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HAEM4Backup:Myelodysplastic Syndrome (MDS) with Multilineage Dysplasia (view source)
Revision as of 12:30, 3 November 2023
, 12:30, 3 November 2023Created page with "==Primary Author(s)*== Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cinci..."
==Primary Author(s)*==
Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
__TOC__
==Cancer Category/Type==
Myelodysplastic Syndrome
==Cancer Sub-Classification / Subtype==
Myelodysplastic Syndrome (MDS) with Multilineage Dysplasia (MLD)
==Definition / Description of Disease==
Myelodysplastic syndrome (MDS) with multilineage dysplasia (MDS-MLD), called Refractory Cytopenia with Multilineage Dysplasia (RCMD) in the 2008 edition of WHO book, is a frequent subtype of myelodysplastic syndrome (MDS) characterized by one or more cytopenias and dysplastic changes in two or more of the myeloid lineages (erythroid, granulocytic, and megakaryocytic), <5% of blasts in bone marrow and <1% blasts in peripheral blood, non-Auer rods<ref name=":0">Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4<sup>th</sup> edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.</ref><ref>{{Cite journal|last=Rosati|first=S.|last2=Mick|first2=R.|last3=Xu|first3=F.|last4=Stonys|first4=E.|last5=Le Beau|first5=M. M.|last6=Larson|first6=R.|last7=Vardiman|first7=J. W.|date=1996-01|title=Refractory cytopenia with multilineage dysplasia: further characterization of an 'unclassifiable' myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/8558932|journal=Leukemia|volume=10|issue=1|pages=20–26|issn=0887-6924|pmid=8558932}}</ref>. The presences of 1% blasts in the peripheral blood excludes a diagnosis of MDS-MLD. Cases with multilineage dysplasia and ≥15% ring sideroblasts or ≥5% ring sideroblasts and ''SF3B1'' mutation is classified as MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD). While cases with multilineage dysplasia or ≥5% but <15% ring sideroblasts with unknown ''SF3B1'' mutation status is classified as MDS-MLD<ref name=":0" />. MDS-MLD has a variable clinical course and prognosis, which is associated with karyotype and degree of cytopenia and dysplasia.
==Synonyms / Terminology==
Refractory cytopenia with multilineage dysplasia, RCMD, MDS-MLD
==Epidemiology / Prevalence==
Exact prevalence is unknown but MDS-MLD accounts for about 30% of patients with MDS<ref name=":0" />.
*Occurs mainly in older patients
*Median age is 65-70 years
*Male predominance
==Clinical Features==
Patients usually present with evidence of bone marrow failure. Most patients present with unicytopenia or bicytopenia<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>. The recommended thresholds for cytopenia suggested by International Prognostic Scoring System (IPSS)<ref>{{Cite journal|last=Greenberg|first=Peter L.|last2=Tuechler|first2=Heinz|last3=Schanz|first3=Julie|last4=Sanz|first4=Guillermo|last5=Garcia-Manero|first5=Guillermo|last6=Solé|first6=Francesc|last7=Bennett|first7=John M.|last8=Bowen|first8=David|last9=Fenaux|first9=Pierre|date=2012-09-20|title=Revised international prognostic scoring system for myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/22740453|journal=Blood|volume=120|issue=12|pages=2454–2465|doi=10.1182/blood-2012-03-420489|issn=1528-0020|pmc=4425443|pmid=22740453}}</ref>:
*Hemoglobin concentration: <10 g/dL
*Absolute neutrophil count: <1.8 x10<sup>9</sup>/L AND
*Platelet count: <100 x10<sup>9</sup>/L
However, some patients present with pancytopenia or milder cytopenia above this threshold levels in the IPSS<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>.
