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Bone marrow neoplastic

Bone marrow - neoplastic myeloid

Myelodysplastic syndromes (MDS)

WHO classification - MDS


Nikhil Sangle, M.D.

Last author update: 25 November 2017
Last staff update: 1 March 2023

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PubMed Search: Myelodysplastic syndrome WHO classification

Nikhil Sangle, M.D.
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Table of Contents
WHO 2016 classification | Clinical features | Diagnosis | Prognostic factors | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Flow cytometry description | Electron microscopy description | Molecular / cytogenetics description | Differential diagnosis | Additional references
Cite this page: Sangle N. WHO classification - MDS. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticMDSWHO.html. Accessed March 30th, 2023.
WHO 2016 classification
  • World Health Organization (WHO) classification of myelodysplastic syndrome (MDS) in 2016
  • MDS with ring sideroblasts (MDS-RS): associated with mutations in the spliceosome gene SF3B1, overall favorable prognosis, must not meet criteria for isolated del(5q), blasts < 5% BM, < 1% PB, no Auer rods
    • MDS-RS and single lineage dysplasia (former RARS): 1 dysplastic lineage, 1 - 2 cytopenias
    • MDS-RS and multilineage dysplasia: 2 - 3 dysplastic lineages, 1 - 3 cytopenias
  • MDS with single lineage dysplasia:
    • 1 dysplastic lineage, 1 - 2 cytopenias
    • Blasts < 5% BM, < 1% PB, no Auer rods
    • Does not meet criteria for MDS-RS or MDS with isolated del(5q)
  • MDS with multilineage dysplasia:
    • 2 - 3 dysplastic lineages, 1 - 3 cytopenias
    • Blasts < 5% BM, < 1% PB, no Auer rods
    • Does not meet criteria for MDS-RS or MDS with isolated del(5q)
  • MDS with isolated del(5q): the only cytogenetic abnormality that defines a subtype
    • Okay if 1 additional cytogenetic abnormality as long as NOT monosomy 7 or del(7q)
    • None or any ring sideroblasts, 1 - 3 dysplastic lineages, 1 - 2 cytopenias
    • Blasts < 5% BM, < 1% PB, no Auer rods
    • Generally good prognosis unless TP53 mutated
  • MDS with excess blasts: 1 - 3 dysplastic lineages, 1 - 3 cytopenias, none or any ring sideroblasts
    • MDS-EB-1: blasts 5 - 9% BM or 2 - 4% PB, no Auer rods
    • MDS-EB-2: blasts 10 - 19% BM or 5 - 19% PB or Auer rods
  • MDS, unclassifiable: 3 different ways to arrive at this diagnosis
    • MDS-U with 1% blood blasts: 1 - 3 dysplastic lineages, 1 - 3 cytopenias, none or any ring sideroblasts, < 5% BM blasts
    • MDS-U with SLD and pancytopenia: 1 dysplastic lineage, pancytopenia, none or any ring sideroblasts, blasts < 5% BM, < 1% PB, no Auer rods
    • MDS-U based on defining cytogenetic abnormality: 0 dysplastic lineages, 1 - 3 cytopenias, < 15% ring sideroblasts, blasts < 5% BM, < 1% PB, no Auer rods; MDS defining cytogenetic abnormality (see below)
  • Refractory cytopenia of childhood: provisional entity
  • Myeloid neoplasms with germline predisposition: specific underlying genetic defect or syndrome should be listed as part of the diagnosis
  • References: Blood 2016;127:2391, Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017

Major changes as compared to WHO 2008 classification for MDS (Blood 2016;127:2391):
  • More emphasis on the degree of dysplasia and blast percentage for classification than specific types of cytopenias (e.g. removed "refractory anemia" and "refractory cytopenia" from terminology, start with "myelodysplastic syndrome" followed by appropriate modifier)
  • Myeloid neoplasms with an erythroid predominance (erythroid precursors ≥ 50% of all BM cells):
    • Calculate blast percentage using all nucleated BM cells in the denominator - prior included only nonerythroid
    • Many cases of erythroid / myeloid subtype of acute erythroid leukemia will now be classified as MDS with excess blasts
  • MDS with ring sideroblasts: if an SF3B1 mutation is identified, only need 5% ring sideroblasts for diagnosis; if not identified, still need 15%
  • RARS (refractory anemia with ring sideroblasts) is now MDS-RS with single lineage dysplasia
  • New section recognizing germline predisposition to MDS, MDS / MPN and AML

