The Impact of Clinicopathological Studies on Staging and Survival in Essential Thrombocythemia, Chronic Idiopathic Myelofibrosis, and Polycythemia Rubra Vera

ABSTRACT

In chronic myeloproliferative disorders (MPDs), varying results regarding staging of disease and assessment of outcome have been reported. Risk classification is mainly based on clinical data; however, in those disorders associated with an elevated platelet count, discrimination of (true) essential thrombocythemia (ET) may be difficult without the possibility to recognize characteristic histopathological bone marrow patterns according to the World Health Organization (WHO) guidelines. Patients with ET reveal no relevant reduction of life expectancy and the impact of disease is significantly higher in elderly patients, especially in chronic idiopathic myelofibrosis (IMF) and polycythemia rubra vera (PV). In high-risk ET, the overall incidence of myelofibrotic transformation after 36 months of follow-up is 2.8% when considering the Polycythemia Vera Study Group guidelines. In contrast, classification according to WHO fails to show a relevant transformation into myelofibrosis either by clinical or morphological standards in (true) ET. Early stages of IMF show a more favorable outcome, but in multivariate risk classification, signs of myeloid metaplasia have the most important impact on prognosis. In PV, the risk for thrombosis increases with age, and furthermore, signs of generalization are generally associated with a worsening of prognosis. It has been shown that examination of bone marrow specimens enhances the diagnostic reliability and also enables the recognition of evolving myelofibrotic transformation in MPDs.

KEYWORDS

Essential thrombocythemia - chronic idiopathic myelofibrosis - polycythemia rubra vera - survival - myelofibrotic transformation - bone marrow histopathology

REFERENCES

• 1 Kvasnicka H M, Thiele J, Schmitt-Graeff A, Schaefer H E. Prognostic factors and survival in chronic myeloproliferative disorders.  Pathologe. 2000;  21 63-72
• 2 Kvasnicka H M, Thiele J, Werden C, Zankovich R, Diehl V, Fischer R. Prognostic factors in idiopathic (primary) osteomyelofibrosis.  Cancer. 1997;  80 708-719
• 3 Thiele J, Kvasnicka H M, Orazi A. Bone marrow histopathology in myeloproliferative disorders-current diagnostic approach.  Semin Hematol. 2005;  42 184-195
• 4 Vardiman J W, Pierre R, Thiele J, Imbert M. Chronic myeloproliferative disorders. In: Jaffe ES, Harris NL, Stein H, Vardiman JW WHO Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France; IARC Press 2001: 16-59
• 5 Gruppo Italiano Studio Policitemia . Polycythemia vera: the natural history of 1213 patients followed for 20 years.  Ann Intern Med. 1995;  123 656-664
• 6 Passamonti F, Rumi E, Pungolino E et al.. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.  Am J Med. 2004;  117 755-761
• 7 Visani G, Finelli C, Castelli U et al.. Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients.  Br J Haematol. 1990;  75 4-9
• 8 Bazzan M, Tamponi G, Schinco P et al.. Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia.  Ann Hematol. 1999;  78 539-543
• 9 Mesa R A, Silverstein M N, Jacobsen S J, Wollan P C, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995.  Am J Hematol. 1999;  61 10-15
• 10 Passamonti F, Malabarba L, Orlandi E et al.. Polycythemia vera in young patients: a study on the long-term risk of thrombosis, myelofibrosis and leukemia.  Haematologica. 2003;  88 13-18
• 11 Rozman C, Giralt M, Feliu E, Rubio D, Cortes M T. Life expectancy of patients with chronic nonleukemic myeloproliferative disorders.  Cancer. 1991;  67 2658-2663
