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Refractory Anemia with Ring Sideroblasts Associated with Marked Thrombocytosis (RARS-T)

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
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

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)
      • 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

Myeloproliferative Neoplasms (MPN)

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

Myelodysplastic Syndromes (MDS)

Therapy Related Myeloid Neoplasms

 

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.
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