Bone marrow neoplastic

Bone marrow - neoplastic myeloid

Myelodysplastic syndromes (MDS)

MDS with multilineage dysplasia



Topic Completed: 13 December 2021

Minor changes: 13 December 2021

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PubMed Search: MDS with multilineage dysplasia "last 5 years" [DP]

Shajo Kunnath-Velayudhan, M.B.B.S., M.M.S.T.
Julia T. Geyer, M.D.
Page views in 2021: 1,476
Page views in 2022 to date: 116
Cite this page: Kunnath-Velayudhan S, Geyer JT. MDS with multilineage dysplasia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/myeloproliferativeRCMD.html. Accessed January 19th, 2022.
Definition / general
  • Myelodysplastic syndrome (MDS) with multilineage dysplasia is characterized by 1 or more cytopenias and dysplastic changes in 2 or more of the myeloid lineages (erythroid, granulocytic and megakaryocytic)
  • Myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia (MDS RS MLD) if ring sideroblasts are > 15% (> 5% with SF3B1 mutation)
Essential features
  • Dysplastic changes in 2 or more of the myeloid lineages
  • Blast counts < 1% in the peripheral blood and < 5% in the bone marrow
  • Assess ring sideroblasts (< 15%) and SF3B1 mutation status (if sideroblasts comprise 5 - 15% of erythroid elements) to categorize as MDS MLD or MDS RS MLD
  • Monocytes < 1 x 109/L
  • Exclusion of other causes of dysplasia
  • References: Leukemia 2015;29:66, Leukemia 2007;21:668
Terminology
  • Refractory cytopenia with multilineage dysplasia
  • Myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia (MDS RS MLD)
ICD coding
  • ICD-0: 9985/3 - refractory cytopenia with multilineage dysplasia
  • ICD-10: D46.A - refractory cytopenia with multilineage dysplasia
Epidemiology
Sites
  • Bone marrow
Pathophysiology
  • Cell of origin is a hematopoietic stem cell
  • Complex interplay between genetic and epigenetic alterations and the bone marrow microenvironment lead to dysregulated hematopoietic differentiation, resulting in impaired differentiation, morphological dysplasia and cytopenia
Etiology
  • Age associated risk attributed to hematopoietic stem cell mutations
  • Exposure to toxins (e.g., benzene, cigarette smoking, agricultural chemicals or solvents)
  • Family history of hematopoietic neoplasms
  • Acquired aplastic anemia
  • References: N Engl J Med 2014;371:2477, N Engl J Med 2014;371:2488
Diagrams / tables

Images hosted on other servers:

Pathogenesis of myelodyspastic syndromes

Clinical features
  • Unicytopenia, bicytopenia (common)
  • Pancytopenia, milder cytopenia (less common)
Diagnosis
  • Peripheral blood analysis
  • Bone marrow examination
Laboratory
  • Hemoglobin concentration < 10 g/dL (recommended by 2016 WHO)
  • Platelet count < 100 x 109/L (recommended by 2016 WHO)
  • Standard hematologic values for cytopenia (hemoglobin < 13 g/dL [males], < 12 g/dL [females] and platelets < 150 109/L) are also used by some authors
  • Absolute neutrophil count < 1.8 x 109/L
  • Monocytes < 1 x 109/L
  • Blasts < 1% in the peripheral blood
  • Reference: Blood 2016;128:2096
Prognostic factors
Case reports
Treatment
  • Transfusion
  • Iron chelation
  • Erythropoiesis stimulating factors
  • Immunosuppressive treatment
  • Lenalidomide for lower risk del(5q) MDS
  • Luspatercept for MDS with ring sideroblasts
  • Azacytidine
  • Decitabine
  • Induction chemotherapy
  • Stem cell transplantation
  • Reference: Blood 2013;122:2943
Microscopic (histologic) description
  • Bone marrow findings (Leuk Res 2013;37:64)
    • General
      • Cellularity: majority of cases are normocellular or hypercellular; a subset of MDS-MLD show age adjusted hypocellularity
      • Erythroid hyperplasia
      • Myeloid hyperplasia with left shift
      • Myeloblasts must be < 5%
      • Occasional fibrosis (16% of cases)
    • Erythroid lineage dysplasia
      • Nuclear: nuclear budding, internuclear bridging, karyorrhexis, multinuclearity, megaloblastoid changes
      • Cytoplasmic: ring sideroblasts (< 15%, < 5% with SF3B1 mutation)
      • Vacuolization
    • Myeloid lineage dysplasia
      • Small or unusually large size
      • Nuclear cytoplasmic asynchrony
      • Nuclear hyposegmentation (pseudo Pelger-Huët anomaly)
      • Nuclear hypersegmentation
      • Decreased granules; agranularity
      • Pseudo Chédiak-Higashi granules
      • Döhle bodies
    • Megakaryocyte dysplasia
      • Micromegakaryocytes (most reliable and reproducible)
      • Nuclear hypolobation or nonlobation
      • Binucleation or multinucleation
Microscopic (histologic) images

Contributed by Julia T. Geyer, M.D. and Shajo Kunnath-Velayudhan, M.B.B.S., M.M.S.T.

Hypercellular bone marrow

Dysplastic megakaryocytes

Cytology images

Contributed by Julia T. Geyer, M.D. and Shajo Kunnath-Velayudhan, M.B.B.S., M.M.S.T.

Dysmegakaryopoiesis

Dysgranulopoiesis

Dyserythropoiesis

Peripheral smear description
  • Red blood cells: anisopoikilocytosis with macrocytosis of red blood cells
  • White blood cells
    • Nuclear clumping
    • Hyposegmentation
    • Lack of lobation (pseudo Pelger-Huët anomaly)
    • Cytoplasmic hypogranularity or agranularity
    • Abnormal granular clumping (similar to Chédiak-Higashi syndrome): infrequent
  • No increase in blasts (must be < 1%)
  • Reference: Haematologica 2013;98:568
Peripheral smear images

Contributed by Genevieve M. Crane, M.D., Ph.D.
Dysplastic neutrophils

Dysplastic neutrophils

Positive stains
Flow cytometry description
  • Flow cytometry findings alone are not diagnostic
  • Decreased side scatter of granulocytes
  • Erythroid: increased coefficient of variation and decreased intensity of CD71 or CD36
  • Aberrant expression of CD56 or CD7 on progenitors, granulocytes or monocytes
  • Asynchrony of CD15 and CD16 on granulocytes
  • Altered expression of CD13 in relation to CD11b or CD16
  • Reference: Leukemia 2014;28:1793
Molecular / cytogenetics description
  • Cytogenetics
    • Trisomy 8
    • Monosomy 7
    • del(7q)
    • Monosomy 5
    • del(5q)
    • del(20q)
    • Complex karyotypes
  • Molecular aberrations
    • Cohesion family (STAG2)
    • Chromatin modifiers (ASXL1)
    • Spliceosome genes (SRSF2)
    • Transcription factors (RUNX1)
    • Signaling molecules (CBL)
    • Tumor suppressors (TP53)
    • DNA modifiers (TET2)
    • SF3B1 (in setting of MDS RS MLD with at least 5% ring sideroblasts)
  • Reference: Leuk Res 2013;37:64
Videos

What is multilineage dysplasia?

Sample pathology report
  • Bone marrow, posterior iliac crest, core biopsy, clot section, aspirate smears and touch imprint:
    • Myelodysplastic syndrome with trilineage dysplasia
    • Flow cytometry: abnormal myeloid blasts present
    • Peripheral blood: anemia, moderate, macrocytic
    • Cytogenetics: 46,XY,+8[16]/46,XY[4]
    • Next generation sequencing:
      • SRSF2 P95R with mutant allele frequency of 31%
      • ASXL1 E635%fs*15 with mutant allele frequency of 28%
Differential diagnosis
  • Secondary causes of dysplasia:
    • Nutritional deficiencies, toxic exposures, drugs and biologic agents, infection, congenital disorders and sideroblastic anemias
    • History and physical examination
    • Appropriate laboratory investigations
  • Myelodysplastic syndrome with single lineage dysplasia:
    • Only 1 hematopoietic lineage shows dysplasia
  • Myelodysplastic syndrome with excess blasts:
    • 5 - 19% myeloblasts in the bone marrow or 2 - 19% blasts in the peripheral blood
    • Presence of Auer rods in blasts
  • Myelodysplastic syndrome, unclassifiable:
    • MDS (MDS with excess blasts excluded) associated with 1% blasts in the peripheral blood on 2 separate occasions
    • MDS (MDS with multilineage dysplasia excluded) associated with pancytopenia
    • Persistent cytopenia with < 2% blasts in the blood and < 5% in the bone marrow and no significant dysplasia in any myeloid lineage and the presence of cytogenetic abnormalities considered presumptive evidence of MDS
Board review style question #1

A 60 year old man with anemia underwent bone marrow core biopsy (an H&E image is shown). Which of the following is essential to make the diagnosis of myelodysplastic syndrome?

  1. Absence of secondary causes of dysplasia
  2. Presence of dysplasia in the erythroid lineage
  3. Presence of dysplasia in the megakaryocyte lineage
  4. Presence of dysplasia in the myeloid lineage
Board review style answer #1
A. Absence of secondary causes of dysplasia

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Reference: MDS with multilineage dysplasia
Board review style question #2
A 90 year old man presents with fatigue and the peripheral blood smear examination shows dysplastic neutrophils. No blasts are present. The evaluation for secondary causes of anemia and dysplastic neutrophils are negative. The bone marrow examination shows dysplasia in erythroid and myeloid lineages and 2% blasts. The iron stain shows 16% ring sideroblasts. This condition is best classified as

  1. Myelodysplastic syndrome, unclassifiable
  2. Myelodysplastic syndrome with multilineage dysplasia
  3. Myelodysplastic syndrome with ring sideroblasts
  4. Myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia
Board review style answer #2
D. Myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia

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Reference: MDS with multilineage dysplasia
Board review style question #3
Which of the following findings is considered the most reliable and reproducible dysplastic feature in the megakaryocyte lineage?

  1. Hyperchromatic nuclei
  2. Micromegakaryocytes
  3. Multinucleation
  4. Nuclear hypolobation
Board review style answer #3
B. Micromegakaryocytes

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Reference: MDS with multilineage dysplasia
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