==Sites of Involvement==
Peripheral blood and bone marrow
==Morphologic Features==
{| class="wikitable"
|+
!'''Categories '''
!'''Morphologic Features'''
|-
|Neutrophil
|Nuclear clumping, lack of lobation (pseudo-Pelger-Huet anomaly), cytoplasmic hypogranularity
|-
|Erythroid precursors
|Increased number, cytoplasmic vacuole, nuclear irregularity (nuclear budding, multinucleation, internuclear chromatin bridging)
|-
|Megakaryocyte
|Non-lobated nuclei, binucleation or multinucleation, micromegakaryocytes (most reliable marker for dysplastic megakaryocyte)<ref>{{Cite journal|last=Matsuda|first=A.|last2=Germing|first2=U.|last3=Jinnai|first3=I.|last4=Iwanaga|first4=M.|last5=Misumi|first5=M.|last6=Kuendgen|first6=A.|last7=Strupp|first7=C.|last8=Miyazaki|first8=Y.|last9=Tsushima|first9=H.|date=2007-04|title=Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification|url=https://pubmed.ncbi.nlm.nih.gov/17268513|journal=Leukemia|volume=21|issue=4|pages=678–686|doi=10.1038/sj.leu.2404571|issn=0887-6924|pmid=17268513}}</ref>
|}
==Immunophenotype==
Same as the MDS immunophenotype and the CD34+ cells are typical <5. However, definitive morphological and/or cytogenetic findings can help establish the diagnosis. Reporting flow cytometry findings in MDS should be done in an integrated diagnostic report, together with morphological, cytogenetic and/or molecular findings<ref>{{Cite journal|last=Porwit|first=A.|last2=van de Loosdrecht|first2=A. A.|last3=Bettelheim|first3=P.|last4=Brodersen|first4=L. Eidenschink|last5=Burbury|first5=K.|last6=Cremers|first6=E.|last7=Della Porta|first7=M. G.|last8=Ireland|first8=R.|last9=Johansson|first9=U.|date=2014-09|title=Revisiting guidelines for integration of flow cytometry results in the WHO classification of myelodysplastic syndromes-proposal from the International/European LeukemiaNet Working Group for Flow Cytometry in MDS|url=https://pubmed.ncbi.nlm.nih.gov/24919805|journal=Leukemia|volume=28|issue=9|pages=1793–1798|doi=10.1038/leu.2014.191|issn=1476-5551|pmid=24919805}}</ref><ref>{{Cite journal|last=van de Loosdrecht|first=Arjan A.|last2=Westers|first2=Theresia M.|date=2013-07|title=Cutting edge: flow cytometry in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/23847222|journal=Journal of the National Comprehensive Cancer Network: JNCCN|volume=11|issue=7|pages=892–902|doi=10.6004/jnccn.2013.0106|issn=1540-1413|pmid=23847222}}</ref><ref>{{Cite journal|last=Xu|first=Lan|last2=Gu|first2=Zhao-Hui|last3=Li|first3=Yang|last4=Zhang|first4=Jin-Li|last5=Chang|first5=Chun-Kang|last6=Pan|first6=Chun-Ming|last7=Shi|first7=Jing-Yi|last8=Shen|first8=Yang|last9=Chen|first9=Bing|date=2014-06-10|title=Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers|url=https://pubmed.ncbi.nlm.nih.gov/24850867|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=23|pages=8589–8594|doi=10.1073/pnas.1407688111|issn=1091-6490|pmc=4060725|pmid=24850867}}</ref>.
==Chromosomal Rearrangements (Gene Fusions)==
No
==Characteristic Chromosomal Aberrations / Patterns==
Trisomy 8, monosomy 7, del(7q), del(5q) or t(5q) Del(20q) and complex karyotypes<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>.
==Genomic Gain/Loss/LOH==
*Nonspecific cytogenetic abnormalities have been observed in 50% of MDS-SLD cases.
*Trisomy 8, monosomy 7, del(7q), del(5q) or t(5q) Del(20q) and complex karyotypes<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>.
==Gene Mutations (SNV/INDEL)==
*More than 50% of MDS-MLD cases share the same gene mutations with MDS with excess blasts.
