Idiopathic Cytopenia of Undetermined Significance (ICUS): Impact of Flow Cytometry Immunophenotyping (FCI) in the Diagnosis of Myelodysplastic Syndrome (MDS) When Morphology Is Not Conclusive.
Authors: Font Patricia , Subira Dolores , Loscertales Javier , Arranz Eva , Alonso Arancha , Perez-Saenz M. Angeles , Escudero Antonio , Fernandez-Rañada Jose Maria , Vallespi Teresa 
Published: April 2020

Abstract
Introduction: Morphology and cytogenetics are the basis for the study of MDS, however sometimes it is difficult to establish this diagnosis. The term ICUS was recently proposed (Mufti, 2005) for cases with persistent idiophatic cytopenia without evidence of dysplasia in the bone marrow (BM) smear, and normal cytogenetics. Aim: To evaluate the utility of FCI in detecting dysplasia when it is not evident by morphology. Patients: 24 patients with idiopathic cytopenia lasting for more than 6 months were evaluated for MDS using BM morphologic examination including iron stain, cytogenetics, FISH (5, 7, 8, 20q) and FCI. In 11 cases biopsy BM sections were examined. Other causes of cytopenia were previously excluded. Material and Methods: FCI in bone marrow samples. Data studied:
In the myeloid lineage: abnormalities in granularity and CD45 distribution, abnormalities in the phenotypic pattern of myeloid development (CD16/CD11b/CD13), and the absence of CD10 expression on mature granulocytes. In the monocytic lineage: CD2 and CD56 expression. In the red cells: abnormalities in CD71 and glycophorin A distribution. In B-cells, detection of a low percentage of CD10+ B-cell precursors (less than 1% of bone marrow B-cells). In myeloblasts, identification of more than &gt;5% CD34+ cells, and evaluation of aberrant expression of CD7 and TdT in these cells (positive expression was described when &gt;10% of CD34+ cells were positive for any of these antigens).
FCI data were suggestive of MDS when at least, 4 of the 10 parameters studied were abnormal, If aberrancies in CD34 were detected, only 3 criteria of abnormalities instead of 4 were needing Results: In all cases, morphology did not establish a definitive diagnosis of MDS, and karyotype and FISH were normal. FCI was highly suggestive of MDS in 14/24 cases. In 9 of 14 patients, their follow-up (1–36 months, median 10 months) confirmed the diagnosis of MDS; among these, 4 cases had hypocellular BM. In 3 of the 14 patients, BM biopsy supported the FCI diagnosis of MDS, but repeat specimens were not possible. One patient with suggestive FCI findings developed transfusion dependent anemia, mild thrombocytopenia, and multiple FCI abnormalities, but although a second BM aspirate was performed, the smear did not demonstrate MDS. Another patient with significant abnormalities by FCI had no evidence of MDS after 1 year of follow-up. The 10 patients whose FCI did not suggest MDS, were clinically stable at the time of writing with mild alterations in hematological parameters, and without evidence of overt MDS (follow-up: 6–40 m, median: 20m). Conclusions: With the number of cases studied, FCI showed more sensitivity in detecting early phases and/or low-risk MDS than morphology. FCI was also useful in detecting hypocellular MDS. Absence of dysplasia by FCI was associated with no evidence of MDS. Incorporation of FCI to the study of ICUS might distinguish early phases or low-risk MDS from other non-clonal ethyologies.