What is the most likely diagnosis given BCL2, MUM1, CMYC, and CD20 positivity with a high Ki-67 index: Burkitt lymphoma, DLBCL or high-grade B-cell NHL?

Diagnostic Classification: High-Grade B-Cell Lymphoma, Unclassifiable (Intermediate between DLBCL and Burkitt Lymphoma)

Based on the immunohistochemical profile showing BCL2 positivity, MUM1 positivity, CMYC positivity, CD20 positivity, and high Ki-67 index, this case most likely represents a high-grade B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (formerly called "double-hit" or "double-expressor" lymphoma), rather than classic Burkitt lymphoma or typical DLBCL. 1

Key Distinguishing Features from Burkitt Lymphoma

The immunophenotypic profile argues strongly against classic Burkitt lymphoma:

• BCL2 positivity excludes Burkitt lymphoma - Burkitt lymphoma is characteristically BCL2-negative, whereas this case shows BCL2 expression 1, 2
• MUM1/IRF4 positivity is atypical for Burkitt - MUM1 expression occurs in only 17% of Burkitt cases but in 63% of DLBCL and intermediate lymphomas 3, 2
• Ki-67 index matters critically - If the Ki-67 is below 95%, this strongly favors DLBCL or intermediate lymphoma over Burkitt, which typically shows ≥95% Ki-67 positivity 1, 3, 2

Why This is Likely Intermediate/Unclassifiable Rather Than Standard DLBCL

The combination of features suggests a more aggressive entity than typical DLBCL:

• CMYC positivity with BCL2 positivity creates a "double-expressor" or potentially "double-hit" phenotype that defines high-grade B-cell lymphoma 1, 3, 4
• This combination occurs in 7.9% of morphologic DLBCL cases and represents a distinct aggressive entity with worse prognosis than standard DLBCL 4
• The ESMO and NCCN guidelines specifically recommend classifying these cases as "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma" when this immunophenotype is present 1

Critical Next Steps for Definitive Classification

FISH testing for MYC, BCL2, and BCL6 rearrangements is mandatory to determine if this is a true "double-hit" or "triple-hit" lymphoma, which would definitively classify it as high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements 1, 4

• If FISH shows MYC rearrangement plus BCL2 rearrangement, this confirms high-grade B-cell lymphoma with double-hit (HGBL-DH) 3, 4
• If FISH shows MYC rearrangement alone with BCL2 protein overexpression (but no BCL2 rearrangement), this is classified as "double-expressor" DLBCL, which still carries poor prognosis 5, 6
• Double-hit lymphomas are confined primarily to germinal center B-cell-like (GCB) subtype (13.3% of GCB vs 1.7% of ABC), so cell-of-origin testing may provide additional context 4

Algorithmic Approach to This Case

1. Confirm B-cell lineage - CD20 positivity establishes this ✓ 1
2. Assess proliferation index - High Ki-67 suggests aggressive lymphoma ✓ 1, 2
3. Evaluate BCL2 expression - Positivity excludes classic Burkitt ✓ 1, 3, 2
4. Check MUM1/IRF4 - Positivity favors DLBCL/intermediate over Burkitt ✓ 3, 2
5. Order FISH for MYC, BCL2, BCL6 - Essential to distinguish double-hit from double-expressor 1, 4
6. Consider cell-of-origin testing (CD10, BCL6 pattern) - GCB phenotype is typical for these cases 4, 6

Clinical Implications and Treatment Considerations

This diagnosis has critical therapeutic implications because standard R-CHOP chemotherapy is inadequate:

• R-CHOP gives poor outcomes for double-hit lymphomas, with median overall survival of only 4.5 months in some series 5, 3
• More intensive Burkitt-type regimens (CODOX-M/IVAC or hyper-CVAD with rituximab) should be considered for younger, fit patients 5
• CNS prophylaxis with intrathecal therapy is mandatory given the high risk of CNS involvement (45% in double-hit cases) 5, 3
• These patients require treatment at specialized centers with expertise in aggressive lymphomas 7

Common Diagnostic Pitfalls to Avoid

• Do not rely on CD10 or BCL6 alone - These are expressed in 75-91% of both Burkitt and DLBCL/intermediate cases and cannot distinguish between them 2
• Do not diagnose Burkitt lymphoma if BCL2 is positive - This is the single most important exclusionary criterion 1, 3, 2
• Do not assume MYC positivity by IHC equals MYC rearrangement - FISH confirmation is required, as MYC protein overexpression without translocation has different implications 5, 6
• Do not delay FISH testing - The distinction between double-hit and double-expressor fundamentally changes treatment approach and prognosis 4, 6