Abstract
Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo- or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.
Highlights
IntroductionMyelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective erythropoiesis, dysplasia involving one or more cell lineages, peripheral cytopenia, and increased risk of transformation to acute myeloid leukemia (AML). [1] In most cases, MDS patients exhibit a normo- or hypercellular bone marrow (BM), whereas 10–20% of cases present a decreased bone marrow cellularity. [2,3,4,5] This group is referred to as hypoplastic MDS (h-MDS) in the World Health Organization (WHO) classification of myeloid neoplasm, without being recognized as a distinct MDS subtype. [6]A higher response rate to immunosuppressive therapy has been reported in hypoplastic MDS (h-MDS) compared with normo-hypercellular MDS (n-MDS). [7,8,9] precise diagnostic criteria for h-MDS have not been clearly defined and conflicting data on clinico-pathological characteristics and prognosis of h-MDS have been reported. [2–5, 9–12] Foremost, this uncertainty encompasses the actual definition of BM hypocellularity
Recurrent somatic mutations in multiple genes have been reported in Myelodysplastic syndromes (MDS). [22, 23] recent studies have shown that mutations in some of these genes are commonly acquired in hematopoietic cells during aging without being associated with a hematologic phenotype. [24,25,26,27] In addition, mutations in genes recurrently mutated in MDS have been detected in patients with AA without evidence of myeloid neoplasm. [28,29,30,31] So far, few genetic studies have focused on hypoplastic MDS (h-MDS), without firm conclusion. [32,33,34,35]
MDS AA c-bone marrow failure syndromes (BMF) Idiopathic cytopenia of undetermined significance (ICUS) World Health Organization (WHO) MDS category MDS del(5q) MDS-ring sideroblasts (RS)-SLD MDS-RS-MLD MDS-SLD MDS-MLD MDS-EB-1 MDS-EB-2 MDS-U IPSS-R risk group Very low Low Intermediate High Very high Aplastic anemia Non-severe Severe Very severe MDS Normo-hypercellular bone marrow (BM) cellularity ≤25% Age-adjusted hypocellularity cutoff value and age-adjusted reference ranges: younger patients with BM cellularity reduced for their age but > 25%; and elderly individuals with a BM cellularity ≤25% but consistent with their age-adjusted reference ranges
Summary
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective erythropoiesis, dysplasia involving one or more cell lineages, peripheral cytopenia, and increased risk of transformation to acute myeloid leukemia (AML). [1] In most cases, MDS patients exhibit a normo- or hypercellular bone marrow (BM), whereas 10–20% of cases present a decreased bone marrow cellularity. [2,3,4,5] This group is referred to as hypoplastic MDS (h-MDS) in the World Health Organization (WHO) classification of myeloid neoplasm, without being recognized as a distinct MDS subtype. [6]A higher response rate to immunosuppressive therapy has been reported in hypoplastic MDS (h-MDS) compared with normo-hypercellular MDS (n-MDS). [7,8,9] precise diagnostic criteria for h-MDS have not been clearly defined and conflicting data on clinico-pathological characteristics and prognosis of h-MDS have been reported. [2–5, 9–12] Foremost, this uncertainty encompasses the actual definition of BM hypocellularity. The definition of hypocellularity appears problematic in the elderly population of MDS patients in whom these values partly overlap with the wide range of age-related changes. [24,25,26,27] In addition, mutations in genes recurrently mutated in MDS have been detected in patients with AA without evidence of myeloid neoplasm. In a recent study on patients with unexplained cytopenia, including MDS and AA, we found that mutation profiling has a high predictive value for identifying individuals with a myeloid neoplasm. In this work, based on a large and well-annotated cohort of consecutive patients with BM hypocellularity from two reference centers, we aimed to define the clinical and histopathological features of h-MDS, and to elucidate the role of genetic profiles in discriminating malignant and nonmalignant BMF in elderly individuals Recurrent somatic mutations in multiple genes have been reported in MDS. [22, 23] recent studies have shown that mutations in some of these genes are commonly acquired in hematopoietic cells during aging without being associated with a hematologic phenotype. [24,25,26,27] In addition, mutations in genes recurrently mutated in MDS have been detected in patients with AA without evidence of myeloid neoplasm. [28,29,30,31] So far, few genetic studies have focused on h-MDS, without firm conclusion. [32,33,34,35]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