*Most frequent mutations: ''STAG2, ASXL1, SRSF2, RUNX1, CBL, TP53 and TET2''<ref>{{Cite journal|last=Haferlach|first=T.|last2=Nagata|first2=Y.|last3=Grossmann|first3=V.|last4=Okuno|first4=Y.|last5=Bacher|first5=U.|last6=Nagae|first6=G.|last7=Schnittger|first7=S.|last8=Sanada|first8=M.|last9=Kon|first9=A.|date=2014-02|title=Landscape of genetic lesions in 944 patients with myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/24220272|journal=Leukemia|volume=28|issue=2|pages=241–247|doi=10.1038/leu.2013.336|issn=1476-5551|pmc=3918868|pmid=24220272}}</ref><ref>{{Cite journal|last=Muscedere|first=John|last2=Sinuff|first2=Tasnim|last3=Heyland|first3=Daren K.|last4=Dodek|first4=Peter M.|last5=Keenan|first5=Sean P.|last6=Wood|first6=Gordon|last7=Jiang|first7=Xuran|last8=Day|first8=Andrew G.|last9=Laporta|first9=Denny|date=2013-11|title=The clinical impact and preventability of ventilator-associated conditions in critically ill patients who are mechanically ventilated|url=https://pubmed.ncbi.nlm.nih.gov/24030318|journal=Chest|volume=144|issue=5|pages=1453–1460|doi=10.1378/chest.13-0853|issn=1931-3543|pmid=24030318}}</ref><ref>{{Cite journal|last=Xu|first=Lan|last2=Gu|first2=Zhao-Hui|last3=Li|first3=Yang|last4=Zhang|first4=Jin-Li|last5=Chang|first5=Chun-Kang|last6=Pan|first6=Chun-Ming|last7=Shi|first7=Jing-Yi|last8=Shen|first8=Yang|last9=Chen|first9=Bing|date=2014-06-10|title=Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers|url=https://pubmed.ncbi.nlm.nih.gov/24850867|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=23|pages=8589–8594|doi=10.1073/pnas.1407688111|issn=1091-6490|pmc=4060725|pmid=24850867}}</ref>.
*''SF3B1'': 1) MDS-MLD: multilineage dysplasia or ≥5% but <15% ring sideroblasts with unknown ''SF3B1'' mutation status 2) MDS-RS-MLD: multilineage dysplasia and ≥15% ring sideroblasts or ≥5% ring sideroblasts and ''SF3B1'' mutation<ref>{{Cite journal|last=Malcovati|first=Luca|last2=Karimi|first2=Mohsen|last3=Papaemmanuil|first3=Elli|last4=Ambaglio|first4=Ilaria|last5=Jädersten|first5=Martin|last6=Jansson|first6=Monika|last7=Elena|first7=Chiara|last8=Gallì|first8=Anna|last9=Walldin|first9=Gunilla|date=2015-07-09|title=SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts|url=https://pubmed.ncbi.nlm.nih.gov/25957392|journal=Blood|volume=126|issue=2|pages=233–241|doi=10.1182/blood-2015-03-633537|issn=1528-0020|pmc=4528082|pmid=25957392}}</ref>.
===Other Mutations===
No
==Epigenomics (Methylation)==
''TET2'' mutations: altered DNA methylation, have been found to be an independent prognostic indicator with a high response rate to hypomethylating agents<ref>{{Cite journal|last=Ganguly|first=Bani Bandana|last2=Kadam|first2=N. N.|date=2016-07|title=Mutations of myelodysplastic syndromes (MDS): An update|url=https://pubmed.ncbi.nlm.nih.gov/27543316|journal=Mutation Research. Reviews in Mutation Research|volume=769|pages=47–62|doi=10.1016/j.mrrev.2016.04.009|issn=1388-2139|pmid=27543316}}</ref>.
==Genes and Main Pathways Involved==
*''STAG2'': involved in the separation of sister chromatids during cell division
*''ASXL1'': involved in chromatin remodeling
*''SRSF2'': involved in pre-mRNA splicing
*''RUNX1'': transcription factor for hematopoiesis cells
*''CBL'': involved in targeting substrates for degradation by the proteasome
*''TP53'': tumor suppressor and TP53 pathway regulates the pathways of cell cycle arrest, apoptosis, and DNA repair
*''TET2'': involved in regulating transcription
*''SF3B1'': involved in pre-mRNA splicing
==Diagnostic Testing Methods==
*Quantification of dysplasia: Microscopy
*Pathology: Immunophenotyping by flow cytometry
*Genetics: Conventional karyotyping, fluorescence in situ hybridization analysis (FISH), microarray and sequencing
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
*Diagnosis: One or more cytopenias and dysplastic changes in two or more of the myeloid lineages. The blast percentage is <1% in the peripheral blood and <5% in the bone marrow.