Clarifications for the 2016 WHO MDS diagnoses:
  • What counts as cytopenia? hemoglobin, < 10 g/dL; platelets, < 100 × 109/L; absolute neutrophil count, < 1.8 × 109/L
  • Diagnosis of MDS may be made with milder levels of cytopenia (rarely); at least 1 cytopenia must be present
  • Threshold for dysplasia remains at 10% dysplastic cells but may still be at that level in nonneoplastic causes of cytopenias; caution advised
  • Same cytogenetic abnormalities remain MDS - defining as in the 2008 WHO in a patient with cytopenia (i.e. even without dysplasia) but must be shown by conventional karyotype (not just by FISH) - see below
    • Loss of chromosome 7 or del(7q)
    • del(5q)
    • Isochromosome 17q or t(17p)
    • Loss of chromosome 13 or del(13q)
    • del(11q)
    • del(12p) or t(12p)
    • del(9q)
    • idic(X)(q13)
    • t(11;16)(q23.3;p13.3)
    • t(3;21)(q26.2;q22.1)
    • t(1;3)(p36.3;q21.2)
    • t(2;11)(p21;q23.3)
    • inv(3)(q21.3;q26.2)/ t(3;3)(21.3;q26.2)
    • t(6;9)(p23;q34.1)
  • Cytogenetic abnormalities not sufficient (also remain from 2008 criteria):
    • Gain of chromosome 8
    • del(20q)
    • Loss of Y
WHO 2008 classification
  • Refractory anemia (RA): < 5% blasts, > 15% ringed sideroblasts; variable marrow cellularity, unicytopenia or bicytopenia, unilineage dysplasia > 10% in one myeloid lineage
  • RA with Ringed Sideroblasts (RARS): 15% or more sideroblasts, less than 5% blasts, erythroid dysplasia only
  • Refractory cytopenia with multilineage dysplasia (RCMD): cytopenia, < 5% blasts, dysplasia in > 10% of cells in two or more lineages, no Auer rods
  • RA with Excess Blasts (RAEB): type 1 has 5 - 9% blasts in blood / marrow, peripheral cytopenia, unilineage or multilineage dysplasia, no Auer rods; type 2 has 10 - 19% blasts in blood / marrow, unilineage or multilineage dysplasia, Auer rods may be present, peripheral cytopenia
  • MDS with isolated 5q- syndrome: anemia, < 5% blasts, del(5q), no Auer rods, normal / increased hypolobated megakarycoytes
  • MDS, unclassified: cytopenia(s), dysplasia in < 10% of cells in one or more myeloid cell lines, accompanied by cytogenetic abnormalities with presumptive evidence of MDS, < 5% blasts
  • Therapy related MDS
Clinical features
  • Clonal disorders of multipotent bone marrow stem cells with cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective or disorderly hematopoiesis and increased risk of development of AML
  • Note: myelodysplasia also means abnormal development of spinal cord
  • "Ineffective hematopoiesis" means cytopenia (anemia most common) despite a cellular / hypercellular marrow with normal or increased precursors for one or more cell lines; cytopenias may be due to aberrant expression of various cytokines and accelerated apoptosis
  • 15K new cases in US each year (Cancer 2008;112:1089)
  • 25 - 45% of patients develop acute myeloid leukemia (AML)
  • Must rule out MDS in any adult with unexplained cytopenias or monocytosis
  • Threshold for cytopenia(s): hemoglobin < 10g/dL, absolute neutrophil count < 1.8 × 109/L, platelets < 100 × 109/L
  • Dysplasia should be evident in > 10% of cells in one or more myeloid cell lines
  • Mean age 65 years; may affect any age but less than 50 years is uncommon
  • Symptoms are related to cytopenias or defective platelet aggregation but 50% are initially asymptomatic (Acta Haematol 2007;118:117)
  • Primary MDS: etiology unknown (age 50+ years)
  • Secondary / therapy related MDS (t-MDS): due to radiation or alkylating agents (2 - 8 years after exposure)
  • Laboratory: usually macrocytic anemia with increased red cell distribution width (RDW) and low / normal reticulocyte count; variable neutropenia or thrombocytopenia
  • Mean survival: refractory anemia - 10 years, refractory anemia with ringed sideroblasts - 7 years; RA with multilineage dysplasia - 3 years (Leuk Res 2006;30:971), refractory anemia with excess blasts or chronic myelomonocytic leukemia - 1 year, therapy related MDS - 5 months; death often due to AML or bleeding / infection
Diagnosis
  • Cellular marrow but peripheral blood cytopenias with dysplastic changes in hematopoietic cells
  • Bone marrow biopsy / aspirate is necessary to confirm diagnosis and obtain material for additional studies; must correlate findings with complete clinical information; by definition, myeloblasts are < 20% (if 20% or more, classify as AML)
Prognostic factors
Poor:
  • Multiple clonal chromosomal abnormalities, severe cytopenias (< 0.5 neutrophils or < 50K platelets), high % blasts in marrow or any blasts in blood, lack of ringed sideroblasts, abnormal localization of immature granulocyte precursors in bone marrow biopsy
  • Patients with Auer rods and < 5% blasts usually progress rapidly to AML or death (Am J Clin Pathol 2005;124:191)
  • Patients with RA, RARS or RCMD with peripheral blasts (even < 1%) have similar prognosis as refractory anemia with excess blasts type 1 (Leuk Res 2008;32:33)
  • Complex ( > 3 abnormalities) or chromosome 7 anomalies

