What are the most likely diagnoses for a patient with symptoms and abnormal bone marrow biopsy results?

Differential Diagnosis for Abnormal Bone Marrow Biopsy

I cannot provide a ranked differential diagnosis without seeing the actual bone marrow biopsy raw data you mentioned. However, I can provide you with a systematic framework for interpreting bone marrow findings based on the most common hematologic disorders.

Key Diagnostic Features to Evaluate

When reviewing bone marrow biopsy results, the following parameters are critical for establishing a diagnosis:

Cellularity Assessment

• Age-corrected cellularity is essential—failure to correct for age leads to overdiagnosis of hypocellular conditions 1
• Hypercellular marrow suggests myeloproliferative neoplasms (MPNs) or myelodysplastic syndromes (MDS) 2
• Hypocellular marrow requires differentiation between aplastic anemia, hypocellular MDS, and hypocellular acute myeloid leukemia (AML) 1

Blast Percentage

• CD34 immunohistochemistry is particularly valuable for identifying blasts in hypocellular or fibrotic specimens where morphologic assessment alone may be inadequate 1
• Blast percentage <1% suggests aplastic anemia versus ≥5% in MDS (or 2-4% in peripheral blood with other MDS features for RAEB-1) 1
• Blasts ≥20% define acute leukemia 2
• The College of American Pathologists recommends performing a 500-cell differential count to ensure reliable blast percentage determination 1

Lineage Dysplasia

• ≥10% dysplastic cells in one or more myeloid lineages is required to qualify as significant dysplasia 2
• Erythroid dysplasia includes binuclearity, internuclear bridging, irregular nuclear edges, and megaloblastoid changes 2
• Granulocytic dysplasia shows nuclear hypolobation (pseudo Pelger-Huët), hypogranulation, and bizarre nuclear shapes 2
• Megakaryocytic dysplasia demonstrates large monolobular forms, small binucleated elements, and micromegakaryocytes 2

Megakaryocyte Morphology

• Polycythemia vera (PV): Pleomorphic, mature megakaryocytes with differences in size, showing trilineage growth (panmyelosis) 2
• Essential thrombocythemia (ET): Increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei 2
• Primary myelofibrosis: Abnormal clustering and atypia of megakaryocytes 2
• Easily identifiable megakaryocytes within architecturally disorganized marrow favor MDS over aplastic anemia 1

Reticulin Fibrosis Grading

• MF-0: Scattered linear reticulin with no intersections (normal) 2
• MF-1: Loose network of reticulin with many intersections, especially perivascular 2
• MF-2: Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of collagen 2
• MF-3: Diffuse and dense increase with coarse bundles of collagen, usually with osteosclerosis 2
• In grades MF-2 or MF-3, an additional trichrome stain is recommended 2

Cytogenetic Abnormalities

• Chromosomal abnormalities are observed in 50-60% of MDS patients 2
• Most frequent MDS abnormalities: del(5q) (10-15%), -7 or del(7q) (10%), trisomy 8, del(20q) 2
• At least 20 metaphases should be analyzed whenever possible 2
• Selected recurrent abnormalities provide presumptive evidence of MDS even without definitive morphologic features 2

Molecular Markers

• JAK2 V617F mutation is present in >95% of PV cases and ~64% of ET cases 2, 3, 4
• CALR mutations occur in ~23% of ET and are associated with increased risk of myelofibrosis transformation 2, 4, 5
• MPL mutations occur in ~4% of ET and are associated with increased risk of myelofibrosis transformation 2, 4, 5
• Approximately 90% of ET patients express mutually exclusive JAK2, CALR, or MPL driver mutations 4, 5, 6
• Spliceosome mutations (SF3B1, SRSF2, U2AF1) are associated with inferior overall and myelofibrosis-free survival 2, 5

Most Common Diagnostic Considerations

1. Myeloproliferative Neoplasms (MPNs)

Polycythemia Vera (PV)

• Requires either all 3 major criteria OR the first 2 major criteria plus the minor criterion 2, 3
• Major criteria: Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women (or hematocrit >49% in men, >48% in women); bone marrow hypercellularity with trilineage growth including pleomorphic mature megakaryocytes; presence of JAK2 V617F or JAK2 exon 12 mutation 2, 3
• Minor criterion: Subnormal serum erythropoietin level (specificity >90%) 2, 3

Essential Thrombocythemia (ET)

