Definition/General
Introduction:
Myelodysplastic Syndrome (MDS) represents a group of clonal hematopoietic stem cell disorders characterized by dysplastic cell morphology and peripheral cytopenias
Despite hypercellular bone marrow, there is ineffective hematopoiesis
MDS shows tendency for leukemic transformation (20-30% cases)
It represents a preleukemic condition with variable clinical course.
Origin:
Arises from pluripotent hematopoietic stem cell with acquired genetic abnormalities
The stem cell compartment shows clonal expansion with impaired differentiation
Apoptosis of maturing cells leads to peripheral cytopenias despite increased production
Genomic instability predisposes to additional mutations
Microenvironment changes contribute to pathogenesis.
Classification:
WHO 2016 classification includes: MDS with single lineage dysplasia (MDS-SLD)
MDS with multilineage dysplasia (MDS-MLD)
MDS with ring sideroblasts (MDS-RS)
MDS with excess blasts (MDS-EB-1, MDS-EB-2)
MDS with isolated del(5q)
MDS, unclassifiable (MDS-U)
Each has specific diagnostic criteria.
Epidemiology:
Incidence 4-5 per 100,000 per year
Median age 70 years (elderly predominance)
Male to female ratio 1.5:1
Primary MDS (de novo) comprises 85% cases
Secondary MDS (therapy-related) 15% cases
In India, presents at younger age (median 55-60 years)
Increasing incidence with aging population.
Clinical Features
Presentation:
Anemia (most common - 85% cases) with fatigue and weakness
Thrombocytopenia (60% cases) with bleeding and petechiae
Neutropenia (50% cases) with recurrent infections
Macrocytosis common even without anemia
Splenomegaly rare (<5% cases)
Lymphadenopathy uncommon.
Symptoms:
Progressive fatigue (anemia-related - 90% cases)
Dyspnea on exertion (severe anemia)
Easy bruising and bleeding (thrombocytopenia)
Recurrent bacterial infections (neutropenia)
Iron overload symptoms (transfusion-dependent cases)
Constitutional symptoms uncommon.
Risk Factors:
Advanced age (>60 years - strongest risk factor)
Previous chemotherapy (alkylating agents, topoisomerase II inhibitors)
Radiation exposure (therapeutic or occupational)
Benzene exposure
Smoking (2-fold increased risk)
Constitutional genetic syndromes (Fanconi anemia, Down syndrome)
Autoimmune disorders.
Screening:
No routine screening recommendations
Suspect in elderly patients with unexplained cytopenias
Consider in patients with macrocytic anemia without B12/folate deficiency
Bone marrow examination required for diagnosis
Cytogenetic analysis essential
Flow cytometry for blast enumeration and dysplasia assessment.
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Gross Description
Appearance:
Bone marrow hypercellularity (>95% cases) with increased cellularity for age
Normal to slightly enlarged spleen (splenomegaly rare)
No significant lymphadenopathy
Bone marrow appears dark red and hypercellular on biopsy
Normal organ architecture in most cases.
Characteristics:
Bone marrow shows increased cellularity (80-100% for age)
All cell lineages may show increased numbers
Erythroid hyperplasia common
Megakaryocytic clustering may be present
Reticulin fibrosis variable (usually grade 0-1)
Hemosiderin deposits increased.
Size Location:
Bone marrow cellularity typically 80-100% (normal for age 40-60%)
Diffuse hypercellularity involving all sites
Spleen normal size or minimally enlarged
Liver normal size
Lymph nodes not enlarged
Extramedullary hematopoiesis rare.
Multifocality:
Bone marrow involvement is universal and primary
Peripheral blood shows cytopenias despite marrow hypercellularity
No significant extramedullary disease
Transformation sites (if AML develops) include bone marrow primarily
Secondary organ involvement rare unless transformed.
Microscopic Description
Histological Features:
Dysplastic changes in all cell lineages (key diagnostic feature)
Erythroid dysplasia: megaloblastoid changes, nuclear irregularities, ring sideroblasts
Granulocytic dysplasia: hypogranularity, Pelger-Huët anomaly, abnormal nuclear segmentation
Megakaryocytic dysplasia: micromegakaryocytes, hypolobated nuclei, multinuclear forms
Increased apoptosis of maturing cells.
Cellular Characteristics:
Ring sideroblasts (>15 granules around nucleus in >15% erythroid precursors)
Pseudo-Pelger-Huët cells (bilobed neutrophils)
Hypogranular neutrophils
Micromegakaryocytes with single or bilobed nuclei
Megaloblastoid erythroid precursors
Increased myeloblasts (<20% for MDS diagnosis).
Architectural Patterns:
Hypercellular bone marrow with maintained architecture
Erythroid islands may be prominent
Abnormal localization of immature precursors (ALIP)
Megakaryocyte clustering away from trabecular bone
Increased reticulin in some cases (especially with del(5q))
Left-shifted hematopoiesis.
Grading Criteria:
Blast percentage defines subgroups: MDS-SLD/MLD: <5% blasts in bone marrow, <2% in blood
MDS-EB-1: 5-9% blasts in bone marrow, 2-4% in blood
MDS-EB-2: 10-19% blasts in bone marrow, 5-19% in blood
≥20% blasts indicates AML transformation
Dysplasia in ≥10% of cells required for diagnosis.