Good:
  • Younger age, normal / moderate neutropenia and thrombocytopenia, low blast percentage in marrow with no blasts in blood, no Auer rods in blasts, ringed sideroblasts present, normal karyotype or -Y, 5q- or 20q- alone
Treatment
Microscopic (histologic) description
Peripheral blood smear (general MDS findings):
  • Erythroid: dimorphic population of oval macrocytes and hypochromic microcytic RBCs, basophilic stippling, erythrocyte vacuoles, nucleated red blood cells, Howell-Jolly bodies
  • Granulocytes: neutropenia with immature, hypogranular forms, pseudo-Pelger-Huet neutrophils (2 lobes), monocytosis, myeloblasts
  • Platelets: thrombocytopenia, giant platelets
  • Note: In severely cytopenic patients, buffy coat smears of peripheral blood can be used to perform differential

Bone marrow: (general MDS findings):
  • Usually hypercellular or normocellular, 10% are hypocellular; iron stores often increased
  • Disordered (dysplastic) differentiation affecting all 3 lineages
  • Myelofibrosis in therapy related MDS
  • Erythroid: erythroid hyperplasia, ringed sideroblasts (iron laden mitochondria visible as perinuclear granules with Prussian iron stain), megaloblastoid nuclear maturation, nuclear budding abnormalities (polypoid outlines, internuclear bridging, nuclear fragments, multinuclearity, nuclear hyperlobation), cytoplasmic vacuolization, PAS positive erythroblasts
  • Leukocytes: myeloblasts may be increased but < 20% of nonerythroid cells (or is defined as AML); abnormally localized immature precursors (ALIP), neutrophils with decreased secondary granules or 2 lobes (pseudo Pelger-Huet cells), toxic granulations, Dohle bodies, Auer rods, irregular nuclear segmentation, increased basophils or monocytes; rarely monocytic nodules (Am J Clin Pathol 2003;120:874); myeloid cells are myeloperoxidase negative; note that in ALIP, aggregates (3 - 5) or clusters (6+) of immature precursors are remote from trabeculae (normal maturing granulocytes extend from trabeculae or blood vessels towards central areas)
  • Megakaryocytes: megakaryocytes occur in clusters; single nuclear lobe, hypolobulation or multiple separate nuclei; micromegakaryocytes present
  • Spleen: splenomegaly uncommon; erythrophagocytosis, red pulp plasmacytosis, extramedullary hematopoiesis or marked red pulp expansion due to monocytic proliferation; splenomegaly usually due to dyspoiesis, not proliferation (Am J Surg Pathol 1998;22:1255)
Microscopic (histologic) images

Images hosted on other servers:

AML with multilineage dysplasia

Erythroid: ringed sideroblasts

Triple X syndrome

Pelger-Huët anomaly


 

Refractory anemia with ringed sideroblasts

 

5q syndrome

Flow cytometry description
  • Can predict morphologic erythroid dysplasia by the pattern of expression of CD105, CD71, H-ferritin in glycophorin A positive cells (Leukemia 2006;20:549)
  • Aberrant maturation patterns in granulopoeisis can predict morphologic dysplasia in granulocytic lineage (Am J Clin Path 2003;120:854)
Electron microscopy description
  • Same findings as AML
  • Erythroid cells show unusual shapes, redundant cell membranes, large vacuoles, duplication of nuclear membrane and nuclear blebs
  • Maturing neutrophils show decreased primary and secondary granules of abnormal size and shape
  • Monocytes show increased cytoplasmic microfilaments and abnormal granules
  • Megakaryocytes and micromegakaryocytes show decreased granules and demarcation membranes, platelets are hypogranular or have large granules
Molecular / cytogenetics description
  • Recommended to use karyotyping or FISH in all suspected patients
  • MDS has no specific cytogenetic abnormalities but abnormalities are present in 30% of de novo MDS and 80% of therapy related MDS
  • Usually chromosomal losses not gains
  • Common findings are complete or partial loss of 5 or 7, +8, 20q- or complex chromosomal abnormalities
  • t(3;5) cases are due to NPM / MLF1 fusion, usually young males with good prognosis (Hum Pathol 2003;34:809)
  • Cytogenetic abnormalities such as deletions of 7q, 5q, 13q, 11q, 12p, 9q and balanced translocations such as t(11;16), t(3;21), t(1;3) are considered presumptive evidence of MDS, in the setting of persistent cytopenias of undetermined origin
Differential diagnosis
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