Skip to main content
SpringerLink
Log in

Mixed Cytoses and Cytopenias

  • Chapter
  • First Online:
Diagnosis of Blood and Bone Marrow Disorders

  • 1996 Accesses

Abstract

Leukocytosis is defined as leukocyte count ≥13 × 109/L; in this chapter, the focus is leukocytosis due to an increase of neutrophils and their precursors. Thrombocytosis is defined by a platelet count ≥450 × 109/L. Leukocytosis either in isolation or as the main abnormal feature of blood is discussed in Chap. 5, whereas thrombocytosis as the primary presenting abnormality is discussed in Chap. 8. This chapter covers conditions presenting with either leukocytosis or thrombocytosis and one or two cytopenias. As well as reactive conditions that may present with this mixed picture in the blood, specific myeloid neoplasms most commonly present with mixed cytosis and cytopenias are discussed here: atypical chronic myeloid leukemia; myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), unclassifiable; and primary myelofibrosis. A proposed algorithmic approach to the diagnosis of neutrophilic leukocytosis accompanied by anemia and/or thrombocytopenia is shown in Fig. 10.1. Myelodysplastic syndromes with isolated del(5q) and with inv(3) that can frequently present with thrombocytosis despite other cytopenias will also be discussed. The MDS/MPN entity with ring sideroblasts and thrombocytosis, although most classically presenting with thrombocytosis and anemia, is discussed separately in Chap. 8.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  1. Al-Tawfiq JA, et al. Hematologic, hepatic, and renal function changes in hospitalized patients with Middle East respiratory syndrome coronavirus. Int J Lab Hematol. 2017;39(3):272–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aird WC. The hematologic system as a marker of organ dysfunction in sepsis. Mayo Clin Proc. 2003;78(7):869–81.

    Article  CAS  PubMed  Google Scholar 

  3. Halfdanarson TR, Litzow MR, Murray JA. Hematologic manifestations of celiac disease. Blood. 2007;109(2):412–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Conlan MG, et al. Clinical significance of hematologic parameters in non-Hodgkin’s lymphoma at diagnosis. Cancer. 1991;67(5):1389–95.

    Article  CAS  PubMed  Google Scholar 

  5. Steensma DP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Xie M, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jaiswal S, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Genovese G, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kwok B, et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood. 2015;126(21):2355–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Vardiman JW, et al. Atypical chronic myeloid leukaemia, BCR-ABL1 negative. In: WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 80–1.

    Google Scholar 

  11. Talati C, Padron E. An exercise in extrapolation: clinical management of atypical CML, MDS/MPN-unclassifiable, and MDS/MPN-RS-T. Curr Hematol Malig Rep. 2016;11(6):425–33.

    Article  PubMed  Google Scholar 

  12. Wang SA, et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood. 2014;123(17):2645–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Piazza R, et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet. 2013;45(1):18–24.

    Article  CAS  PubMed  Google Scholar 

  14. Breccia M, et al. Identification of risk factors in atypical chronic myeloid leukemia. Haematologica. 2006;91(11):1566–8.

    PubMed  Google Scholar 

  15. Hernandez JM, et al. Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol. 2000;11(4):441–4.

    Article  CAS  PubMed  Google Scholar 

  16. Kurzrock R, et al. BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol. 2001;19(11):2915–26.

    Article  CAS  PubMed  Google Scholar 

  17. Koldehoff M, et al. Outcome of hematopoietic stem cell transplantation in patients with atypical chronic myeloid leukemia. Bone Marrow Transplant. 2004;34(12):1047–50.

    Article  CAS  PubMed  Google Scholar 

  18. Ouyang J, et al. Flow cytometry immunophenotypic analysis of Philadelphia-negative myeloproliferative neoplasms: correlation with histopathologic features. Cytometry B Clin Cytom. 2015;88(4):236–43.

    Article  PubMed  Google Scholar 

  19. Xu Y, et al. A BCR-JAK2 fusion gene from ins(22;9)(q11;p13p24) in a patient with atypical chronic myeloid leukemia. Leuk Lymphoma. 2013;54(10):2322–4.

    Article  PubMed  Google Scholar 

  20. Bellesso M, et al. Atypical chronic myeloid leukemia with t(9;22)(p24,11.2), a BCR-JAK2 fusion gene. Rev Bras Hematol Hemoter. 2013;35(3):218–9.

    PubMed  PubMed Central  Google Scholar 

  21. Muta T, Osaki K, Yamano Y. Translocation t(9;22) (p23;q11) in atypical chronic myeloid leukemia (aCML) presenting osteolytic lesions. Int J Hematol. 2002;76(4):344–8.

