Definition
Provisional entity exhibiting features of both RARS and Essential Thrombocythemia
Note
In at least some patients this represents acquisition of a prothrombocythemic JAK2 mutation in a background of RARS
Diagnostic Criteria
Must satisfy diagnostic features of RARS
Refractory anemia - Hemoglobin <10 mg/dL
Dysplasia involving erythroid lineage (see below for criteria for dysplasia)
Must involve ≥10% of erythroids
Ring sideroblasts (see definition below)
Must involve ≥15% of total erythroid precursors
Sustained platelet elevation ≥450 x 103 /μL Bone marrow biopsy with megakaryocytic hyperplasia
Large to giant mature megakaryocytes
Abundant cytoplasm
Deeply lobulated nuclei (staghorn-like)
Not hyperchromatic and clustered (as in cellular phase primary myelofibrosis )
Not monolobated or multinucleated (as in MDS )
JAK2V617F (present in about 60%)
MPL W515K/L mutation less frequent
<5% blasts in the marrow
Morphologic features of erythroid dysplasia
Dyserythropoeisis
Dimorphic red blood cells (RBC)
Mixture of normal or macrocytic RBC and hypochromic microcytic RBC
High RDW
Basophilic stippling (Pappenheimer bodies)
Bone marrow erythroid lineage abnormalties
Ring sideroblasts
≥5 iron granules encircling ≥1/3 of the nucleus
Must involve ≥15% of erythroids to make the diagnosis of RARS
Usually either many or none
Erythroid hyperplasia
Megaloblastoid / megaloblastic changes
Dyssynchronous maturation of nucleus and cytoplasm of erythroid precursors
Nucleus lags behind cytoplasm
Cytoplasmic vacuoles
Also seen in copper deficiency
Nuclear changes
Multinuclearity
Nuclear budding, hyperlobulation and satellite nuclei
Internuclear bridging
Often increased iron in histiocytes
Due to lysis of defective erythrocytes
Differential Diagnosis
Exclude non-neoplastic causes of ring sideroblasts
Drug/toxin to include alcohol, isoniazid, lead, benzene
Zinc excess/copper deficiency
Congenital sideroblastic anemia
If chemotherapy or radiation therapy related, should be reported as "therapy-related myeloid neoplasm "
Clinical
Optimal management of this rare and poorly characterized patient subgroup is not yet established
Dita Gratzinger MD PhD
Original posting: 10/23/11
General Criteria for Myelodysplasia
Myelodysplasia is defined by morphologic features of abnormal cellular maturation in at least one bone marrow lineage
Not all features are applicable to all disorders
Dyserythropoeisis
Peripheral blood erythrocyte abnormalities
Normocytic, normochromic anemia
Macrocytosis
Dimorphic red blood cells (RBC)
Mixture of normal RBC and hypochromic microcytic RBC
Basophilic stippling
Poikilocytosis
Varying shapes, frequently macro-ovalocytes
Bone marrow erythroid lineage abnormalties
Erythroid hyperplasia or hypoplasia
Megaloblastoid / megaloblastic changes
Dyssynchronous maturation of nucleus and cytoplasm of erythroid precursors
Nucleus lags behind cytoplasm
Ring sideroblasts
≥5 iron granules encircling ≥1/3 of the nucleus
Usually either many or none
Cytoplasmic vacuoles
Also seen in copper deficiency
Nuclear changes
Multinuclearity
Nuclear budding, hyperlobulation and satellite nuclei
Internuclear bridging
Dysgranulopoiesis
Peripheral blood and/or bone marrow findings (easier seen in peripheral blood)
Hypogranularity
Pale cytoplasm almost indistinguishable from background on slide
Nuclear hypolobation or irregular hypersegmentation (>5 lobes)
Pseudo Pelger-Huet anomaly
Two equal size nuclear lobes connected by a thin strand of chromatin
Infrequent findings
Abnormal cytoplasmic granules (pseudo Chediak-Higashi granules)
Giant grey to red granules
Dohle bodies
Small blue cytoplasmic inclusions
Often found at periphery of cell
Auer rods
Rod-like structures formed by fusion of primary granules
May be found in blasts or maturing granulocytes
Dysmegakaryopoiesis
Peripheral blood platelet abnormalities
Giant
Larger than a red blood cell
Bizarre
Irregular shapes and protrusions
Hypogranularity
Compare to normal platelets with purple granules
Bone marrow megakaryocyte abnormalities
Micromegakaryocytes
Smaller than a promyelocyte
Nuclear hypolobation
Prominent in 5q- syndrome
A single lobe is typically seen in a small megakaryocyte
Multinucleation
Distinct nuclei without a connecting strand of chromatin
Cytoplasmic hypogranularity
Classification / Lists
WHO 2008 Classification of Myeloid Neoplasms
Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)
Bibliography
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2008
Hall J, Foucar K, Diagnosing myelodysplastic/myeloproliferative neoplasms: laboratory testing strategies to exclude other disorders, International Journal of Laboratory Hematology, 2010, 32
Orazi A, Germing U. (2008) The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia, 22, 1308–1319.
Malcovati L, Della Porta MG, Pietra D, Boveri E, Pellagatti A, Gallì A, Travaglino E, Brisci A, Rumi E, Passamonti F, Invernizzi R, Cremonesi L, Boultwood J, Wainscoat JS, Hellström-Lindberg E, Cazzola M. Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Blood. 2009 Oct 22;114(17):3538-45.