*Prognosis: International Prognostic Scoring System (IPSS) was adopted and accepted introduced by the Myelodysplastic Syndrome Working Group<ref>{{Cite journal|last=Greenberg|first=P.|last2=Cox|first2=C.|last3=LeBeau|first3=M. M.|last4=Fenaux|first4=P.|last5=Morel|first5=P.|last6=Sanz|first6=G.|last7=Sanz|first7=M.|last8=Vallespi|first8=T.|last9=Hamblin|first9=T.|date=1997-03-15|title=International scoring system for evaluating prognosis in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/9058730|journal=Blood|volume=89|issue=6|pages=2079–2088|issn=0006-4971|pmid=9058730}}</ref>. The clinical course of the patients with a diagnosis of MDS-MLD varies from case to case, which is related to the karyotype and degree of cytopenia and dysplasia<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>. Median survival of patients with MDS-MLD is approximately 36 months with the rate of progression to acute myeloid leukemia 28% at 5 years<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref><ref name=":0" />.
*Therapeutic: Supportive care is important for MDS-MLD patients regardless of whether other treatments are planned. However, patients with MDS-MLD are often evaluated for immunosuppressive treatment. The antithymocyte globulin (ATG) treatment is recommended for MDS-MLD patient with symptomatic anemia and/or thrombocytopenia and/or neutropenia with increased susceptibility to infections<ref>{{Cite journal|last=Bennett|first=John M.|date=2016-11|title=Changes in the Updated 2016: WHO Classification of the Myelodysplastic Syndromes and Related Myeloid Neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/27693133|journal=Clinical Lymphoma, Myeloma & Leukemia|volume=16|issue=11|pages=607–609|doi=10.1016/j.clml.2016.08.005|issn=2152-2669|pmid=27693133}}</ref>.
==Familial Forms==
None
==Other Information==
None
==Links==
Put your links here (use link icon at top of page)
==References==
<references />
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.
Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
__TOC__
==Cancer Category/Type==
Myelodysplastic Syndrome
==Cancer Sub-Classification / Subtype==
Myelodysplastic Syndrome (MDS) with Multilineage Dysplasia (MLD)
==Definition / Description of Disease==
Myelodysplastic syndrome (MDS) with multilineage dysplasia (MDS-MLD), called Refractory Cytopenia with Multilineage Dysplasia (RCMD) in the 2008 edition of WHO book, is a frequent subtype of myelodysplastic syndrome (MDS) characterized by one or more cytopenias and dysplastic changes in two or more of the myeloid lineages (erythroid, granulocytic, and megakaryocytic), <5% of blasts in bone marrow and <1% blasts in peripheral blood, non-Auer rods<ref name=":0">Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4<sup>th</sup> edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.</ref><ref>{{Cite journal|last=Rosati|first=S.|last2=Mick|first2=R.|last3=Xu|first3=F.|last4=Stonys|first4=E.|last5=Le Beau|first5=M. M.|last6=Larson|first6=R.|last7=Vardiman|first7=J. W.|date=1996-01|title=Refractory cytopenia with multilineage dysplasia: further characterization of an 'unclassifiable' myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/8558932|journal=Leukemia|volume=10|issue=1|pages=20–26|issn=0887-6924|pmid=8558932}}</ref>. The presences of 1% blasts in the peripheral blood excludes a diagnosis of MDS-MLD. Cases with multilineage dysplasia and ≥15% ring sideroblasts or ≥5% ring sideroblasts and ''SF3B1'' mutation is classified as MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD). While cases with multilineage dysplasia or ≥5% but <15% ring sideroblasts with unknown ''SF3B1'' mutation status is classified as MDS-MLD<ref name=":0" />. MDS-MLD has a variable clinical course and prognosis, which is associated with karyotype and degree of cytopenia and dysplasia.
==Synonyms / Terminology==
Refractory cytopenia with multilineage dysplasia, RCMD, MDS-MLD
==Epidemiology / Prevalence==
Exact prevalence is unknown but MDS-MLD accounts for about 30% of patients with MDS<ref name=":0" />.
