The Clinical And Laboratory Characteristics Of Patients With Idiopathic Cytopenia Of Undetermined Significance

BackgroundIn clinical work,we often encounter a group of patients who show one or more cytopenia with varying degrees of bone marrow hematopoietic failure,no bone marrow(or mild<10%)dysplasia hematopoiesis,blast cells is small,and there is no typical cytogenetic abnormality of Myelodysplastic syndrome(MDS),which does not meet the minimum diagnostic criteria of MDS,and excludes secondary cytopenia caused by other diseases.It is often difficult for us to give a definitive diagnosis for this part of patients.It has been reported that the number of this part of the patient is much larger than that of MDS,which is about 5 times of MDS.In order to avoid over-diagnosis and better manage these patients,at the 8th International Working Group On Morphology Of Myelodysplastic Syndrome(IWGM-MDS)in 2005,Mufti first proposed "idiopathic cytopenia with uncertain(undetermined)significance.,ICUS]".A concept is used to define such a group of cytopenic patients who do not meet the minimum diagnostic criteria for MDS and cannot find other causes.Currently,ICUS is considered to be a new group of cytopenia diseases,which are mainly characterized by anemia,hemorrhage and infection.The studies have shown that some patients with ICUS can progress to MDS or other hematological malignancies or non-hematological disorders.In recent years,with the development of second-generation gene sequencing technology,research on the clinical features and pathogenesis of ICUS has become more and more in-depth.The study found that approximately 35%of ICUS carry gene mutations associated with MDS.Especially for ICUS with mild dysplasia,more than 60%of patients carry gene mutations,and only 20%of ICUS without dysplasia have gene mutations,and the average number of gene mutations per patient is 1.3-1.5,among which TET2,DNMT3A,TP53,ASXL1,EZH2,and U2AF1 are the most common.Moreover,the greater the number of genetic mutations carried,the higher the allele mutation frequency(VAF),the higher the risk of progression to myeloid tumors such as MDS.However,there have been studies followed for many years,and the results show that even if ICUS patients carry MDS-related gene mutations,they have not found progression to MDS or other myeloid tumors,and their peripheral blood counts remain stable.At present,there is little understanding of ICUS,and limited retrospective series of studies have reported inconsistencies in the likelihood of ICUS progressing to significant MDS or other hematologic malignancies.ICUS patients may be heterogeneous,and the pathophysiology of some ICUS patients may differ from MDS.However,the pathogenesis of these cases is unclear.How to predict whether the disease is benign or worse?It is currently a huge challenge for clinicians.MethodsA retrospective analysis of 149 patients with ICUS admitted to the Department of Hematology,Guangdong Provincial People’s Hospital from January 2009 to September 2018,collected all their datas,and summarized their clinical and laboratory characteristics.Results1.Among the 149 ICUS patients,86 were male and 63 were female,male:female was 1.36:1,and median age was 51(range:1-83).Six patients had a family history of tumors,all of whose Dad had gastrointestinal malignancies.5 cases were associated with localized lymphadenopathy,11 cases with splenomegaly,and 5 cases with hepatomegaly,of which only 3 cases showed hepatosplenomegaly.All patients were excluded from exposure to chemical,radiological,and chemotherapeutic drugs.2.0f the 149 ICUS patients,128 showed anemia,118 showed thrombocytope-nia,and 94 had neutropenia.Pancytopenia in peripheral blood was the most common(53%),and 77%of patients had granulocyte dysplasia hematopoiesis.The proportion of bone marrow dysplasia was positively correlated with age.The age of onset of ICUS with≥10%dysplasia hematopoiesis was significantly greater than that of ICUS without dysplasia(P=0.013).3.Chromosome karyotype:12/127cases(9.4%)with karyotype abnormalities,and 115/127cases(90.6%)with normal karyotype.In the karyotype abnormal group,3/12(25%)progressed to MDS with a median progression time of 24 months(range:5-80 months);22/115(19.13%)of the normal karyotype group progressed to MDS,the median progression time was 34.5 months(range:5-115 months).There was no significant difference in disease progression and median progression between the two groups(P=0.417;P=0.69).Among them,5/115 patients in the normal karyotype group had abnormalities in the karyotype when the disease progressed,including 2 cases +8,1 case 5q-,1 case 7q-,and 1 case combined with 20q-and aneuploidy.4.0f the 63 patients,WTI was abnormally expressed in 27 patients(43%),with a median value of 7.39(0-53.52)in the bone marrow and a median value of 0.195(0-4.23)in the peripheral blood.Among the 4 patients who progressed to MDS,the level of WT1 in bone marrow was significantly increased,and the difference was statistically significant(P=0.02).5.Gene mutation:71.1%(37/52 cases)patients with positive mutations,28.9%(15/52 cases)with negative gene mutations,among which TET2,RUNX1,ASXL1,FAT1 and SRSF2 mutations were the most common.The number of mutations per patient is 1-6,30%(11/37 cases)carry≥3 mutant genes,51.35%(19/37 cases)carry MDS-related gene mutations.Among the ICUS patients with gene mutations,8/37(21.62%)progressed to MDS,and 1/15(6.6%)of ICUS without gene mutation progressed to MDS.The difference was statistically significant(p= 0.00).6.The median follow-up time was 50 months(range:2-450),of which 7 were lost to follow-up(loss of 4.7%),and the median survival time of the remaining 142 patients was 61 months(95%CI 52.34 to 69.65),the survival rate of 5 years is 67.85%.25 patients progressed to MDS,12 patients progressed to aplastic anemia(AA),2 patients with pure red cell aplastic anemia(PRCA),and 1 patient with megaloblastic anemia 1 case of large granular lymphocytic leukemia and 1 case of rheumatic immune disease.The mortality rate of this group of patients was 20.13%(30/149 cases).Conclusion1.With the increase of age,dysplastic cells in the bone marrow also increase,especially granulocyte-like hematopoiesis.Therefore,in the identification of ICUS and MDS,we should pay attention to the relationship between age and pathological hematopoiesis.2.The expression level of WTI gene in ICUS patients is close to that of healthy people.When it progresses to MDS,WT1 expression is significantly increased.3.Some patients with ICUS can carry MDS-related gene mutations and/or chromosomal abnormalities,and ICUS with gene mutations is more likely to progress to MDS.Therefore,patients with ICUS must have regular hematologic follow-up.