How to diagnose and differentiate a bone marrow tumor?

Differentiation of Bone Marrow Tumors

Accurate diagnosis and differentiation of bone marrow tumors requires a systematic approach combining bone marrow aspiration and biopsy with specialized laboratory and imaging studies. The definitive diagnosis depends on comprehensive morphological, immunophenotypic, cytogenetic, and molecular analyses.

Initial Diagnostic Approach

Bone Marrow Sampling

• Both bone marrow aspiration AND biopsy should be performed simultaneously as they provide complementary information 1:
  • Aspiration: Evaluates individual cell morphology and enables flow cytometry
  • Biopsy: Assesses marrow architecture, cellularity, and fibrosis

Site Selection

• Posterior iliac crest is the preferred site (safest with fewest complications)
• Sternal aspiration carries risk of cardiac tamponade and should be avoided 1, 2
• CT or fluoroscopic guidance may improve safety and accuracy in difficult cases 3

Specific Diagnostic Tests for Major Bone Marrow Tumors

Multiple Myeloma

1. Serum studies 4:

   • Serum protein electrophoresis (SPEP)
   • Serum immunofixation electrophoresis (SIFE)
   • Quantitative immunoglobulin levels (IgG, IgA, IgM)
   • Serum free light chain (FLC) assay

2. Urine studies 4:

   • 24-hour urine for total protein
   • Urine protein electrophoresis (UPEP)
   • Urine immunofixation electrophoresis (UIFE)

3. Bone marrow examination 4, 1:

   • ≥10% clonal plasma cells required for diagnosis
   • Assess for abnormal plasma cell morphology
   • Flow cytometry to confirm clonality (CD138+, CD38+, light chain restriction)

4. Imaging 4:

   • Full skeletal radiographic survey for lytic bone lesions
   • Consider advanced imaging (MRI, PET/CT) for better sensitivity

5. Cytogenetics/FISH 4:

   • t(4;14), t(14;16), t(11;14)
   • 17p13 deletion (p53)
   • Chromosome 13 deletion
   • Chromosome 1 amplification

Ewing Sarcoma

1. Imaging 4:

   • Plain radiographs in two planes
   • CT/MRI of entire involved bone
   • Chest CT to rule out lung metastases
   • 99mTc bone scintigraphy for osseous metastases
   • Consider PET scanning

2. Bone marrow examination 4:

   • Small blue round-cell tumor appearance
   • PAS-positive and CD99 (MIC2)-positive
   • Bone marrow aspirates and biopsies from sites distant from primary tumor

3. Molecular/genetic testing 4:

   • EWS gene rearrangement on chromosome 22
   • Most common: t(11;22)(q24;q12)
   • Other variants: t(21;22)(q22;q12), t(7;22), t(17;22), t(2;22)

4. Additional markers 4:

   • Serum LDH levels (prognostic)
   • Tumor size/volume assessment

Acute Lymphoblastic Leukemia (ALL)

1. Morphology 4:

   • Bone marrow aspirate showing lymphoblasts
   • TdT expression (except mature B-ALL)

2. Immunophenotyping 4:

   • B-lineage ALL (75-80% of cases):
     • CD19, CD22, cytoplasmic CD79a
     • Further classification: pro-B, common, pre-B, mature B-ALL
   • T-lineage ALL (20-25% of cases):
     • Cytoplasmic CD3, surface CD7
     • Further classification: pro-T, pre-T, cortical, mature T-ALL
     • ETP-ALL: weak CD5, myeloid/stem cell markers

3. Molecular genetics 4:

   • B-ALL: t(9;22), t(4;11)/KMT2A, t(1;19)/TCF3::PBX1
   • T-ALL: LMO2/HOXA aberrations

Differential Diagnostic Algorithm

1. Assess cell lineage by immunophenotyping:

   • Myeloid markers (MPO, CD13, CD33)
   • B-lymphoid markers (CD19, CD20, CD79a)
   • T-lymphoid markers (CD3, CD7)
   • Plasma cell markers (CD138, CD38)

2. Evaluate morphology:

   • Small round blue cells: Consider Ewing sarcoma, lymphoma, ALL
   • Plasma cells: Consider multiple myeloma, plasmacytoma
   • Blasts: Consider leukemia (ALL, AML)

3. Apply molecular/cytogenetic testing based on suspected diagnosis:

   • Multiple myeloma: FISH for specific translocations
   • Ewing sarcoma: FISH for EWS gene rearrangements
   • ALL: Comprehensive cytogenetic and molecular panel

Common Pitfalls to Avoid

1. Inadequate sampling:

   • Ensure sufficient material for all required tests
   • Consider repeating biopsy if initial sample is inadequate 5

2. Relying solely on aspiration:

   • Some conditions (fibrotic marrow, packed marrow) may result in "dry tap"
   • Always perform both aspiration AND biopsy 1, 5

3. Failure to correlate with clinical data:

   • Integrate laboratory findings with clinical presentation
   • Consider serum LDH, calcium, and other markers 4

4. Missing rare variants:

   • Non-secretory myeloma (3% of cases) lacks serum/urine M-protein 4
   • Unusual immunophenotypes may require expanded panels

5. Inadequate molecular testing:

   • Fresh tissue should be collected for molecular studies
   • Consider biobanking for future testing 4

By following this systematic approach and utilizing the complementary nature of various diagnostic modalities, clinicians can accurately differentiate bone marrow tumors and guide appropriate treatment decisions to optimize patient outcomes.