*Occurs mainly in older patients
*Median age is 65-70 years
*Male predominance
==Clinical Features==
Patients usually present with evidence of bone marrow failure. Most patients present with unicytopenia or bicytopenia<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>. The recommended thresholds for cytopenia suggested by International Prognostic Scoring System (IPSS)<ref>{{Cite journal|last=Greenberg|first=Peter L.|last2=Tuechler|first2=Heinz|last3=Schanz|first3=Julie|last4=Sanz|first4=Guillermo|last5=Garcia-Manero|first5=Guillermo|last6=Solé|first6=Francesc|last7=Bennett|first7=John M.|last8=Bowen|first8=David|last9=Fenaux|first9=Pierre|date=2012-09-20|title=Revised international prognostic scoring system for myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/22740453|journal=Blood|volume=120|issue=12|pages=2454–2465|doi=10.1182/blood-2012-03-420489|issn=1528-0020|pmc=4425443|pmid=22740453}}</ref>:
*Hemoglobin concentration: <10 g/dL
*Absolute neutrophil count: <1.8 x10<sup>9</sup>/L AND
*Platelet count: <100 x10<sup>9</sup>/L
However, some patients present with pancytopenia or milder cytopenia above this threshold levels in the IPSS<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>.
==Sites of Involvement==
Peripheral blood and bone marrow
==Morphologic Features==
{| class="wikitable"
|+
!'''Categories '''
!'''Morphologic Features'''
|-
|Neutrophil
|Nuclear clumping, lack of lobation (pseudo-Pelger-Huet anomaly), cytoplasmic hypogranularity
|-
|Erythroid precursors
|Increased number, cytoplasmic vacuole, nuclear irregularity (nuclear budding, multinucleation, internuclear chromatin bridging)
|-
|Megakaryocyte
|Non-lobated nuclei, binucleation or multinucleation, micromegakaryocytes (most reliable marker for dysplastic megakaryocyte)<ref>{{Cite journal|last=Matsuda|first=A.|last2=Germing|first2=U.|last3=Jinnai|first3=I.|last4=Iwanaga|first4=M.|last5=Misumi|first5=M.|last6=Kuendgen|first6=A.|last7=Strupp|first7=C.|last8=Miyazaki|first8=Y.|last9=Tsushima|first9=H.|date=2007-04|title=Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification|url=https://pubmed.ncbi.nlm.nih.gov/17268513|journal=Leukemia|volume=21|issue=4|pages=678–686|doi=10.1038/sj.leu.2404571|issn=0887-6924|pmid=17268513}}</ref>
|}
==Immunophenotype==
Same as the MDS immunophenotype and the CD34+ cells are typical <5. However, definitive morphological and/or cytogenetic findings can help establish the diagnosis. Reporting flow cytometry findings in MDS should be done in an integrated diagnostic report, together with morphological, cytogenetic and/or molecular findings<ref>{{Cite journal|last=Porwit|first=A.|last2=van de Loosdrecht|first2=A. A.|last3=Bettelheim|first3=P.|last4=Brodersen|first4=L. Eidenschink|last5=Burbury|first5=K.|last6=Cremers|first6=E.|last7=Della Porta|first7=M. G.|last8=Ireland|first8=R.|last9=Johansson|first9=U.|date=2014-09|title=Revisiting guidelines for integration of flow cytometry results in the WHO classification of myelodysplastic syndromes-proposal from the International/European LeukemiaNet Working Group for Flow Cytometry in MDS|url=https://pubmed.ncbi.nlm.nih.gov/24919805|journal=Leukemia|volume=28|issue=9|pages=1793–1798|doi=10.1038/leu.2014.191|issn=1476-5551|pmid=24919805}}</ref><ref>{{Cite journal|last=van de Loosdrecht|first=Arjan A.|last2=Westers|first2=Theresia M.|date=2013-07|title=Cutting edge: flow cytometry in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/23847222|journal=Journal of the National Comprehensive Cancer Network: JNCCN|volume=11|issue=7|pages=892–902|doi=10.6004/jnccn.2013.0106|issn=1540-1413|pmid=23847222}}</ref><ref>{{Cite journal|last=Xu|first=Lan|last2=Gu|first2=Zhao-Hui|last3=Li|first3=Yang|last4=Zhang|first4=Jin-Li|last5=Chang|first5=Chun-Kang|last6=Pan|first6=Chun-Ming|last7=Shi|first7=Jing-Yi|last8=Shen|first8=Yang|last9=Chen|first9=Bing|date=2014-06-10|title=Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers|url=https://pubmed.ncbi.nlm.nih.gov/24850867|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=23|pages=8589–8594|doi=10.1073/pnas.1407688111|issn=1091-6490|pmc=4060725|pmid=24850867}}</ref>.
