Can Burkitt lymphoma be mistaken for pre‑B acute lymphoblastic leukemia in children and young adults?

Can Burkitt Lymphoma Be Mistaken for Pre-B ALL?

Yes, Burkitt lymphoma/leukemia can absolutely be mistaken for pre-B acute lymphoblastic leukemia, particularly when Burkitt presents with atypical immunophenotypic features or when pre-B ALL harbors IG-MYC rearrangements—this diagnostic confusion has critical treatment implications since these diseases require fundamentally different therapeutic approaches. 1

Key Distinguishing Features

Classic Immunophenotypic Differences

The most reliable way to differentiate these entities is through multicolor flow cytometry (at least 8 colors) combined with cytogenetics 1:

Burkitt lymphoma/leukemia typically shows:

• TdT negative (this is the single most important distinguishing feature) 1
• CD20 bright positive (86-100% of cases) 1
• Surface immunoglobulin positive with light chain restriction 1, 2
• CD10 positive 1
• Ki-67 approaching 100% 1, 3
• BCL2 negative, BCL6 positive 1

Pre-B ALL typically shows:

• TdT positive (expressed by all B-cell progenitors except mature B-ALL) 1
• CD20 dim or variable (only 30-50% of cases) 1
• Surface immunoglobulin negative 1, 2
• CD10 positive (common ALL) 1
• Cytoplasmic μ heavy chain positive 1

Critical Diagnostic Pitfalls

The diagnostic confusion arises in several scenarios:

1. Burkitt with atypical immunophenotype: Some Burkitt cases may show precursor-like features including TdT positivity, creating diagnostic uncertainty 2. When morphology shows FAB L3 blasts but immunophenotype is atypical, proceed immediately to cytogenetics for MYC rearrangement confirmation 2.

2. Pre-B ALL with IG-MYC rearrangement: Approximately 90 cases have been identified where immunophenotypically immature BCP-ALL carries IG-MYC rearrangement, mimicking Burkitt 4. These cases represent high-risk BCP-ALL with 3-year event-free survival of only 47% and overall survival of 60% 4.

3. Overlapping CD58 and proliferation markers: CD58 shows significantly higher expression in Burkitt compared to BCP-ALL, and Ki-67 levels are markedly elevated in Burkitt, reflecting aggressive proliferative potential 3.

Algorithmic Approach to Diagnosis

Step 1: Perform comprehensive immunophenotyping

• Check TdT status first—if negative, strongly favor Burkitt 1
• Assess CD20 intensity (bright vs. dim) 1, 2
• Evaluate surface immunoglobulin and light chain restriction 1, 2

Step 2: Obtain cytogenetics/FISH immediately

• Test for t(8;14) or MYC variants (diagnostic for Burkitt) 1
• Test for common ALL translocations: t(12;21)[ETV6::RUNX1], t(1;19)[TCF3::PBX1], t(9;22)[BCR::ABL1] 1
• Note: Cryptic t(12;21) can coexist with t(2;8) in rare cases 5

Step 3: If immunophenotype is equivocal

• Add CD58, Ki-67, and cell cycle analysis by flow cytometry 3
• Higher CD58 and Ki-67 approaching 100% favor Burkitt 3
• Check BCL2 (negative in Burkitt, may be positive in ALL) 1

Step 4: Molecular confirmation

• MYC rearrangement by FISH or cytogenetics is essential 1
• If IG-MYC rearrangement is found in TdT-positive disease, classify as high-risk BCP-ALL, not Burkitt 4
• DNA methylation profiling can definitively separate V(D)J-rearranged IG-MYC cases from true Burkitt 4

Treatment Implications

This distinction is absolutely critical because treatment differs fundamentally:

• Burkitt lymphoma/leukemia requires short-duration, high-intensity chemotherapy (CODOX-M, hyper-CVAD, or dose-adjusted EPOCH) plus rituximab, with complete remission possible in 75-90% of cases 1, 2

• Pre-B ALL requires prolonged ALL-directed therapy with different drug combinations and maintenance phases 1

• BCP-ALL with IG-MYC rearrangement should receive intensive ALL therapy adapted by minimal residual disease monitoring, not Burkitt-directed regimens 4. However, if there is poor response to ALL therapy in cases with IG-MYC fusion, therapy for mature B-cell lymphoma may be considered 1

Common Pitfalls to Avoid

Do not rely on morphology alone: FAB L3 morphology with vacuolization can occasionally be seen in pre-B ALL with atypical features 5, 2. Always confirm with immunophenotyping and cytogenetics 1.

Do not assume TdT-negative disease is always Burkitt: Rare cases of AML can also be TdT-negative, requiring additional myeloid markers for exclusion 1.

Do not delay cytogenetics: The WHO 2008 classification recognizes that it may not always be possible to distinguish between DLBCL and Burkitt lymphoma based on immunophenotype alone—aggressive therapy is appropriate in selected cases when distinction cannot be made 1.

Recognize that bone marrow involvement matters: Unlike precursor T-LBL, B-LBL rarely involves bone marrow, but when >25% blasts are present in marrow, the designation shifts to leukemia 1, 6.