• Requires all 4 major criteria OR the first 3 major criteria plus the minor criterion 2
• Major criteria: Platelet count ≥450 × 10⁹/L; bone marrow showing proliferation mainly of megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei; not meeting WHO criteria for other myeloid neoplasms; presence of JAK2, CALR, or MPL mutation 2, 4
• Minor criterion: Presence of clonal marker or absence of evidence for reactive thrombocytosis 2
• Critical distinction: Must exclude prefibrotic myelofibrosis, which is the most important differential 5, 6

Primary Myelofibrosis

• Characterized by megakaryocyte atypia and clustering, reticulin/collagen fibrosis, and leukoerythroblastosis 2
• Grading based on WHO myelofibrosis criteria (MF-0 through MF-3) 2

2. Myelodysplastic Syndromes (MDS)

Diagnostic Requirements

• Dysplasia in ≥10% of cells in one or more myeloid lineages 2
• Blast percentage determines subtype: <5% (RCUD, RCMD, RARS), 5-9% (RAEB-1), 10-19% (RAEB-2) 2
• Cytogenetic abnormalities provide presumptive evidence even with <10% dysplasia 2

Key Subtypes

• Refractory cytopenia with unilineage dysplasia (RCUD): Unicytopenia or bicytopenia, unilineage dysplasia ≥10%, <5% blasts 2
• Refractory anemia with ring sideroblasts (RARS): Anemia, ≥15% ring sideroblasts, erythroid dysplasia only 2
• Refractory cytopenia with multilineage dysplasia (RCMD): Cytopenias, dysplasia in ≥10% of cells in two or more lineages 2
• Refractory anemia with excess blasts (RAEB-1/2): RAEB-1 has 5-9% blasts, RAEB-2 has 10-19% blasts 2

Aggressive Features

• Abnormal blast aggregates or clusters (ALIP) that are CD34-positive are associated with poor prognosis and increased progression to acute leukemia 1

3. Plasma Cell Disorders

Multiple Myeloma

• Requires ≥10% clonal bone marrow plasma cells AND presence of end-organ damage (CRAB criteria) 2
• CRAB criteria: Hypercalcemia (≥11.5 mg/dL), renal insufficiency (creatinine >2 mg/dL), anemia (hemoglobin <10 g/dL or >2 g/dL below normal), bone lesions (lytic lesions or severe osteopenia) 2

Smoldering Multiple Myeloma (SMM)

• Serum M-protein ≥3 g/dL and/or bone marrow clonal plasma cells ≥10% 2
• Absence of end-organ damage attributable to plasma cell disorder 2
• Median time to progression is 2-3 years 2

MGUS (Monoclonal Gammopathy of Undetermined Significance)

• M-protein <3 g/dL, <10% bone marrow plasma cells, absence of end-organ damage 2

4. Aplastic Anemia

Distinguishing Features

• Hypocellular marrow with blast percentage <1% 1
• Absence of easily identifiable megakaryocytes, architectural disorganization, and reticulin fibrosis (which would favor MDS) 1
• No clonal cytogenetic abnormalities 2

5. Acute Myeloid Leukemia (AML)

Diagnostic Threshold

• ≥20% blasts in bone marrow or peripheral blood 2
• CD34 immunohistochemistry correlates well with flow cytometry for blast quantification 1

Common Pitfalls to Avoid

• Do not dismiss low blast counts in the setting of significant dysplasia and cytogenetic abnormalities, as this may represent MDS 2
• Do not overlook age-corrected cellularity, as this leads to diagnostic errors 1
• Do not diagnose ET without excluding prefibrotic myelofibrosis, as bone marrow morphology is critical for this distinction 5, 6
• Do not attribute laboratory abnormalities to plasma cell disorders without excluding concomitant diseases common in elderly patients (diabetes, hypertension, vitamin deficiencies, myelodysplastic syndrome) 2
• Do not rely solely on morphology in hypocellular or fibrotic specimens—CD34 immunohistochemistry is essential 1

Next Steps for Definitive Diagnosis

Essential Laboratory Tests

• Complete blood count with differential, peripheral blood smear review 2
• Serum erythropoietin level (for suspected PV) 2, 3
• JAK2 V617F, CALR, and MPL mutation testing (for suspected MPNs) 2, 4, 5
• Cytogenetic analysis with at least 20 metaphases 2
• Flow cytometry for blast immunophenotyping and dysplasia assessment 2
• Serum protein electrophoresis, immunofixation, free light chains (for suspected plasma cell disorders) 2

To provide you with a specific ranked differential diagnosis, please share the bone marrow biopsy findings including cellularity, blast percentage, dysplasia assessment, megakaryocyte morphology, reticulin grade, and any available cytogenetic or molecular results.