Myelodysplastic Syndrome (MDS)

 

Epidemiology and Etiology:

    • Marrow is completely or partly replaced by the progeny of a mutant multipotent stem cell that retains the capacity to differentiate into the trilineages but in an ineffective and disordered fashion
    • Idiopathic:
      • >50y mainly (median 70y)
    • therapy-related (t-MDS)
      • occurs 2-8y after treatment
      • genotoxic drugs (alkylating agent type usually)
      • radiation therapy
    • other risk factors:
      • benzene exposure
      • smoking
      • Fanconi’s anemia
    • Some causes of non-clonal myelodysplasia:
      • Vitamin B12 deficiency
      • Folic acid deficiency
      • Heavy metal exposure (arsenic)
      • Congenital dyserythropoietic anemia (confined to erythroid cells)
      • Parvovirus B19 infection
      • Drugs:
        • Chemotherapy
        • G-CSF (neutrophil dysplasia)

 

Common sites:

    •  

 

Gross features:

    •  

 

Histologic features:

    • peripheral blood:
      • Myeloblasts <20%
      • red cell changes:
        • oval macrocytes
        • poikilocytes
        • coarse basophilic stippling
        • polychromasia
        • dimorphic population
        • nucleated red cells (rosette nuclei)
      • granulocytic changes:
        • Neutrophils with dysplastic nucleus / agranular cytoplasm
          • cytoplasmic granules decreased or absent
            1. pale bluish cytoplasm
          • irregular nuclear lobation
          • chromatin normally clumped
          • 10-15um
        • degranulation
        • abnormally large granules
        • pseudo Pelger-Huet change
        • monocytoid change
      • monocyte changes:
        • increase in number
        • granulocytic change
        • hyperlobulation of nucleus
      • platelet changes:
        • giant forms (>7um / bigger than a red cell)
        • hypogranulation
        • bizarre shapes
      • dysplastic megakaryocytes or megakaryocytes nuclei may be present (see below)
    • bone marrow:
      • usually hypercellular
        • may be normocellular or less commonly hypocellular
      • myeloblasts may be increased but <20%
      • dysplasia in one or more of the major myeloid cell lines
        • requisite 10% of cells showing dysplastic changes to call the lineage dysplastic
      • abnormal localization of immature precursors (ALIP) may be seen in biopsy:
        • small clusters / aggregates of myeloblasts and promyelocytes (5-8 cells)
        • located away from the vascular structures and endosteal surface of the bone trabeculae
        • need 3 or more to call ALIP positive
      • red cell changes:
        • ringed sideroblasts
        • megaloblastoid and megaloblastic erythropoiesis
        • nuclear budding (nuclei with misshapen, often polypoid outlines)
        • intranuclear bridges
        • multinucleation
        • karyorrhexis
        • Howell-Jolly bodies
        • coarse basophilic stippling
        • intercellular contacts between cells
        • vacuolization of cytoplasm
          • PAS staining of vacuoles (“block-like”)
        • irregular cytoplasmic contours
        • excessive siderotic granules by Prussian blue staining
      • granulocyte changes:
        • Neutrophils with dysplastic nucleus / agranular cytoplasm
          • cytoplasmic granules decreased or absent
            1. pale bluish cytoplasm
          • irregular nuclear lobation
          • chromatin normally clumped
          • 10-15um
        • nucleus completely lacking segmentation
        • monocytoid change
        • degranulation
        • abnormally large granules (toxic granulations)
        • Dohle bodies
        • pseudo Pelger-Huet change
          • neutrophils with 2 nuclear lobes
        • increased blast count
      • monocyte changes:
        • increased number
        • granulocytoid change
      • megakaryocyte changes:
        • micromegakaryoctyes
          • 15-39um (most <20um)
          • N:C ratio 1:1 or 1:2
          • Hypolobation or multiple small lobes (impaired polyploidization)
        • hyper and hypolobulation
          • pawnball nuclei (3 lobes all separated) are uncommon but clear markers of dysplasia
          • “Marty Feldman Cells” with 2 clearly separated nuclei are indicative of dysplasia
          • single nuclear lobe
        • nuclei may be separated (normally one nucleus connected in series)
        • abnormal  chromatin clumping
        • cytoplasmic hypogranularity
        • abnormal clustering
        • paratrabecular location
        • striking variability from cell to cell
    • myelodysplastic syndromes (double check for 2008 updates):
      • Refractory cytopenia with unilineage dysplasia (RCUD)
      • refractory anemia (RA)
        • erythroid dysplasia only
        • <5% blasts in marrow; none or rare in PB
        • <15% ringed sideroblasts
      • Refractory neutropenia (RN)
      • Refractory thrombocytopenia (RT)
      • refractory anemia (RA) with ringed sideroblasts (RARS) (WHO 2008 reviewed)
        • erythroid dysplasia only (BM)
          • nuclear lobation
          • megaloblastoid features
        • <5% blasts in BM; none in PB
        • >= 15% ringed sideroblasts among red cell precursors
          • 5 or more iron granules encircling one third or more of the nucleus
          • NOTE: ringed sideroblasts are frequently observed in other types of MDS
            • RAEB
            • RCMD
        • Secondary causes of ringed sideroblasts must be excluded
          • Alcohol
          • Toxins (lead, benzene)
          • Drugs (isoniazid, zinc)
          • Copper deficiency
          • Congenital sideroblastic anemia
        • Dimorphic RBC pattern in PB smear maybe
          • Major population of normochromic cells
          • Minor population of hypochromic cells
        • Hemosiderin-laden macrophages often abundant (BM)
        • Normocellular to markedly hypercellular, usually with marked erythroid proliferation
        • Megakaryocytes normal in number and morphology
          • If large, abnormal megas, consider RARS-T diagnosis (see MDS / MPN section)
        • If elevated platelets, do JAK2 / CALR / MPL, and consider RARS-T diagnosis (see MDS/MPN section)
      • refractory cytopenia with multilineage dysplasia (RCMD):
        • dysplasia in >=10% of cells in 2 or more myeloid cell lines
        • <5% blasts in marrow; none or rare in PB
        • <15% ringed sideroblasts
        • no Auer rods
        • <1x10e9/L monocytes in PB
      • refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS):
        • dysplasia in >=10% of the cells in 2 or more myloid cell lines
        • <5% blasts in the marrow; none or rare in PB
        • >=15% ringed sideroblasts
        • no Auer rods
        • <1x10e9/L monocytes in PB
      • refractory anemia with excess blasts - 1 (RAEB-1):
        • unilineage or multilneage dysplasia
        • 5-9% blasts in marrow; <5% blasts in PB
        • no Auer rods
        • <1x10e9/L monocytes in PB
      • refractory anemia with excess blasts – 2 (RAEB-2)
        • unilineage or multilineage dysplasia
        • 10-19% blasts in marrow; 5-19% blasts in PB
        • +/- Auer rods
        • <1x10e9/L monocytes
      • muyelodysplastic syndrome – unclassified (MDS-U):
        • unilineage dysplasia
        • <5% blasts in marrow; none or rare in PB
        • no Auer rods
      • MDS associated with isolated del(5q):
        • Normal to increased megakaryocytes with hypolobated nuclei
        • <5% blasts in marrow; <5% blasts in PB
        • no Auer rods
        • anemia; usually normal or increased plastely count
    • Parvovirus B19 infection:
      • Erythroblastopenia
      • Giant megaloblastoid erythroblasts

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 

 

 
    •   MDS-RARS: aberrant immunophenotypic features of erythropoietic precursors by flow maybe
    • Flow cytometry (FCM score) recommendations by International/European LeukemiaNet Working Group:
      • Ogata score minimum panel for FCM score
      • Westers et al. more comprehensive FCM score
      • sensitivity for MDS diagnosis between 59 and 98%
      • specificity of 93–100%
      • PPV ~92%
      • limited NPV as a stand-alone test (similar to morphology and cytogenetics alone)
        • Best used in conjunction with morphology and cytogenetics for a comprehensive diagnosis
      •  (note: these sensitivities and specificities are based on pathologic diagnosis as a gold standard)
      • Recommendations for integration of FCM results:
        • In cases with minimal morphological dysplasia and no detected cytogenetic/molecular abnormalities, aberrant FCM findings may support MDS diagnosis. Conversely, normal FCM findings should prompt further investigation for other causes of cytopenias, close follow-up and retesting when clinically indicated.
        • In patients with cytological findings suggesting MDS of RCUD (refractory anemia subtype) or refractory anemia with ringed sideroblasts categories, aberrant FCM findings in the granulopoietic or myelomonocytic lineages may indicate multilineage dysplasia, which is of prognostic significance.2 Morphological findings in these cases should be thoroughly re-evaluated to avoid misclassification.
        • Enumeration of CD34 + cells by FCM has been reported as more relevant for prognosis than the percentage of blasts evaluated by morphology, and a limit of 42% CD34 + cells within nucleated CD45 + cells has been reported to be significant.  Of note, revised IPSS uses 42% of morphologically determined blasts as the first limit for significant blast percentage categories.

 

Molecular features:

    • Acute leukemia testing guidelines
    • Clonal cytogenetic abnormalities (50%) (5-20% of MDS-RARS):
      • Unless otherwise indicated, the presence of one of these abnormalities in the setting of a refractory cytopenia is considered presumptive evidence for MDS (even in the absence of morphologic dysplasia)
        • On the contrary the presence of t(8;21), inv(16), t(16;16), or t(15;17) is diagnostic for AML regardless of blast percentage in the BM
      • ~10% of patients with minimal dysplasia (insufficient for WHO criteria MDS diagnosis) have MDS-related cytogenetic findings (such as 20q- characteristically in a subset)
      • -5/5q deletions (10-20%) (40% of t-MDS)
        • Associated with previous exposure to alkylating agents
        • Associated with significant occupational exposures to potential carcinogens (ex. benzene, ionizing radiation)
          • May be a marker of mutagen-induced hematological malignancies
        • 5q as sole anomaly (good prognosis)
          • “5q syndrome” – primarily in women
          • EGR1, RPS14, CTNNA1 may be involved
          • RA or RAEB morphology
            • associated with hypolobated megakaryocytes
          • Refractory macrocytic anemia
          • Normal or increased platelet count
          • Favourable clinical course (best of any subgroup)
            • Low rates of leukemic transformation
            • Relatively long survival of several years
        • With other cytogenetic abnormalities
          • Poor prognosis with early progression to leukemia, resistance to treatment, and short survival
      • -7/7q deletions (poor prognosis)
        • sole abnormality  in:
          • 5% of adults with de novo MDS
          • 50% of children with de novo MDS
          • ~55% of patients with t-MDS
        • Poor prognosis
        • Monosomy 7 syndrome in young children:
          • Males (4:1)
          • Hepatosplenomegaly
          • Leukocytosis
          • Thrombocytopenia
          • Poor prognosis
        • Associated with previous exposure to alkylating agents
        • Associated with significant occupational exposures to potential carcinogens (ex. benzene, ionizing radiation, smoking)
          • May be a marker of mutagen-induced hematological malignancies
      • trisomy 8 (~10%)
        • not definitive evidence for MDS in the absence of morphological criteria
      • +21 (3-4%)
      • 20q deletions (5% of cytogenetically abnormal MDS, 7% of t-MDS) (good prognosis as sole abnormality)
        • Morphology:
          • associated with prominent dysplasia in erythroid and megakaryocyte lineages
        • not definitive evidence for MDS in the absence of morphological criteria
        • prognosis (isolated abnormality):
          • low-risk disease (usually RA)
          • low rate of progression to AML
          • prolonged survival
      • 17p deletions (up to 5%)
        • TP53 gene deleted (17p13.1)
        • associated with p53 mutation on remaining allele (~70%)
        • Various forms:
          • Simple deletion
          • Unbalanced translocation
          • Dicentric rearrangement (particularly with chr 5)
            • dic(5;17)(q11.1-13;p11.1-13)
          • -17
          • i(17)(q10)
        • Morphology:
          • pseudo Pelger-Huet anomaly
          • hypolobatd neutrophils (often bilobed)
          • small vacuolated neutrophils
        • associated cytogenetic abnormalities:
          • most have complex karyotypes
          • -7/del(7)(q)
          • +8
        • most common in t-MDS (~1/3)
        • 17p- syndrome:
          • Aggressive disease
          • Resistance to treatment
          • Short survival
      • complex karyotypes (>= 3 anomalies, typically as above)
        • unfavourable prognosis
      • 3q abnormalities (poor prognosis)
        • inv(3)(q21q26.2)
        • t(3;3)(q21;q26.2)
        • t(3;21)(q26.2;q22.1)
          • RPL22L1 (EAP) gene at 3q26.2
            • Encodes Epstein Barr small RNAs-associated protein
          • MDS1/EVI1 gene at 3q26.2, centromeric to RPL22L1
          • EVI gene at 3q26.2, centromeric to RPL22L1
          • RUNX1 at 21q22.1
        • t(3;12)(q26.2;p13)
          • above 3q26.2 genes
          • TEL at 12p13
        • associated with MDS and AML with increased abnormal megakaryocytes
        • associated with previous history of cytotoxic exposure (t-MDS/t-AML)
        • most are associated with chromosome 7 abnormalities
      • -Y (good prognosis as sole abnormality)
        • Not definitive evidence of MDS in the absence of morphological criteria
        • Can occur with age
      • Normal karyotype (30-60%) (good prognosis)
      • Note: presence of the following aberrations is diagnostic for AML:
        • t(8;21)
        • inv(16)
        • t(15;17)
    • mutations:
      • JAK2 V617F (4%)
        • More frequently in MDS with thrombocytosis

 

 

Other features:

    • preneoplastic
      • 25% develop AML
      • more frequent in therapy-related MDS (t-MDS)
      • subtypes with higher proportion of blasts in the marrow or peripheral blood have increased risk
      • ALIP positive is associated with a more rapid evolution to acute leukemia
    • gray zone between myelodysplasia and neoplasia
    • usually manifest clinically as peripheral blood cytopenias
      • MDS-RARS:
        • Moderate anemia typically
        • Thrombocytopenia or neutropenia maybe
          • If thrombocytosis, consider RARS-T diagnosis (MDS / MPN section)
        • Progressive iron overload symptoms maybe
    • prognosis:
      • median survival 9-29 months (4-8months in t-MDS)
      • 3 risk groups:
        • Low-risk:
          • RCUD
          • RARS (69-108 months median OS)
        • Intermediate-risk:
          • RCMD with or without RS
          • RAEB-1
        • High-risk:
          • RAEB-2
      • 3 major risk categories of cytogenetic findings:
        • i) good risk
          • Normal karyotype
          • Isolated del(5)(q)
          • Isolated del(20)(q)
          • –Y
        • ii) poor risk
          • Complex abnormalities (>=3 abnormalities)
          • Abnormalities of chromosome 7
        • iii) intermediate risk
          • all other abnormalities
      • Number of cytopenias is a factor
      • Age (>60y is worse)

 

References:

    • CAP Color Atlas of Hematology, 1998
    • Robbins 2005
    • WHO book 2001
    • Swerdlow. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. WHO Publications; 2008.
    • Heim S, Mitelman F. Cancer Cytogenetics. 3rd ed. Wiley-Blackwell; 2009.
    • Porwit et al.  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.  Leukemia (2014) 1 – 6; doi:10.1038/leu.2014.191