How do I interpret bone marrow morphology?

How to Read Bone Marrow Morphology

Bone marrow morphology interpretation requires a systematic, multi-step approach that integrates peripheral blood examination, bone marrow aspirate analysis, core biopsy evaluation, and ancillary studies including immunohistochemistry, cytogenetics, and flow cytometry.

Essential Components of Bone Marrow Morphological Assessment

1. Peripheral Blood Film Examination

Start by counting at least 100 cells on the peripheral blood smear 1:

• Enumerate dysplastic features in granulocytes (hypolobation, hypogranulation, pseudo-Pelger-Huët anomaly)
• Count blasts if present
• Look for circulating abnormal cells

2. Bone Marrow Aspirate Analysis

Perform a 500-cell differential count whenever possible 1:

Assess dysplasia across all three lineages:

• Erythroid lineage: Nuclear budding, multinuclearity, megaloblastic changes, ring sideroblasts (requires iron stain)
• Granulocytic lineage: Hypogranulation, nuclear hypolobation, abnormal chromatin clumping
• Megakaryocytic lineage: Hypolobated or separated nuclei, micromegakaryocytes, giant forms

Count blast percentage - this is critical for distinguishing normal marrow from myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML):

• Normal: <5% blasts
• MDS: typically <20% blasts (varies by subtype)
• AML: ≥20% blasts 2

3. Bone Marrow Core Biopsy Evaluation

Assess cellularity using age-adjusted reference ranges 3:

• Ages 20-40 years: 40-70% (mean 55%)
• Ages 40-60 years: 35-65% (mean 50%)
• Ages >60 years: 30-60% (mean 45%)

Key architectural features to identify:

ALIP (Abnormally Localized Immature Precursors) 1:

• Look for clusters (3-5 immature cells) or aggregates (>5 immature cells) of blasts in abnormal central marrow locations
• Presence of ≥3 such clusters indicates ALIP-positive status
• ALIP suggests aggressive MDS and poor prognosis

Megakaryocyte morphology and distribution 4, 5:

• Normal: scattered distribution, mature lobulated nuclei
• Abnormal: clustering, hypolobation, naked nuclei, size variations (dwarf or giant forms)
• These features help distinguish myeloproliferative neoplasms from reactive conditions

Fibrosis assessment 1:

• Perform reticulin stain routinely
• Grade fibrosis (0-3 scale)
• Increased fibrosis favors MDS over aplastic anemia

4. Immunohistochemistry on Core Biopsy

CD34 staining is essential for blast identification 1:

• Highlights immature precursors that may be difficult to identify on H&E
• Helps identify ALIP
• Quantifies blast percentage in hypocellular specimens

Additional useful markers 1:

• CD117: immature myeloid cells
• Myeloperoxidase: granulocytic differentiation
• CD68/Lysozyme: monocytic lineage

5. Ancillary Studies

Cytogenetics/FISH 1:

• Standard karyotyping is critical
• In hypocellular marrows with cytogenetic failure, use peripheral blood FISH
• MDS-defining abnormalities (del 5q, -7, +8) can establish diagnosis even without morphologic dysplasia 2

Flow cytometry 1:

• Use comprehensive panels (myeloid, monocytic, lymphoid markers)
• Identifies blast percentage and immunophenotypic aberrancies
• Caveat: Results may be affected by hemodilution in hypocellular/fibrotic marrows

PNH screening 1:

• Use sensitive flow cytometry or molecular techniques
• Important in differential diagnosis of hypocellular marrows

Critical Diagnostic Pitfalls to Avoid

In hypocellular marrows (<20% cellularity) 1:

• Aspirate smears are often paucicellular and unreliable
• Core biopsy becomes the primary diagnostic tool
• Distinguishing hypocellular MDS/AML from aplastic anemia requires:
  • Identification of dysplasia (though may be minimal)
  • Detection of ALIP on CD34 staining
  • Cytogenetic abnormalities
  • Presence of easily identifiable megakaryocytes in disorganized architecture

Post-therapy changes 6:

• Chemotherapy induces reactive morphologic changes that can mimic dysplasia
• Targeted therapies (tyrosine kinase inhibitors, immunomodulators) cause drug-specific morphologic alterations
• Always correlate with treatment history to avoid misdiagnosis

Age-related changes 7, 3:

• Normal cellularity decreases approximately 3% per decade in adults
• Red-to-yellow marrow conversion is age-dependent and predictable
• Use age-adjusted reference ranges, not the outdated "100 minus age" formula

Systematic Diagnostic Algorithm

1. Start with peripheral blood → identify cytopenias, dysplasia, blasts
2. Perform 500-cell aspirate differential → quantify dysplasia and blasts in each lineage
3. Evaluate core biopsy → assess cellularity, architecture, ALIP, fibrosis
4. Apply CD34 immunohistochemistry → confirm blast percentage and identify ALIP
5. Integrate cytogenetics → identify clonal abnormalities
6. Use flow cytometry → detect immunophenotypic aberrancies
7. Synthesize all findings → make final diagnosis using WHO classification criteria 2

For cases with unilineage dysplasia and no cytogenetic abnormalities, defer diagnosis for 6-month observation period if blast count is normal 2.