• 12 Kreft A, Weiss M, Wiese B et al.. Chronic idiopathic myelofibrosis: prognostic impact of myelofibrosis and clinical parameters on event-free survival in 122 patients who presented in prefibrotic and fibrotic stages. A retrospective study identifying subgroups of different prognoses by using the RECPAM method.  Ann Hematol. 2003;  82 605-611
• 13 Kvasnicka H M, Thiele J, Regn C, Zankovich R, Diehl V, Fischer R. Prognostic impact of apoptosis and proliferation in idiopathic (primary) myelofibrosis.  Ann Hematol. 1999;  78 65-72
• 14 Strasser-Weippl K, Steurer M, Kees M et al.. Age and hemoglobin level emerge as most important clinical prognostic parameters in patients with osteomyelofibrosis: introduction of a simplified prognostic score.  Leuk Lymphoma. 2006;  47 441-450
• 15 Hakulinen T. Cancer survival corrected for heterogeneity in patient withdrawal.  Biometrics. 1982;  38 933-942
• 16 Hakama M, Hakulinen T. Estimating the expectation of life in cancer survival studies with incomplete follow-up information.  J Chronic Dis. 1977;  30 585-597
• 17 Michiels J J. Normal life expectancy and thrombosis-free survival in aspirin treated essential thrombocythemia.  Clin Appl Thromb Hemost. 1999;  5 30-36
• 18 Imbert M, Pierre R, Thiele J, Vardiman J W, Brunning R D, Flandrin G. Essential thrombocythaemia. In: Jaffe ES, Harris NL, Stein H, Vardiman JW WHO Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France; IARC Press 2001: 39-41
• 19 Thiele J, Kvasnicka H M. A critical reappraisal of the WHO classification of the chronic myeloproliferative disorders.  Leuk Lymphoma. 2006;  47 381-396
• 20 Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia.  Semin Hematol. 1999;  36 9-13
• 21 Michiels J J, 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
• 22 Thiele J, Kvasnicka H M, Zankovich R, Diehl V. Relevance of bone marrow features in the differential diagnosis between essential thrombocythemia and early stage idiopathic myelofibrosis.  Haematologica. 2000;  85 1126-1134
• 23 Thiele J, Kvasnicka H M. Diagnostic differentiation of essential thrombocythaemia from thrombocythaemias associated with chronic idiopathic myelofibrosis by discriminate analysis of bone marrow features-a clinicopathological study on 272 patients.  Histol Histopathol. 2003;  18 93-102
• 24 Thiele J, Imbert M, Pierre R, Vardiman J W, Brunning R D, Flandrin G. Chronic idiopathic myelofibrosis. In: Jaffe ES, Harris NL, Stein H, Vardiman JW WHO Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues; Lyon, France IARC Press; 2001: 35-38
• 25 Thiele J, Kvasnicka H M, Fischer R. Histochemistry and morphometry on bone marrow biopsies in chronic myeloproliferative disorders-aids to diagnosis and classification.  Ann Hematol. 1999;  78 495-506
• 26 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
• 27 Harrison C N, Campbell P J, Buck G et al.. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.  N Engl J Med. 2005;  353 33-45
• 28 Harrison C N. Essential thrombocythaemia: challenges and evidence-based management.  Br J Haematol. 2005;  130 153-165
• 29 Kreft A, Buche G, Ghalibafian M, Buhr T, Fischer T, Kirkpatrick C J. The incidence of myelofibrosis in essential thrombocythaemia, polycythaemia vera and chronic idiopathic myelofibrosis: a retrospective evaluation of sequential bone marrow biopsies.  Acta Haematol. 2005;  113 137-143
• 30 Tefferi A. Recent progress in the pathogenesis and management of essential thrombocythemia.  Leuk Res. 2001;  25 369-377
• 31 Thiele J, Kvasnicka H M, 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
• 32 Barosi G, Ambrosetti A, Finelli C et al.. The Italian consensus conference on diagnostic criteria for myelofibrosis with myeloid metaplasia.  Br J Haematol. 1999;  104 730-737
