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Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)

Written2016-10Matthew Koo, Robert S. Ohgami
Department of Pathology, Stanford University, Stanford, CA, USA; ROhgami@stanfordhealthcare.org

Abstract Review on Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis

Keywords Myelodysplastic syndrome; myeloproliferative syndrome; ring sideroblasts; thrombocytosis

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Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9982/3 Refractory anemia with ring sideroblasts associated with marked thrombocytosis; Refractory anaemia with ring sideroblasts
Atlas_Id 1396

Clinics and Pathology

Disease Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), formerly a provisional diagnosis of refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) under the MDS/MPN unclassifiable group, has been recognized as a full entity in the 2016 WHO classification (Arber et al., 2016). It is characterized by thrombocytosis of ≥450 x 109/L, refractory anemia, dyserythropoiesis with excess ring sideroblasts (≥15% of erythroid precursors, irrespective of SF3B1 mutational status), and megakaryocytes morphologically resembling that which may be seen in primary myelofibrosis (PMF) or essential thrombocythemia (ET).
Phenotype / cell stem origin The etiopathogenesis of MDS/MPN-RS-T is heterogeneous (Gurevich et al., 2011). Ring sideroblasts be a manifestation of abnormal erythropoiesis with mitochondrial iron overload (Patnaik et al., 2015).
Epidemiology MDS/MPN-RS-T is a rare disorder accounting for <1% of all cases of MDS (Orazi et al. 2008). In one study of 18 patients, M:F ratio was 1.25:1 and age range was 40-83 years with a median of 66 years (Gurevich et al., 2011).
Clinics The Gurevich et al. study also found presenting signs and symptoms of fatigue (5/18), "heavy"/abnormal menstrual bleeding (2/18), nosebleed (2/18), upper respiratory tract infection/flu-like symptoms (2/18), weight loss (1/18), and chest pain (1/18). 5/18 patients reported no significant symptoms and presented with incidental anemia and/or thrombocytopenia. Splenomegaly was palpable in 2/18 patients; the remainder of the patients (16/18) had an unremarkable physical examination. Platelet count ranged from 515-1100 x 109/L with a median of 645 x 109/L. Hemoglobin ranged from 7.2-12.6 g/dL with a median of 10.2 g/dL. Leukocyte count was normal in 14/18 patients and slightly below reference range in 1/18 patients. The remaining 3/18 patients showed a mildly elevated leukocyte count that ranged from 12.9-16.3 x 109/L (Gurevich et al., 2011).
Pathology Peripheral blood findings include thrombocytosis with megathrombocytes, macrocytic or normocytic normochromic anemia with anisopoikilocytosis, and myeloid left shift with mild dysplastic features. Bone marrow aspirate smear findings include increased megakaryocytes, myeloid left shift with mild dysplastic features (including hypogranulation and abnormal nuclear lobation) and <5% blasts, relative erythroid preponderance with dysplastic features (including nuclear-cytoplasmic dyssynchrony, megaloblastic changes, binucleated erythroids, karyorrhexis, and nuclear budding) and increased ring sideroblasts (≥15%). Bone marrow core biopsy and clot section findings include a hypercellular marrow with megakaryocyte hyperplasia and increased clustering with dysplastic cytomorphology (including abnormally large, hyperchromatic, hypolobated, and micromegakaryocytic forms) (Gurevich et al., 2011).
 
Figure: Image showing a peripheral blood smear in the left panel with thrombocytosis. A bone marrow biopsy is shown on the right with an atypical megakaryocyte and numerous ring sideroblasts (right inset).
Treatment Management is typically individualized to address the anemia (erythropoiesis stimulating agents and/or transfusion) and the thrombotic risk (aspirin). The value of cytoreductive therapy (hydroxyurea, lenalidomide, IFN-?, busulfan, anagrelide) is uncertain and may exacerbate the baseline anemia.
Prognosis Using either the IPSS for MDS or the revised IPSS, most patients with MDS/MPN-RS-T fall into a low risk group. Overall prognosis is intermediate between that of ET and myelodysplastic syndrome with ring sideroblasts (MDS-RS) (Patnaik et al. 2015). Compared to patients with ET, patients with MDS/MPN-RS-T have been found to have a shorter overall and leukemia-free survival but a lower risk of thrombosis. Compared to patients with MDS-RS, patients with MDS/MPN-RS-T have been found to have better survival but a higher risk of thrombosis (Broseus et al., 2012).