    Article  PubMed  Google Scholar 

  22. Gambacorti-Passerini CB, et al. Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. Blood. 2015;125(3):499–503.

    Article  CAS  PubMed  Google Scholar 

  23. Maxson JE, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368(19):1781–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Geyer JT, Orazi A. Myeloproliferative neoplasms (BCR-ABL1 negative) and myelodysplastic/myeloproliferative neoplasms: current diagnostic principles and upcoming updates. Int J Lab Hematol. 2016;38(Suppl 1):12–9.

    Article  PubMed  Google Scholar 

  25. Arber DA, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    Article  CAS  PubMed  Google Scholar 

  26. Park HJ, et al. Delta neutrophil index as an early marker for differential diagnosis of adult-onset Still's disease and sepsis. Yonsei Med J. 2014;55(3):753–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lawrence YR, et al. Extreme leukocytosis in the emergency department. QJM. 2007;100(4):217–23.

    Article  CAS  PubMed  Google Scholar 

  28. Juturi JV, Hopkins T, Farhangi M. Severe leukocytosis with neutrophilia (leukemoid reaction) in alcoholic steatohepatitis. Am J Gastroenterol. 1998;93(6):1013.

    Article  CAS  PubMed  Google Scholar 

  29. Kawada T. Smoking-induced leukocytosis can persist after cessation of smoking. Arch Med Res. 2004;35(3):246–50.

    Article  CAS  PubMed  Google Scholar 

  30. Biezeveld MH, et al. Sustained activation of neutrophils in the course of Kawasaki disease: an association with matrix metalloproteinases. Clin Exp Immunol. 2005;141(1):183–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Meyerson HJ, Farhi DC, Rosenthal NS. Transient increase in blasts mimicking acute leukemia and progressing myelodysplasia in patients receiving growth factor. Am J Clin Pathol. 1998;109(6):675–81.

    Article  CAS  PubMed  Google Scholar 

  32. Dale DC, et al. Comparison of agents producing a neutrophilic leukocytosis in man. Hydrocortisone, prednisone, endotoxin, and etiocholanolone. J Clin Invest. 1975;56(4):808–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Christensen RD, Hill HR. Exercise-induced changes in the blood concentration of leukocyte populations in teenage athletes. Am J Pediatr Hematol Oncol. 1987;9(2):140–2.

    Article  CAS  PubMed  Google Scholar 

  34. Marinella MA. Extreme leukemoid reaction associated with retroperitoneal hemorrhage. Arch Intern Med. 1998;158(3):300–1.

    Article  CAS  PubMed  Google Scholar 

  35. Ascensao JL, et al. Leukocytosis and large cell lung cancer. A frequent association. Cancer. 1987;60(4):903–5.

    Article  CAS  PubMed  Google Scholar 

  36. Kayashima T, et al. Leukemoid reaction associated with diabetic ketoacidosis: with measurement of plasma levels of granulocyte colony-stimulating factor. Intern Med. 1993;32(11):869–71.

    Article  CAS  PubMed  Google Scholar 

  37. Kohmura K, et al. Granulocyte colony stimulating factor-producing multiple myeloma associated with neutrophilia. Leuk Lymphoma. 2004;45(7):1475–9.

    Article  CAS  PubMed  Google Scholar 

  38. Vardiman JW, et al. Myelodysplastic/myeloproliferative neoplasm, unclassifiable. In: WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 85–6.

    Google Scholar 

  39. DiNardo CD, et al. Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy. Leukemia. 2014;28(4):958–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Srour SA, et al. Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001–12. Br J Haematol. 2016;174(3):382–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tiu RV, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood. 2011;117(17):4552–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zoi K, Cross NC. Molecular pathogenesis of atypical CML, CMML and MDS/MPN-unclassifiable. Int J Hematol. 2015;101(3):229–42.

    Article  CAS  PubMed  Google Scholar 

  43. Dunbar AJ, et al. 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res. 2008;68(24):10349–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Clara JA, Sallman DA, Padron E. Clinical management of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes. Cancer Biol Med. 2016;13(3):360–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Meggendorfer M, et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia. 2013;27(9):1852–60.

    Article  CAS  PubMed  Google Scholar 

  46. Guglielmelli P, et al. Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. Blood. 2017;129(24):3227–36.

    Article  CAS  PubMed  Google Scholar 

  47. Thiele J, et al. Primary myelofibrosis. In: WHO classification of tumours of haematopoietic and lymphoid Tissues. Lyon: IARC; 2008. p. 44–7.

    Google Scholar 

  48. Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(12):1262–71.

    Article  CAS  PubMed  Google Scholar 

  49. Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol. 2005;23(33):8520–30.

    Article  CAS  PubMed  Google Scholar 

  50. Barosi G, et al. Evidence that prefibrotic myelofibrosis is aligned along a clinical and biological continuum featuring primary myelofibrosis. PLoS One. 2012;7(4):e35631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Thiele J, et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90(8):1128–32.

    PubMed  Google Scholar 

  52. Mesa RA, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105(3):973–7.

    Article  CAS  PubMed  Google Scholar 

  53. Feng B, et al. Aberrant myeloid maturation identified by flow cytometry in primary myelofibrosis. Am J Clin Pathol. 2010;133(2):314–20.