• 33 Van de Pette J E, Prochazka A V, Pearson T C, Singh A K, Dickson E R, Wetherley-Mein G. Primary thrombocythaemia treated with busulphan.  Br J Haematol. 1986;  62 229-237
• 34 Pearson T C. Primary thrombocythaemia: diagnosis and management.  Br J Haematol. 1991;  78 145-148
• 35 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.  Semin Hematol. 1997;  34 29-39
• 36 Fenaux P, Simon M, Caulier M T, Lai J L, Goudemand J, Bauters F. Clinical course of essential thrombocythemia in 147 cases.  Cancer. 1990;  66 549-556
• 37 Bellucci S, Janvier M, Tobelem G et al.. Essential thrombocythemias. Clinical evolutionary and biological data.  Cancer. 1986;  58 2440-2447
• 38 Annaloro C, Lambertenghi Deliliers G, Oriani A et al.. Prognostic significance of bone marrow biopsy in essential thrombocythemia.  Haematologica. 1999;  84 17-21
• 39 Barbui T, Finazzi G. When and how to treat essential thrombocythemia.  N Engl J Med. 2005;  353 85-86
• 40 Thiele J, Kvasnicka H M, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity.  Haematologica. 2005;  90 1128-1132
• 41 Barosi G. Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines.  J Clin Oncol. 1999;  17 2954-2970
• 42 Laszlo J. Myeloproliferative disorders (MPD): myelofibrosis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia.  Semin Hematol. 1975;  12 409-432
• 43 Thiele J, Kvasnicka H M, Boeltken B, Zankovich R, Diehl V, Fischer R. Initial (prefibrotic) stages of idiopathic (primary) myelofibrosis (IMF)-a clinicopathological study.  Leukemia. 1999;  13 1741-1748
• 44 Georgii A, Buhr T, Buesche G, Kreft A, Choritz H. Classification and staging of Ph-negative myeloproliferative disorders by histopathology from bone marrow biopsies.  Leuk Lymphoma. 1996;  22(suppl 1) 15-29
• 45 Thiele J, Kvasnicka H M. Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients.  Ann Hematol. 2003;  82 148-152
• 46 Thiele J, Kvasnicka H M. Hematopathologic findings in chronic idiopathic myelofibrosis.  Semin Oncol. 2005;  32 380-394
• 47 Lengfelder E, Hochhaus A, Kronawitter U et al.. Should a platelet limit of 600 × 10⁹/l be used as a diagnostic criterion in essential thrombocythaemia? An analysis of the natural course including early stages.  Br J Haematol. 1998;  100 15-23
• 48 Barbui T, Barosi G, Grossi A et al.. Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.  Haematologica. 2004;  89 215-232
• 49 Barbui T, Finazzi G. Management of essential thrombocythemia.  Crit Rev Oncol Hematol. 1999;  29 257-266
• 50 Anger B, Seidler R, Haug U, Popp C, Heimpel H. Idiopathic myelofibrosis: a retrospective study of 103 patients.  Haematologica. 1990;  75 228-234
• 51 Manoharan A, Smart R C, Pitney W R. Prognostic factors in myelofibrosis.  Pathology. 1982;  14 455-461
• 52 Hasselbalch H C. Idiopathic myelofibrosis-an update with particular reference to clinical aspects and prognosis.  Int J Clin Lab Res. 1993;  23 124-138
• 53 Varki A, Lottenberg R, Griffith R, Reinhard E. The syndrome of idiopathic myelofibrosis. A clinicopathologic review with emphasis on the prognostic variables predicting survival.  Medicine (Baltimore). 1983;  62 353-371
• 54 Rupoli S, Da Lio L, Sisti S et al.. Primary myelofibrosis: a detailed statistical analysis of the clinicopathological variables influencing survival.  Ann Hematol. 1994;  68 205-212
• 55 Okamura T, Kinukawa N, Niho Y, Mizoguchi H. Primary chronic myelofibrosis: clinical and prognostic evaluation in 336 Japanese patients.  Int J Hematol. 2001;  73 194-198
• 56 Reilly J T. Idiopathic myelofibrosis: pathogenesis, natural history and management.  Blood Rev. 1997;  11 233-242
• 57 Barosi G, Berzuini C, Liberato L N, Costa A, Polino G, Ascari E. A prognostic classification of myelofibrosis with myeloid metaplasia.  Br J Haematol. 1988;  70 397-401
