Main Article Content
MDS, RCUD, refractory thrombocytopenia, refractory neutropenia, refractory anemia, refractory anemia with multilineage dysplasia
Background. The 2008 WHO classification identified refractory cytopenia with unilineage dysplasia (RCUD) as a composite entity encompassing refractory anemia, refractory thrombocytopenia (RT), and refractory neutropenia (RN), characterized by 10% or more dysplastic cells in the bone marrow respective lineage. The diagnosis of RT and RN is complicated by several factors. Diagnosing RT first requires exclusion of familial thrombocytopenia, chronic auto-immune thrombocytopenia, concomitant medications, viral infections, or hypersplenism. Diagnosis of RN should also be made after ruling out differential diagnoses such as ethnic or familial neutropenia, as well as acquired, drug-induced, infection-related or malignancy-related neutropenia. An accurate quantification of dysplasia should be performed in order to distinguish RT or RN from the provisional entity named idiopathic cytopenia of unknown significance (ICUS). Cytogenetic analysis, and possibly in the future somatic mutation analysis (of genes most frequently mutated in MDS), and flow cytometry analysis aberrant antigen expression on myeloid cells may help in this differential diagnosis. Importantly, we and others found that, while isolated neutropenia and thrombocytopenia are not rare in MDS, those patients can generally be classified (according to WHO 2008 classification) as refractory cytopenia with multilineage dysplasia or refractory anemia with excess blasts, while RT and RN (according to WHO 2008) are quite rare.These results suggest in particular that identification of RT and RN as distinct entities could be reconsidered in future WHO classification updates.
2. Jaffe ES Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues (World Health Organization Classification of Tumours). 2002
3. Swerdlow SH, Campo E, Harris NL, et al. Who Classification of Tumors of Haematopoietic and Lymphoid Tissues. 2008
4. Verburgh E, Achten R, Louw VJ, et al. A new disease
categorization of low-grade myelodysplastic syndromes based on the expression of cytopenia and dysplasia in one versus more than one lineage improves on the WHO classification. Leukemia 2007;21:668–677.
5. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2009;115:168–186.
6. Padhi S, Varghese R, Phansalkar M, Sarangi R Isolated deletion of the long arm of chromosome 20 [del(20q12)] in myelodysplastic syndrome: a case report and literature review. Singapore Med J 2013;54:e185–e189.
7. Sashida G, Takaku T-I, Shoji N, et al. Clinico-hematologic features of myelodysplastic syndrome presenting as isolated thrombocytopenia: an entity with a relatively favorable prognosis. Leuk Lymphoma 2003;44:653–658.
8. Haase D, Fonatsch C, Freund M, et al. Cytogenetic findings in 179 patients with myelodysplastic syndromes. Ann Hematol 1995;70:171–187.
9. Chang J, Park C-J, Seo E-J, et al. A case of refractory thrombocytopenia with 5q deletion: myelodysplastic syndrome mimicking idiopathic thrombocytopenic purpura. Ann Lab Med 2014;34:466–8.
10. Hebbar M, Kaplan C, Caulier MT, et al. Low incidence of specific anti-platelet antibodies detected by the MAIPA assay in the serum of thrombocytopenic MDS patients and lack of correlation between platelet autoantibodies, platelet lifespan and response to danazol therapy. Br J Haematol 1996;94:112–115.
11. Sarpatwari A, Provan D, Erqou S, et al. Autologous 111 In-labelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy: a report from the United Kingdom ITP Registry. Br J Haematol 2010;151:477–487.
12. Chan H, Moore JC, Finch CN, et al. The IgG subclasses of platelet-associated autoantibodies directed against platelet glycoproteins IIb/IIIa in patients with idiopathic thrombocytopenic purpura. Br J Haematol 2003;122:818–824.
13. Chabannon C, Molina L, Pégourié-Bandelier B, et al. A Review of 76 Patients with Myelodysplastic Syndromes Treated with Danazol. Cancer 1994;94:3073–80.
14. Patel PD, Samanich JM, Mitchell WB, Manwani D A unique presentation of Wiskott-Aldrich syndrome in relation to platelet size. Pediatr Blood Cancer 2011;56:1127–1129.
15. Gibson C, Berliner N How we evaluate and treat neutropenia in adults. Blood 2014;124:1251–8; quiz 1378.
16. Bishop CR, Rothstein G, Ashenbrucker HE, Athens JW Leukokinetic studies. XIV. Blood neutrophil kinetics in chronic, steady-state neutropenia. J Clin Invest 1971;50:1678–1689.