    Article  PubMed  Google Scholar 

  54. Hussein K, Van Dyke DL, Tefferi A. Conventional cytogenetics in myelofibrosis: literature review and discussion. Eur J Haematol. 2009;82(5):329–38.

    Article  PubMed  Google Scholar 

  55. Milosevic Feenstra JD, et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016;127(3):325–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tefferi A, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28(7):1472–7.

    Article  CAS  PubMed  Google Scholar 

  57. Loghavi S, et al. Myeloproliferative neoplasms with calreticulin mutations exhibit distinctive morphologic features. Am J Clin Pathol. 2016;145(3):418–27.

    Article  CAS  PubMed  Google Scholar 

  58. Tefferi A, et al. JAK2 germline genetic variation affects disease susceptibility in primary myelofibrosis regardless of V617F mutational status: nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival. Leukemia. 2010;24(1):105–9.

    Article  CAS  PubMed  Google Scholar 

  59. Tefferi A, et al. Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Leukemia. 2008;22(4):756–61.

    Article  CAS  PubMed  Google Scholar 

  60. Guglielmelli P, et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood. 2009;114(8):1477–83.

    Article  CAS  PubMed  Google Scholar 

  61. Guglielmelli P, et al. JAK2V617F mutational status and allele burden have little influence on clinical phenotype and prognosis in patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis. Haematologica. 2009;94(1):144–6.

    Article  PubMed  Google Scholar 

  62. Tefferi A, et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia. 2012;26(3):475–80.

    Article  CAS  PubMed  Google Scholar 

  63. Guglielmelli P, et al. EZH2 mutational status predicts poor survival in myelofibrosis. Blood. 2011;118(19):5227–34.

    Article  CAS  PubMed  Google Scholar 

  64. Lasho TL, et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood. 2012;120(20):4168–71.

    Article  CAS  PubMed  Google Scholar 

  65. Vannucchi AM, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861–9.

    Article  CAS  PubMed  Google Scholar 

  66. Tefferi A, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494–500.

    Article  CAS  PubMed  Google Scholar 

  67. Pullarkat V, et al. Primary autoimmune myelofibrosis: definition of a distinct clinicopathologic syndrome. Am J Hematol. 2003;72(1):8–12.

    Article  PubMed  Google Scholar 

  68. Vergara-Lluri ME, et al. Autoimmune myelofibrosis: an update on morphologic features in 29 cases and review of the literature. Hum Pathol. 2014;45(11):2183–91.

    Article  CAS  PubMed  Google Scholar 

  69. Barbui T, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29(23):3179–84.

    Article  PubMed  Google Scholar 

  70. Kvasnicka HM, Thiele J. Prodromal myeloproliferative neoplasms: the 2008 WHO classification. Am J Hematol. 2010;85(1):62–9.

    PubMed  Google Scholar 

  71. Sangle N, et al. Myelofibrotic transformations of polycythemia vera and essential thrombocythemia are morphologically, biologically, and prognostically indistinguishable from primary myelofibrosis. Appl Immunohistochem Mol Morphol. 2014;22(9):663–8.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Fu B, et al. Bone marrow fibrosis in patients with primary myelodysplastic syndromes has prognostic value using current therapies and new risk stratification systems. Mod Pathol. 2014;27(5):681–9.

    Article  PubMed  Google Scholar 

  73. Fu B, et al. The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes. Ann Hematol. 2013;92(10):1335–43.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Loghavi S, et al. TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis. Br J Haematol. 2015;171(1):91–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Dingli D, et al. Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia. Br J Haematol. 2005;130(2):229–32.

    Article  CAS  PubMed  Google Scholar 

  76. Hasserjian R, et al. Myelodysplastic syndrome with isolated del(5q). In: WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 102.

    Google Scholar 

  77. Washington LT, et al. Myeloid disorders with deletion of 5q as the sole karyotypic abnormality: the clinical and pathologic spectrum. Leuk Lymphoma. 2002;43(4):761–5.

    Article  PubMed  Google Scholar 

  78. Ingram W, et al. The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow. Leukemia. 2006;20(7):1319–21.

    Article  CAS  PubMed  Google Scholar 

  79. Rogers HJ, et al. Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014;99(5):821–9.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sanam Loghavi M.D. & Sa A. Wang

Authors
  1. Sanam Loghavi M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sa A. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanam Loghavi M.D. .

Editor information

Editors and Affiliations

  1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sa A. Wang

  2. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Robert P. Hasserjian

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Loghavi, S., Wang, S.A. (2018). Mixed Cytoses and Cytopenias. In: Wang, S., Hasserjian, R. (eds) Diagnosis of Blood and Bone Marrow Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-20279-2_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-20279-2_10

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-20278-5

  • Online ISBN: 978-3-319-20279-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation