Clonal stem cell disorder with ineffective hematopoiesis, cytopenias, dysplasia, and risk of AML transformation.
Also known as: MDS, myelodysplasia, preleukemia, refractory anemia
Overview
Heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, morphologic dysplasia in one or more lineages, and variable risk of progression to acute myeloid leukemia.
Epidemiology
Median age at diagnosis 70 years; rare under 50 (except therapy-related). Annual incidence ~4 per 100,000 overall, ~30 per 100,000 in those >70. Male predominance.
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Question 1HematologyMedium
A 72-year-old man presents with several months of fatigue and easy bruising. Complete blood count shows hemoglobin 9.8 g/dL, white blood cells 4,200/mm3, platelets 88,000/mm3, and mean corpuscular volume 104 fL. Bone marrow biopsy reveals neutrophils with hypolobated nuclei (pseudo-Pelger-Huet cells), hypogranular platelets, and 8% myeloblasts. Which of the following is the most likely diagnosis?
APrimary myelofibrosis
BAcute myeloid leukemia
CAplastic anemia
DMyelodysplastic syndrome
EFolate deficiency anemia
Reveal answer & full explanation
Correct answer: D — Myelodysplastic syndrome
APrimary myelofibrosis
BAcute myeloid leukemia
CAplastic anemia
DMyelodysplastic syndrome✓
EFolate deficiency anemia
Why Myelodysplastic syndrome is correct
Myelodysplastic syndrome is a clonal hematopoietic stem cell disorder defined by dysplastic maturation plus peripheral cytopenias, both present here.
Pseudo-Pelger-Huet neutrophils, hypogranular platelets, and macrocytosis (MCV 104 fL) are classic dysplastic findings.
8% marrow blasts falls in the 5-9% range of MDS with excess blasts, which carries a higher risk of transformation to acute myeloid leukemia.
Why the others are wrong
Folate deficiency anemia - the macrocytosis is a buzzword trap, but folate deficiency causes megaloblastic change (hypersegmented neutrophils), not pseudo-Pelger-Huet dysplasia or marrow blasts.
Aplastic anemia - also produces pancytopenia (premature-closure trap), but the marrow is hypocellular without dysplasia or excess blasts; 8% blasts and dysplastic forms exclude it.
Acute myeloid leukemia - requires 20% or more blasts; 8% does not meet the threshold (right-disease-spectrum, wrong-cutoff).
Primary myelofibrosis - another clonal myeloid neoplasm of older adults that causes anemia (look-alike trap), but its hallmarks are marrow fibrosis with atypical megakaryocytes, often a dry tap, a leukoerythroblastic smear with teardrop cells, and splenomegaly, not pseudo-Pelger-Huet neutrophils and hypogranular platelets.
Question 2HematologyMedium
A 74-year-old woman is evaluated for 3 months of progressive fatigue and exertional dyspnea. She has no melena, weight loss, or prior chemotherapy, and she takes no medications. Examination shows conjunctival pallor without splenomegaly or lymphadenopathy. Laboratory studies show hemoglobin 8.4 g/dL with an MCV of 108 fL, platelet count 95,000/µL, and a reticulocyte count that is inappropriately low. Serum vitamin B12, folate, copper, and TSH are normal. Which of the following findings on the peripheral blood smear best supports the diagnosis of myelodysplastic syndrome?
ATeardrop cells with nucleated red blood cells
BRound macrocytes with numerous target cells
CBilobed neutrophils, hypogranular cytoplasm
DHypersegmented neutrophils with oval macrocytes
ESpherocytes, polychromasia, and schistocytes
Reveal answer & full explanation
Correct answer: C — Bilobed neutrophils, hypogranular cytoplasm
ATeardrop cells with nucleated red blood cells
BRound macrocytes with numerous target cells
CBilobed neutrophils, hypogranular cytoplasm✓
DHypersegmented neutrophils with oval macrocytes
ESpherocytes, polychromasia, and schistocytes
Why Bilobed neutrophils, hypogranular cytoplasm is correct
Bilobed neutrophils with condensed chromatin (pseudo-Pelger-Huët cells) and hypogranular granulocytes reflect dysgranulopoiesis, the morphologic dysplasia that defines MDS.
In an older patient with persistent macrocytic anemia, thrombocytopenia, and an inappropriately low reticulocyte count after reversible causes (B12, folate, copper, thyroid) are excluded, these dysplastic neutrophils on smear are the key clue that should prompt bone marrow aspirate/biopsy with cytogenetics.
Per WHO/ICC 2022 criteria, MDS requires persistent cytopenia(s), dysplasia in >=10% of cells in >=1 lineage, exclusion of other causes, and <20% blasts.
Why the others are wrong
Hypersegmented neutrophils with oval macrocytes are classic for B12 or folate deficiency (megaloblastic anemia), which is already excluded here by normal B12 and folate, so they would not support MDS.
Spherocytes, polychromasia, and schistocytes point to a hemolytic process (autoimmune hemolysis or a microangiopathy); hemolysis raises the reticulocyte count, the opposite of this patient's inappropriately low count.
Teardrop cells with nucleated red blood cells form a leukoerythroblastic picture suggesting marrow infiltration or primary myelofibrosis, which typically presents with splenomegaly rather than the isolated dysplastic cytopenias seen here.
Round macrocytes with numerous target cells — this is the non-megaloblastic pattern of alcohol use or chronic liver disease, a common cause of macrocytosis with a low platelet count once B12 and folate are normal; round macrocytes and target cells reflect red cell membrane lipid changes, not the dysplasia that defines MDS.