17. Campion G, Maddison PJ, Goulding N, et al. The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations. Medicine (Baltimore) 1990;69:69–80.
18. Saway PA, Prasthofer EF, Barton JC Prevalence of granular lymphocyte proliferation in patients with rheumatoid arthritis and neutropenia. Am J Med 1989;86:303–307.
19. Gong X, Lu X, Wu X, et al. Role of bone marrow imprints in haematological diagnosis: a detailed study of 3781 cases. Cytopathology 2012;23:86–95.
20. Wimazal F, Fonatsch C, Thalhammer R, et al. Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface. Leuk Res 2007;31:1461–8.
21. Giagounidis A, Haase D Morphology, cytogenetics and classification of MDS. Best Pract Res Clin Haematol 2013;26:337–53.
22. Valent P, Horny H, Bennett JM, et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes?: Consensus statements and report from a working conference. 2007;1–10.
23. Valent P, Horny H-P Minimal diagnostic criteria for myelodysplastic syndromes and separation from ICUS and IDUS: update and open questions. Eur J Clin Invest 2009;39:548–553.
24. Bacher U, Haferlach T, Schnittger S, et al. Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact. Br J Haematol 2014;164:822–33.
25. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011;364:2496–506.
26. Bejar R, Stevenson KE, Caughey B a, et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 2012;30:3376–82.
27. Jaiswal S, Fontanillas P, Flannick J, et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. N Engl J Med
28. Matsuda A, Germing U, Jinnai I, et al. Differences in the distribution of subtypes according to the WHO classification 2008 between Japanese and German patients with refractory anemia according to the FAB classification in myelodysplastic syndromes. Leuk Res 2010;34:974–80.
29. Maassen A, Strupp C, Giagounidis A, et al. Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts. Leuk Res 2013;37:64–70.
30. Marinier DE, Mesa H, Rawal A, Gupta P Refractory cytopenias with unilineage dysplasia: a retrospective analysis of refractory neutropenia and refractory thrombocytopenia. Leuk Lymphoma 2010;51:1923–6.
31. Breccia M, Latagliata R, Cannella L, et al. Refractory cytopenia with unilineage dysplasia: analysis of prognostic factors and survival in 126 patients. Leuk Lymphoma 2010;51:783–8.
32. Font P, Loscertales J, Benavente C, et al. Inter-observer variance with the diagnosis of myelodysplastic syndromes (MDS) following the 2008 WHO classification. Ann Hematol 2013;92:19–24.
33. Font P, Loscertales J, Soto C, et al. Interobserver variance in myelodysplastic syndromes with less than 5 % bone marrow blasts: unilineage vs. multilineage dysplasia and reproducibility of the threshold of 2 % blasts. Ann Hematol (in press)
34. Cazzola M Risk assessment in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Haematologica 2011;96:349–352.
35. Oka S, Muroi K, Fujiwara S, et al. Prediction of Progression from Refractory Cytopenia with Unilineage Dysplasia by Analysis of Bone Marrow Blast Cell Composition. J Clin Exp Hematop 2012;52:63–66.
36. Cordoba I, Gonzalez-Porras JR, Such E, et al. The degree of neutropenia has a prognostic impact in low risk myelodysplastic syndrome. Leuk Res 2012;36:287–292.
37. Breccia M, Loglisci G, Salaroli A, et al. Neutropenia at baseline could indicate poor prognosis in low/intermediate risk myelodysplastic syndrome patients. Leuk Res 2012;36:546–547.
38. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012;120:2454–65.
39. Westers TM, Ireland R, Kern W, et al. Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group. Leukemia 2012;26:1730–41.
40. Ogata K, Kishikawa Y, Satoh C, et al. Diagnostic application of flow cytometric characteristics of CD34+ cells in low-grade myelodysplastic syndromes. Blood 2006;108:1037–44.
41. Della Porta MG, Picone C, Pascutto C, et al. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study. Haematologica 2012;97:1209–17.
42. Van de Loosdrecht AA, Westers TM, Westra AH, et al. Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry. Blood 2008;111:1067–77.
43. Kern W, Haferlach C, Schnittger S, Haferlach T Clinical utility of multiparameter flow cytometry in the diagnosis of 1013 patients with suspected myelodysplastic syndrome: correlation to cytomorphology, cytogenetics, and clinical data. Cancer 2010;116:4549–63.
44. Kohlmann A, Bacher U, Schnittger S, Haferlach T Perspective on how to approach molecular diagnostics in acute myeloid leukemia and myelodysplastic syndromes in the era of next-generation sequencing. Leuk Lymphoma 2014;55:1725–1734.