• 58 Cervantes F, Pereira A, Esteve J et al.. Identification of ‘short-lived' and ‘long-lived' patients at presentation of idiopathic myelofibrosis.  Br J Haematol. 1997;  97 635-640
• 59 Dupriez B, Morel P, Demory J L et al.. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system.  Blood. 1996;  88 1013-1018
• 60 Njoku O S, Lewis S M, Catovsky D, Gordon-Smith E C. Anaemia in myelofibrosis: its value in prognosis.  Br J Haematol. 1983;  54 79-89
• 61 Ozen S, Ferhanoglu B, Senocak M, Tuzuner N. Idiopathic myelofibrosis (agnogenic myeloid metaplasia): clinicopathological analysis of 32 patients.  Leuk Res. 1997;  21 125-131
• 62 Reilly J T, Snowden J A, Spearing R L et al.. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases.  Br J Haematol. 1997;  98 96-102
• 63 Demory J L, Dupriez B, Fenaux P et al.. Cytogenetic studies and their prognostic significance in agnogenic myeloid metaplasia: a report on 47 cases.  Blood. 1988;  72 855-859
• 64 Passamonti F, Rumi E, Arcaini L et al.. Leukemic transformation of polycythemia vera: a single center study of 23 patients.  Cancer. 2005;  104 1032-1036
• 65 Anger B, Haug U, Seidler R, Heimpel H. Polycythemia vera. A clinical study of 141 patients.  Blut. 1989;  59 493-500
• 66 Ania B J, Suman V J, Sobell J L, Codd M B, Silverstein M N, Melton III L J. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989.  Am J Hematol. 1994;  47 89-93
• 67 Bilgrami S, Greenberg B R. Polycythemia rubra vera.  Semin Oncol. 1995;  22 307-326
• 68 Ellis J T, Peterson P, Geller S A, Rappaport H. Studies of the bone marrow in polycythemia vera and the evolution of myelofibrosis and second hematologic malignancies.  Semin Hematol. 1986;  23 144-155
• 69 Brandt L, Anderson H. Survival and risk of leukaemia in polycythaemia vera and essential thrombocythaemia treated with oral radiophosphorus: are safer drugs available?.  Eur J Haematol. 1995;  54 21-26
• 70 Finazzi G, Caruso V, Marchioli R et al.. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study.  Blood. 2005;  105 2664-2670
• 71 Marchioli R, Finazzi G, Landolfi R et al.. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.  J Clin Oncol. 2005;  23 2224-2232
• 72 Thiele J, Kvasnicka H M. Diagnostic impact of bone marrow histopathology in polycythemia vera (PV).  Histol Histopathol. 2005;  20 317-328
• 73 Najean Y, Rain J D, Dresch C et al.. Risk of leukaemia, carcinoma, and myelofibrosis in 32P- or chemotherapy-treated patients with polycythaemia vera: a prospective analysis of 682 cases. The “French Cooperative Group for the Study of Polycythaemias”.  Leuk Lymphoma. 1996;  suppl 1 111-119
• 74 Najean Y, Rain J D, Billotey C. Epidemiological data in polycythaemia vera: a study of 842 cases.  Hematol Cell Ther. 1998;  40 159-165
• 75 Spivak J L. Polycythemia vera: myths, mechanisms, and management.  Blood. 2002;  100 4272-4290
• 76 Nielsen I, Hasselbalch H C. Acute leukemia and myelodysplasia in patients with a Philadelphia chromosome negative chronic myeloproliferative disorder treated with hydroxyurea alone or with hydroxyurea after busulphan.  Am J Hematol. 2003;  74 26-31
• 77 Sterkers Y, Preudhomme C, Lai J L et al.. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion.  Blood. 1998;  91 616-622
• 78 Thiele J, Kvasnicka H M, Diehl V. Bone marrow features of diagnostic impact in erythrocytosis.  Ann Hematol. 2005;  84 362-367
• 79 Thiele J, Kvasnicka H M, Diehl V. Initial (latent) polycythemia vera with thrombocytosis mimicking essential thrombocythemia.  Acta Haematol. 2005;  113 213-219
• 80 Thiele J M, Kvasnicka H M. Diagnosis of polycythemia vera based on bone marrow pathology.  Curr Hematol Rep. 2005;  4 218-223