Introduction: Myelodysplastic syndromes (MDS) are heterogeneous hematological disorders characterized by hematopoietic dysplasia and/or chromosomal aberrations. However, the diagnosis of dysplasia is subjective and chromosomal aberrations are not always present. Thus, the diagnosis of MDS is not always straightforward when lacking specific characteristics. To resolve this diagnostic problem, a novel flow cytometry technique standardized by the European LeukemiaNet (ELN) working group for MDS [Haematologica 94: 1124, 2009] was proposed. However, this ELN MDS index has not been validated for the diagnosis of idiopathic cytopenia of undetermined significance (ICUS).
Purpose: To determine the diagnostic value of the ELN MDS index for ICUS, we analyzed the diagnostic accuracy of morphology, cytogenetics, and flow cytometry for cytopenia.
Methods: We investigated 253 consecutive patients who underwent bone marrow aspiration to examine the cause of cytopenia at our institute between 2012 and 2015. We used the ELN MDS index verified by Ogata et al. for low-grade MDS [Haematologica 94: 1066, 2009]. The ELN MDS index consists of the following four parameters: (1) CD34+ myeloblasts on all nucleated cells, ≥2.4%; (2) CD34+ B cells on all CD34+ cells, ≤5.0%; (3) lymphocyte/myeloblast CD45 MFI ratio, ≤4.0 or ≥7.8; and (4) granulocyte/lymphocyte SCC peak ratio, ≤6.0. When two or more parameters met the criteria, the patient was diagnosed with MDS by cytometry. We evaluated the accuracy of diagnosis with cytometry by using the clinical diagnosis as a standard reference. The clinical diagnosis was determined by more than two hematologists/specialists. Patients with MDS and ICUS were included in this study. ICUS was defined as follows: bone marrow blast, <5.0%; single- or multi-lineage dysplasia, <10%; and no detection of clonal chromosomal abberation characteristic to MDS.
Results: A total of 253 bone marrow samples were evaluated (117 females). The median patient age was 66 years (range, 1-92 years). The clinical diagnosis was MDS in 60 patients (24 females; median age, 69 years; range, 30-91 years) and ICUS in 17 patients (9 females; median age, 76 years; range, 54-88 years). Other patients were identified to have non-MDS/non-ICUS diseases and were used as a control group. MDS subcategories were as follows: RCUD (n = 14), RARS (n = 3), RCMD (n = 10), RAEB-1 (n = 9), RAEB-2 (n = 12), MDS-U (n = 8), and 5q− syndrome (n = 4). Two or more criteria of the ELN MDS index were met in 34 MDS (56.7%; 34/60) and 4 ICUS patients (23.5%; 4/17). Positivity with the ELN MDS index among the MDS subcategories varied as follows: 6 RCUD (42.9%; 6/14), 1 RARS (33.3%; 1/3), 5 RCMD (50.0%; 5/10), 7 RAEB-1 (77.8%; 7/9), 12 RAEB-2 (100%; 12/12), 2 MDS-U (25.0%; 2/8), and 1 5q− syndrome cases (25.0%; 1/4). When cutoff scores were set as the ELN MDS index of ≥2, sensitivities for diagnoses of MDS and ICUS were 56.7% (34/60) and 25.0% (4/16), specificities were 83.1% (147/177) and 83.1% (147/177), positive predictive values were 53.1% (34/64) and 11.8% (4/34), and negative predictive values were 85.0% (147/173) and 92.5% (147/159), respectively.
Conclusion: Application of the ELN MDS index in MDS revealed sensitivity and specificity in line with those of previous studies, while 25.0% of ICUS patients were indicated to have MDS. This prevalence of MDS in ICUS may correspond to 27.5% (33/120) of patients with ICUS who had genetically clonal evidence identified by targeted sequencing of 22 MDS-associated genes [Kwok et al., Blood 2015; 126: 2355]. Our data suggest that the ELN MDS index is a practical tool to identify a subset of ICUS patients with MDS trait.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.