Immunohistochemistry
Positive Markers:
CD34 (blast enumeration and distribution assessment)
CD117 (immature myeloid cells)
Glycophorin C (erythroid precursors)
CD61, CD41 (megakaryocytes and platelets)
CD68 (monocytes/macrophages)
Tryptase (mast cells - may be increased)
CD138 (plasma cells).
Negative Markers:
TdT usually negative (unlike acute leukemia)
CD20 negative in myeloid blasts
CD3 negative in myeloid cells
Aberrant marker expression may occur: CD7 on myeloid cells
CD56 on megakaryocytes
CD19 rarely on myeloid cells.
Diagnostic Utility:
CD34 staining essential for blast enumeration and ALIP detection
Aberrant antigen expression supports clonality
Flow cytometry detects immunophenotypic abnormalities in >85% cases
CD7 expression on myeloid precursors suggestive of MDS
Decreased CD38 on erythroid precursors
Altered CD45 expression patterns.
Molecular Subtypes:
Immunophenotypic abnormalities correlate with specific genetic subtypes
del(5q) MDS: characteristic megakaryocyte morphology
SF3B1-mutated MDS: ring sideroblasts with specific features
TP53-mutated MDS: complex immunophenotypic abnormalities
Flow cytometry scoring systems aid diagnosis.
Molecular/Genetic
Genetic Mutations:
SF3B1 mutations (20-25% of MDS, associated with ring sideroblasts)
TET2 mutations (20-25% cases)
ASXL1 mutations (15-20% cases, poor prognosis)
DNMT3A mutations (10-15% cases)
SRSF2 mutations (10-15% cases)
U2AF1 mutations (8-10% cases)
TP53 mutations (8-10% cases, very poor prognosis).
Molecular Markers:
Chromosomal abnormalities in 50% of primary MDS cases
Complex karyotype (≥3 abnormalities) in 10-15% cases
Clonal hematopoiesis demonstrated by X-inactivation studies
Microsatellite instability in some cases
Telomere shortening common
Somatic mutation burden increases with age.
Prognostic Significance:
Cytogenetic risk groups: Very good [del(11q), -Y], Good [normal, del(5q), del(12p), del(20q)], Intermediate [del(7q), +8, +19, i(17q)], Poor [complex, -7, inv(3)/t(3;3)], Very poor [complex with ≥3 abnormalities]
TP53 mutations predict poor response to therapy
SF3B1 mutations generally favorable prognosis.
Therapeutic Targets:
Hypomethylating agents (azacitidine, decitabine) for high-risk MDS
Lenalidomide highly effective in del(5q) MDS
Iron chelation for transfusion-dependent patients
Luspatercept for SF3B1-mutated MDS with ring sideroblasts
Allogeneic stem cell transplant for eligible patients
Supportive care for low-risk disease.
Differential Diagnosis
Similar Entities:
Acute Myeloid Leukemia (≥20% blasts)
Aplastic Anemia (hypocellular bone marrow)
Megaloblastic Anemia (B12/folate deficiency)
Chronic Myelomonocytic Leukemia (monocytosis >1000/μL)
Primary Myelofibrosis (fibrosis, JAK2/CALR mutations)
Paroxysmal Nocturnal Hemoglobinuria (hemolysis, CD55/CD59 loss).
Distinguishing Features:
MDS: <20% blasts, dysplasia, hypercellular marrow
AML: ≥20% blasts, may lack dysplasia
AA: Hypocellular marrow, no dysplasia
Megaloblastic: B12/folate low, reversible dysplasia
CMML: Monocytosis, dysplasia
PMF: Fibrosis, JAK2/CALR+
PNH: Hemolysis, flow cytometry diagnostic.
Diagnostic Challenges:
Distinguishing MDS from megaloblastic anemia (B12/folate levels, reversibility)
Therapy-related versus primary MDS (history, cytogenetics)
Low-grade MDS versus age-related changes (clonality studies)
MDS versus reactive dysplasia (drug effects, infections)
Hypocellular MDS versus aplastic anemia (challenging cases).
Rare Variants:
Hypocellular MDS (15% cases, may mimic aplastic anemia)
MDS with fibrosis (increased reticulin, del(5q) association)
Childhood MDS (different biology, genetic predisposition syndromes)
MDS/MPN overlap syndromes (CMML, JMML, aCML)
Familial MDS (GATA2, RUNX1, CEBPA mutations).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy, peripheral blood smear
Peripheral Blood Findings
Cytopenias: [specify which lineages affected and severity]
Bone Marrow Cellularity
Cellularity: [X]% (hypercellular for age)
Dysplasia Assessment
Erythroid: [X]%, Granulocytic: [X]%, Megakaryocytic: [X]%
Blast Count
Blasts: [X]% of bone marrow cells, [X]% of peripheral blood
Iron Stain
Ring sideroblasts: [X]% of erythroid precursors
Cytogenetic Analysis
[karyotype], Risk group: [Very good/Good/Intermediate/Poor/Very poor]
Flow Cytometry
Immunophenotypic abnormalities: [present/absent], [specific findings]
WHO Classification
[MDS subtype per WHO 2016 criteria]
Prognostic Assessment
IPSS-R score: [value], Risk category: [Very low/Low/Intermediate/High/Very high]
Final Diagnosis
Myelodysplastic Syndrome, [specific WHO subtype]