19.
    Gianelli U, Iurlo A, Cattaneo D, Lambertenghi-Deliliers G (2014) Cooperation between pathologists and clinicians allows a better diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms. Expert Rev Hematol 7(2):255–264CrossRefPubMedGoogle Scholar
  20. 20.
    International Committee for Standardization in Haematology (1980) Recommended methods for measurement of red-cell and plasma volume. J Nucl Med 21(8):793–800Google Scholar
  21. 21.
    Pearson TC, Guthrie DL, Simpson J, Chinn S, Barosi G, Ferrant A, Lewis SJ, Najean Y (1995) Interpretation of measured red cell mass and plasma volume in adults: expert panel on radionuclides of the International Council for Standardization in Haematology. Br J Haematol 89(4):748–756CrossRefPubMedGoogle Scholar
  22. 22.
    Todorovic-Tirnanic M, Pavlovic S, Obradovic V, Elezovic I, Marisavljevic D, Miljic P, Milosevic RA, Bogdanovic AD, Bosnjakovic VB (2004) Clinical significance of optimal red cell mass and plasma volume estimation methods. Nucl Med Rev 7(1):31–38Google Scholar
  23. 23.
    Jaffe ES, Harris NLSH, Vardiman JW (eds) (2001) World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, LyonGoogle Scholar
  24. 24.
    Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, Randi ML, Vaidya R, Cazzola M, Rambaldi A, Gisslinger B, Pieri L, Ruggeri M, Bertozzi I, Sulai NH, Casetti I, Carobbio A, Jeryczynski G, Larson DR, Müllauer L, Pardanani A, Thiele J, Passamonti F, Barbui T (2013) Survival and prognosis among 1,545 patients with contemporary polycythemia vera: an international study. Leukemia 27(9):1874–1188CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tefferi A, Thiele J, Vardiman J, Vannucchi AM, Barbui T (2014) An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia 28(7):1407–1413CrossRefPubMedGoogle Scholar
  26. 26.
    Spivak JL, Silver RT (2008) The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood 112(2):231–239CrossRefPubMedGoogle Scholar
  27. 27.
    Vannucchi AM, Grossi A, Pancrazzi A, Antonioli E, Guglielmelli P, Balestri F, Biscardi M, Bulgarelli S, Longo G, Graziano C, Gugliotta L, Bosi A (2004) PRV-1, erythroid colonies and platelet Mpl are unrelated to thrombosis in essential thrombocythaemia. Br J Haematol 127(2):214–219CrossRefPubMedGoogle Scholar
  28. 28.
    Westwood NB, Pearson TC (1996) Diagnostic applications of haemopoietic progenitor culture techniques in polycythaemias and thrombocythaemias. Leuk Lymphoma 22(1):95–103CrossRefPubMedGoogle Scholar
  29. 29.
    Casadevall N, Lacombe C, Varet B (1990) Erythroid cultures and erythropoietin assay: clinical and diagnostic value. Nouv Rev Fr Hematol 32(1):77–81PubMedGoogle Scholar
  30. 30.
    Zwicky C, Theiler L, Zbaren K, Ischi E, Tobler A (2002) The predictive value of clonogenic stem cell assays for the diagnosis of polycythaemiavera. Br J Haematol 117(3):598–604CrossRefPubMedGoogle Scholar
  31. 31.
    Kvasnicka HM, Orazi A, Thiele J, Barosi G, Bueso-Ramos CE, Vannucchi AM, Hasserjian RP, Kiladjian JJ, Gianelli U, Silver R, Mughal TI, Barbui T (2017) European leukemia net study on the reproducibility of bone marrow features in masked polycythemia vera and differentiation from essential thrombocythemia. Am J Hematol 92(10):1062–1067CrossRefPubMedGoogle Scholar
  32. 32.
    Thiele J, Kvasnicka HM, Diehl V (2005) Initial (latent) polycythemia vera with thrombocytosis mimicking essential thrombocythemia. Acta Haematol 113(4):213–209CrossRefPubMedGoogle Scholar
  33. 33.
    Gianelli U, Iurlo A, Vener C, Moro A, Fermo E, Bianchi P, Graziani D, Radelli F, Coggi G, Bosari S, Delillers GL, Zanella A (2008) The significance of bone marrow biopsy and JAK2V617F mutation in the differential diagnosis between the “early” prepolycythemic phase of polycythemia vera and essential thrombocythemia. Am J Clin Pathol 30(3):336–342CrossRefGoogle Scholar
  34. 34.
    Barbui T, Thiele J, Kvasnicka HM, Carobbio A, Vannucchi AM, Tefferi A (2014) Essential thrombocythemia with high hemoglobin levels according to the revised WHO classification. Leukemia 28(10):2092–2094CrossRefPubMedGoogle Scholar
  35. 35.
    Barbui T, Thiele J, Carobbio A, Guglielmelli P, Rambaldi A, Vannucchi AM, Tefferi A (2014) Discriminating between essential thrombocythemia and masked polycythemia vera in JAK2 mutated patients. Am J Hematol 89(6):588–590CrossRefPubMedGoogle Scholar
  36. 36.
    Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, De Stefano V, Elli E, Iurlo A, Latagliata R, Lunghi F, Lunghi M, Marfisis RM, Musto P, Masciulli A, Musolino C, Cascavilla N, Quarta G, Randi ML, Rapezzi D, Ruggeri M, Rumi E, Scortechini AR, Santini S, Scarano M, Siragusa S, Spadea A, Tieghi A, Angelucci E, Visani G, Vannucchi AM, Barbui T, CYTO-PV Collaborative Group (2013) Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 368(1):22–33CrossRefPubMedGoogle Scholar
  37. 37.
    Tefferi A, Vannucchi AM, Barbui T (2018) Polycythemia vera treatment algorithm 2018. Blood Cancer J 8(1):3CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P, Orazi A, Tefferi A (2018) The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J 8(2):15CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ljubomir Jakovic
    • 1
  • Mirjana Gotic
    • 1
    • 2
  • Heinz Gisslinger
    • 3
  • Ivan Soldatovic
    • 4
  • Dijana Sefer
    • 1
  • Mila Tirnanic
    • 2
    • 5
  • Danijela Lekovic
    • 1
  • Maja Perunicic Jovanovic
    • 6
  • Martin Schalling
    • 3
  • Bettina Gisslinger
    • 3
  • Christine Beham-Schmid
    • 7
  • Ingrid Simonitsch-Klupp
    • 8
  • Jürgen Thiele
    • 9
  1. 1.Clinic of HematologyClinical Center of SerbiaBelgradeSerbia
  2. 2.Medical FacultyUniversity of BelgradeBelgradeSerbia
  3. 3.Department of Internal Medicine I, Division of Hematology and HemostaseologyMedical University of ViennaViennaAustria
  4. 4.Institute for Medical Statistics and Informatics, Medical FacultyUniversity of BelgradeBelgradeSerbia
  5. 5.Nuclear Medicine InstituteClinical Center of SerbiaBelgradeSerbia
  6. 6.Department of HistopathologyClinical Center of SerbiaBelgradeSerbia
  7. 7.Institute of PathologyMedical University of GrazGrazAustria
  8. 8.Clinical Institute of PathologyMedical University of ViennaViennaAustria
  9. 9.Institute of PathologyUniversity of CologneCologneGermany

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