==Chromosomal Rearrangements (Gene Fusions)==
No
==Characteristic Chromosomal Aberrations / Patterns==
Trisomy 8, monosomy 7, del(7q), del(5q) or t(5q) Del(20q) and complex karyotypes<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>.
==Genomic Gain/Loss/LOH==
*Nonspecific cytogenetic abnormalities have been observed in 50% of MDS-SLD cases.
*Trisomy 8, monosomy 7, del(7q), del(5q) or t(5q) Del(20q) and complex karyotypes<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>.
==Gene Mutations (SNV/INDEL)==
*More than 50% of MDS-MLD cases share the same gene mutations with MDS with excess blasts.
*Most frequent mutations: ''STAG2, ASXL1, SRSF2, RUNX1, CBL, TP53 and TET2''<ref>{{Cite journal|last=Haferlach|first=T.|last2=Nagata|first2=Y.|last3=Grossmann|first3=V.|last4=Okuno|first4=Y.|last5=Bacher|first5=U.|last6=Nagae|first6=G.|last7=Schnittger|first7=S.|last8=Sanada|first8=M.|last9=Kon|first9=A.|date=2014-02|title=Landscape of genetic lesions in 944 patients with myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/24220272|journal=Leukemia|volume=28|issue=2|pages=241–247|doi=10.1038/leu.2013.336|issn=1476-5551|pmc=3918868|pmid=24220272}}</ref><ref>{{Cite journal|last=Muscedere|first=John|last2=Sinuff|first2=Tasnim|last3=Heyland|first3=Daren K.|last4=Dodek|first4=Peter M.|last5=Keenan|first5=Sean P.|last6=Wood|first6=Gordon|last7=Jiang|first7=Xuran|last8=Day|first8=Andrew G.|last9=Laporta|first9=Denny|date=2013-11|title=The clinical impact and preventability of ventilator-associated conditions in critically ill patients who are mechanically ventilated|url=https://pubmed.ncbi.nlm.nih.gov/24030318|journal=Chest|volume=144|issue=5|pages=1453–1460|doi=10.1378/chest.13-0853|issn=1931-3543|pmid=24030318}}</ref><ref>{{Cite journal|last=Xu|first=Lan|last2=Gu|first2=Zhao-Hui|last3=Li|first3=Yang|last4=Zhang|first4=Jin-Li|last5=Chang|first5=Chun-Kang|last6=Pan|first6=Chun-Ming|last7=Shi|first7=Jing-Yi|last8=Shen|first8=Yang|last9=Chen|first9=Bing|date=2014-06-10|title=Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers|url=https://pubmed.ncbi.nlm.nih.gov/24850867|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=23|pages=8589–8594|doi=10.1073/pnas.1407688111|issn=1091-6490|pmc=4060725|pmid=24850867}}</ref>.
*''SF3B1'': 1) MDS-MLD: multilineage dysplasia or ≥5% but <15% ring sideroblasts with unknown ''SF3B1'' mutation status 2) MDS-RS-MLD: multilineage dysplasia and ≥15% ring sideroblasts or ≥5% ring sideroblasts and ''SF3B1'' mutation<ref>{{Cite journal|last=Malcovati|first=Luca|last2=Karimi|first2=Mohsen|last3=Papaemmanuil|first3=Elli|last4=Ambaglio|first4=Ilaria|last5=Jädersten|first5=Martin|last6=Jansson|first6=Monika|last7=Elena|first7=Chiara|last8=Gallì|first8=Anna|last9=Walldin|first9=Gunilla|date=2015-07-09|title=SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts|url=https://pubmed.ncbi.nlm.nih.gov/25957392|journal=Blood|volume=126|issue=2|pages=233–241|doi=10.1182/blood-2015-03-633537|issn=1528-0020|pmc=4528082|pmid=25957392}}</ref>.
