April 2021 – Presented by Dr. Alexander Ladenheim (Mentored by Dr. Elham Vali Betts)


The patient has dysplastic erythroid precursors (approximately 20% of cells), ring sideroblasts (approximately 20% of cells), and dysplastic megakaryocytes (approximately 15% of cells). There is no evidence of increased blasts. A molecular diagnostic panel for myelodysplastic syndrome was performed and found a mutation in SF3B1 among several others. The diagnosis rendered was myelodysplastic syndrome with ring sideroblasts with multilineage dysplasia (MDS-RS-MLD).


Myelodysplastic syndrome (MDS) is a disorder of hematopoietic progenitor cells resulting in ineffective hematopoiesis and dysplastic, poorly functioning forms in one or more cell lineages. This ineffective hematopoiesis causes cytopenias (the thresholds for cytopenias are summarized in Table 1), most commonly anemia, and if severe can progress to transfusion dependence and bone marrow failure. Further, patients with MDS can progress to acute myeloid leukemia (AML).1 The criteria for the diagnosis of MDS on a bone marrow biopsy are dysplasia in >10% of cells and cytopenia in one or more cell lineages. Furthermore, other causes of dysplasia and the many mimics of MDS must be excluded, including drug/toxin exposure, viral infections, congenital disorders, and vitamin deficiencies (such as copper and vitamin B6 deficiencies).2

Table 1. Cytopenia threshold for diagnosis of MDS




Hemoglobin <10 g/dL Absolute neutrophil count <1.8 x 109/L Platelets <100 x 109/L

In the erythroid lineage, this dysplasia can take the form of multinucleation, irregular nuclear contours and blebbing, karyorrhectic forms, and megaloblastoid change as well as the presence of ring sideroblasts. Ring sideroblasts are defined as cells with five or more perinuclear iron granules stained by Prussian blue that encompass at least 1/3 of the nuclear circumference.1

Dysplastic myeloid cells commonly have abnormalities of granule formation, including hypogranular and pseudo-Chediak-Highashi forms, as well as nuclear hypolobation and pseudo-Pelger-Huet forms. Megakaryocytes with dysplasia often have hypolobated nuclei or are dyslobated (the presence of multiple, separate, small nuclei within a cell). 1 Micromegakaryocytes, which are promyelocyte-sized or smaller and have a non- or bilobated nucleus,2 are considered a reliable indicator of megakaryocyte dysplasia.

MDS is classified based on several factors, including the lineage(s) affected (myeloid, erythroid, or megakaryocytic), the presence of ring sideroblasts, and blast count. Dysplastic forms must account for ≥10% of cells in one or more lineages. The diagnosis of MDS with ring sideroblasts (MDS-RS) is based on ring sideroblasts accounting for ≥15% of erythroid precursors; however, in a patient with a known SF3B1 mutation (see below), this threshold is decreased (≥5% ring sideroblasts).2

Certain subtypes of MDS have a more favorable prognosis, being less likely to cause bone marrow failure or lead to AML. In general, MDS with single lineage dysplasia (MDS-SLD) has a better prognosis than MDS with multilineage dysplasia (MDS-MLD). In MDS-SLD, median overall survival is 66 months with 10% progressing to AML by 5 years; by contrast, in MDS-MLD, overall survival is 36 months with approximately 30% progressing to AML by 5 years. MDS with ring sideroblasts (MDS-RS) is a less common subtype, but it has a better prognosis when dysplasia is restricted to a single lineage (overall survival 69-108 months, 1-2% progress to AML). However, in MDS-RS-MLD, generally outcomes are similar to typical MDS-MLD.2

In MDS-RS, mutations in SF3B1 are found in 90% of MDS-RS-SLD cases (and 30-70% of MDS-RS-MLD). The gene codes for a protein important to RNA splicing. It has been found that patients with MDS-RS bearing a mutation in SF3B1 have better outcomes than other subtypes of MDS; however, data is conflicting as to whether the mutation independently confers a better prognosis or if this is confounded by the large proportion of these individuals also having single lineage dysplasia and other favorable prognostic factors.2 There is at least some evidence to support SF3B1 mutation as an independent predictor of better outcomes, even in MDS-RS-MLD.3


  1. Salama M, Teruya-Feldstein J, Kremyankaya M. Atlas of Diagnostic Hematology. Philadelphia, PA: Elsevier; 2021.
  2. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer; 2017.
  3. Malcovati L, Karimi M, Papemmanuil E et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126(2):233-241. PMID 25957392.