Genetics

Somatic mutations in several genes are seen in MDS/MPN-RS-T. Notably mutations in JAK2 are frequent, seen in 30-70% of cases. Most cases harbor a specific JAK2 point mutation: JAK2V617F. Mutations in SF3B1 are also common (70-95% of cases) and associated with the morphologic finding of ring sideroblasts. MPL and CALR mutations are rare (<5% of cases).

Cytogenetics

Cytogenetics Morphological No clonal cytogenetic abnormality is detected in about 80% of patients (Patnaik et al., 2015). Recurrent cytogenetic abnormalities have not been described to date.

Genes involved and Proteins

Gene Name MPL
Location 1p34.2
Protein MPL encodes for CD110, also known as thrombopoietin receptor, which plays a critical role in thrombopoiesis. Thrombopoietin ( THPO)-CD110 binding leads to receptor dimerization and downstream signaling. Mutations leading to constitutive activation of CD110 have been linked to overproduction of abnormal megakaryocytes (Tefferi et al., 2014).
Gene Name SF3B1
Location 2q33.1
Protein SF3B1 encodes for subunit one of the splicing factor 3b protein complex. Splicing factor 3b, splicing factor 3a, and a 12S RNA unit combine to form the U2 small nuclear riboproteins complex (U2 snRNP). The splicing factor 3a/3b complex may function as an anchor region for U2 snRNP to bind pre-mRNA.
Gene Name JAK2
Location 9p24.1
Protein JAK2 encodes for the predominant kinase of erythropoietin receptor signaling. JAK2V617F mutations lead to constitutive activation of and downstream signalling by this kinase, which allows hematopoietic cells to grow in a cytokine-independent manner.
Gene Name CALR
Location 19p13.13
Protein CALR encodes for calreticulin, which has many functions including calcium homeostasis, protein folding, cell proliferation, and apoptosis. CALR mutations may be found in patients with JAK2-negative/MPL-negative ET and PMF.

Bibliography

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia
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Blood 2016 May 19;127(20):2391-405
PMID 27069254
 
Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis
Broseus J, Florensa L, Zipperer E, Schnittger S, Malcovati L, Richebourg S, Lippert E, Cermak J, Evans J, Mounier M, Raya JM, Bailly F, Gattermann N, Haferlach T, Garand R, Allou K, Besses C, Germing U, Haferlach C, Travaglino E, Luno E, Pinan MA, Arenillas L, Rozman M, Perez Sirvent ML, Favre B, Guy J, Alonso E, Ahwij N, Jerez A, Hermouet S, Maynadié M, Cazzola M, Girodon F
Haematologica 2012 Jul;97(7):1036-41
PMID 22532522
 
Refractory anemia with ring sideroblasts associated with marked thrombocytosis: a mixed group exhibiting a spectrum of morphologic findings
Gurevich I, Luthra R, Konoplev SN, Yin CC, Medeiros LJ, Lin P
Am J Clin Pathol 2011 Mar;135(3):398-403
PMID 21350094
 
Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2
Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR
N Engl J Med 2013 Dec 19;369(25):2391-405
PMID 24325359
 
The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features
Orazi A, Germing U
Leukemia 2008 Jul;22(7):1308-19
PMID 18480833
 
Refractory anemia with ring sideroblasts and RARS with thrombocytosis
Patnaik MM, Tefferi A
Am J Hematol 2015 Jun;90(6):549-59
PMID 25899435
 
CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons
Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, Maffioli M, Caramazza D, Passamonti F, Pardanani A
Leukemia 2014 Jul;28(7):1472-7
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Citation

This paper should be referenced as such :
Koo M, Ohgami RS
Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/MDS-MPN-RS-TID1396.html


External links

arrayMapMorph ( 9982/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databaseMyelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
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