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Acquired somatic mutations in hematopoietic stem cells (commonly TET2, SF3B1, ASXL1, DNMT3A, SRSF2, RUNX1, TP53) drive clonal expansion and impaired differentiation. The dysfunctional clone produces morphologically abnormal but functionally inadequate blood cells that undergo intramedullary apoptosis — paradoxical bone marrow hypercellularity with peripheral cytopenias. Progressive genetic instability eventually leads to AML in ~30%.
Clinical presentation
Symptoms
Fatigue and exertional dyspnea from anemia (most common)
Recurrent or atypical infections from neutropenia or neutrophil dysfunction
Easy bruising, petechiae, mucosal bleeding from thrombocytopenia
Often asymptomatic — discovered on routine CBC
Signs / physical exam
Pallor, petechiae, mucosal bleeding
Splenomegaly uncommon (more suggestive of MDS/MPN overlap or CMML)
Skin lesions (Sweet syndrome, leukemia cutis) in advanced disease
Classic findings
Older patient with persistent unexplained macrocytic anemia, bicytopenia, or pancytopenia and dysplastic morphology on smear/marrow.
Differential diagnosis
Aplastic anemia — Hypocellular marrow with no dysplasia; younger patients; PNH clone screening
B12 or folate deficiency — Macrocytic anemia with hypersegmented neutrophils; normal copper; replacement reverses morphologic findings
Copper deficiency — Pancytopenia mimicking MDS; ring sideroblasts; ataxia/myelopathy; check ceruloplasmin and copper
Acute myeloid leukemia — ≥20% blasts in marrow or blood; certain cytogenetics (t(8;21), inv(16), t(15;17)) define AML regardless of blast count
Chronic myelomonocytic leukemia (CMML) — Persistent monocytosis ≥0.5 × 10⁹/L and ≥10% of WBC (WHO/ICC 2022); classified separately (MDS/MPN overlap)
WHO 5th edition (2022) classification (a separate, parallel International Consensus Classification, ICC 2022, differs in some details) — requires persistent cytopenia(s), dysplasia in ≥10% of cells in ≥1 lineage, exclusion of other causes, and <20% blasts in marrow/blood. Specific entities include MDS with low blasts (formerly RA/RCMD), MDS with ring sideroblasts (SF3B1 mutation), MDS with isolated del(5q), MDS with biallelic TP53 inactivation, and MDS with increased blasts (formerly RAEB).
Labs
CBC with differential — cytopenias affecting ≥1 lineage; MCV often elevated
Reticulocyte count — inappropriately low for degree of anemia
Iron chelation (deferasirox, deferoxamine) for chronic transfusion dependence (>20-30 units RBC or ferritin >2500)
Higher-risk MDS — hypomethylating agents: azacitidine or decitabine
Lower-risk MDS (IPSS-R very low/low/intermediate)
Erythropoiesis-stimulating agents (ESA) if symptomatic anemia and EPO <500
Luspatercept for anemia, especially with ring sideroblasts/SF3B1 mutation
Lenalidomide for transfusion-dependent del(5q) MDS
Iron chelation if chronic transfusion dependence
Higher-risk MDS (IPSS-R high/very high)
Hypomethylating agents — azacitidine (IV or subcutaneous; the HMA with a proven overall survival benefit) or decitabine (IV, or oral decitabine-cedazuridine); oral azacitidine is approved only for AML maintenance, not MDS
Allogeneic hematopoietic stem cell transplant — only curative option; offer to transplant-eligible patients
Venetoclax + HMA combinations under investigation
Therapy-related MDS
Typically aggressive course with complex/monosomal karyotype, TP53 mutations
Allo-HSCT if eligible; HMA otherwise
Second-line / adjunct
Immunosuppression (ATG + cyclosporine) for hypoplastic MDS variant
Allogeneic stem cell transplant — only curative therapy
Clinical trial enrollment for novel agents
Complications
Progression to acute myeloid leukemia (30% overall; higher in high-risk subtypes)
Severe infections from neutropenia and granulocyte dysfunction
Bleeding from thrombocytopenia
Transfusion-related iron overload causing cardiac, hepatic, endocrine dysfunction
Cardiovascular complications from chronic anemia
Treatment toxicity: cytopenias from HMA, transplant-related morbidity
PANCE pearls
Always exclude reversible causes (B12, folate, copper deficiency, HIV, alcohol) before labeling cytopenias as MDS.
SF3B1 mutation with low blasts (or ≥15% ring sideroblasts if SF3B1 is wild-type or not tested) defines MDS with SF3B1 mutation/ring sideroblasts (favorable subtype).
Isolated del(5q) MDS — 'classic 5q- syndrome' — presents in older women with macrocytic anemia, normal/elevated platelets, and responds dramatically to lenalidomide.
Pseudo-Pelger-Huët cells (bilobed neutrophils) on smear should raise suspicion for MDS.
TP53 mutations carry poor prognosis and may blunt response to standard therapy.
Allogeneic stem cell transplant is the only cure — refer transplant-eligible higher-risk patients early.
References
NCCN Guidelines — NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes (current version).
IPSS-M — Bernard E et al. Molecular International Prognostic Scoring System for myelodysplastic syndromes. NEJM Evidence 2022.
WHO/ICC 2022 — Khoury JD et al. 5th edition WHO Classification of Haematolymphoid Tumours: Myeloid Neoplasms. Leukemia 2022; Arber DA et al. International Consensus Classification. Blood 2022.
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