===Other Mutations===
No
==Epigenomics (Methylation)==
''TET2'' mutations: altered DNA methylation, have been found to be an independent prognostic indicator with a high response rate to hypomethylating agents<ref>{{Cite journal|last=Ganguly|first=Bani Bandana|last2=Kadam|first2=N. N.|date=2016-07|title=Mutations of myelodysplastic syndromes (MDS): An update|url=https://pubmed.ncbi.nlm.nih.gov/27543316|journal=Mutation Research. Reviews in Mutation Research|volume=769|pages=47–62|doi=10.1016/j.mrrev.2016.04.009|issn=1388-2139|pmid=27543316}}</ref>.
==Genes and Main Pathways Involved==
*''STAG2'': involved in the separation of sister chromatids during cell division
*''ASXL1'': involved in chromatin remodeling
*''SRSF2'': involved in pre-mRNA splicing
*''RUNX1'': transcription factor for hematopoiesis cells
*''CBL'': involved in targeting substrates for degradation by the proteasome
*''TP53'': tumor suppressor and TP53 pathway regulates the pathways of cell cycle arrest, apoptosis, and DNA repair
*''TET2'': involved in regulating transcription
*''SF3B1'': involved in pre-mRNA splicing
==Diagnostic Testing Methods==
*Quantification of dysplasia: Microscopy
*Pathology: Immunophenotyping by flow cytometry
*Genetics: Conventional karyotyping, fluorescence in situ hybridization analysis (FISH), microarray and sequencing
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
*Diagnosis: One or more cytopenias and dysplastic changes in two or more of the myeloid lineages. The blast percentage is <1% in the peripheral blood and <5% in the bone marrow.
*Prognosis: International Prognostic Scoring System (IPSS) was adopted and accepted introduced by the Myelodysplastic Syndrome Working Group<ref>{{Cite journal|last=Greenberg|first=P.|last2=Cox|first2=C.|last3=LeBeau|first3=M. M.|last4=Fenaux|first4=P.|last5=Morel|first5=P.|last6=Sanz|first6=G.|last7=Sanz|first7=M.|last8=Vallespi|first8=T.|last9=Hamblin|first9=T.|date=1997-03-15|title=International scoring system for evaluating prognosis in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/9058730|journal=Blood|volume=89|issue=6|pages=2079–2088|issn=0006-4971|pmid=9058730}}</ref>. The clinical course of the patients with a diagnosis of MDS-MLD varies from case to case, which is related to the karyotype and degree of cytopenia and dysplasia<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref>. Median survival of patients with MDS-MLD is approximately 36 months with the rate of progression to acute myeloid leukemia 28% at 5 years<ref>{{Cite journal|last=Maassen|first=Anna|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Kuendgen|first4=Andrea|last5=Nachtkamp|first5=Kathrin|last6=Hildebrandt|first6=Barbara|last7=Gattermann|first7=Norbert|last8=Aul|first8=Carlo|last9=Haas|first9=Rainer|date=2013-01|title=Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts|url=https://pubmed.ncbi.nlm.nih.gov/23122806|journal=Leukemia Research|volume=37|issue=1|pages=64–70|doi=10.1016/j.leukres.2012.09.021|issn=1873-5835|pmid=23122806}}</ref><ref name=":0" />.
*Therapeutic: Supportive care is important for MDS-MLD patients regardless of whether other treatments are planned. However, patients with MDS-MLD are often evaluated for immunosuppressive treatment. The antithymocyte globulin (ATG) treatment is recommended for MDS-MLD patient with symptomatic anemia and/or thrombocytopenia and/or neutropenia with increased susceptibility to infections<ref>{{Cite journal|last=Bennett|first=John M.|date=2016-11|title=Changes in the Updated 2016: WHO Classification of the Myelodysplastic Syndromes and Related Myeloid Neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/27693133|journal=Clinical Lymphoma, Myeloma & Leukemia|volume=16|issue=11|pages=607–609|doi=10.1016/j.clml.2016.08.005|issn=2152-2669|pmid=27693133}}</ref>.
==Familial Forms==
None
==Other Information==
None
==Links==
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==References==
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==Notes==
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