Introduction
Burkitt lymphoma (BL) is a highly aggressive form of non-Hodgkin lymphoma, characterized by its rapid proliferation rate and unique clinical and pathological features. While a definitive diagnosis of Burkitt lymphoma relies on a combination of morphology, immunophenotype, and genetic findings, establishing an accurate differential diagnosis is crucial for effective patient management. This is especially important due to the aggressive nature of BL, which necessitates prompt and intensive treatment. This article provides an in-depth exploration of the differential diagnosis of Burkitt lymphoma, contrasting it with other entities that may present with overlapping features. Understanding these distinctions is paramount for clinicians to ensure timely and appropriate therapeutic strategies are implemented, ultimately impacting patient outcomes.
Etiology and Pathophysiology of Burkitt Lymphoma: Key Considerations for Differential Diagnosis
While not directly part of the differential diagnosis itself, understanding the underlying etiology and pathophysiology of Burkitt lymphoma aids in appreciating its unique characteristics and how it differs from similar lymphomas. Burkitt lymphoma is strongly associated with specific factors including Epstein-Barr virus (EBV) infection, particularly in endemic forms, human immunodeficiency virus (HIV) in immunodeficiency-related cases, and characteristic chromosomal translocations involving the MYC gene.
The hallmark genetic event in Burkitt lymphoma is the translocation of the c-MYC gene on chromosome 8, most commonly the t(8;14)(q24;q32) translocation, juxtaposing MYC with the immunoglobulin heavy chain (IgH) locus. This translocation results in the overexpression of the MYC protein, a transcription factor that drives cell cycle progression and proliferation. While MYC translocation is highly characteristic of Burkitt lymphoma, it is not entirely specific and can be found in other high-grade B-cell lymphomas, complicating the differential diagnosis.
The rapid proliferation of Burkitt lymphoma cells is a critical pathophysiological feature. This high proliferation rate contributes to its aggressive clinical presentation, including rapid tumor growth, elevated lactate dehydrogenase (LDH) levels, and the risk of tumor lysis syndrome. Histopathologically, this is reflected in a high mitotic index and a Ki-67 proliferation fraction approaching 100%.
Understanding these etiological and pathophysiological underpinnings helps frame the differential diagnosis by highlighting the features that are highly suggestive of Burkitt lymphoma (e.g., rapid growth, high proliferation index, MYC translocation) and those that, while present, are not exclusive to it.
Core Differential Diagnoses for Burkitt Lymphoma
The primary differential diagnoses for Burkitt lymphoma include other aggressive CD10-positive B-cell lymphomas. These entities share some clinical and morphological features with Burkitt lymphoma, necessitating careful distinction. The main entities to consider in the differential diagnosis are:
1. Diffuse Large B-cell Lymphoma (DLBCL)
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and represents a significant diagnostic challenge in differentiating it from Burkitt lymphoma. Both can present as aggressive lymphomas with rapid growth and similar clinical presentations. However, crucial distinctions exist in morphology, immunophenotype, and genetic characteristics.
Morphological Differences: DLBCL cells are typically larger than Burkitt lymphoma cells and exhibit greater pleomorphism. While Burkitt lymphoma cells are described as intermediate-sized and monomorphic, DLBCL cells show more variation in size and shape. The chromatin in DLBCL can be more vesicular, and nucleoli can be more prominent and multiple compared to the typically single to few small nucleoli in Burkitt lymphoma. While the “starry sky” appearance due to tingible body macrophages can be seen in both, it is classically more pronounced in Burkitt lymphoma due to its even higher cell turnover rate.
Immunophenotypic Differences: Immunohistochemistry is vital in distinguishing DLBCL from Burkitt lymphoma. Both are typically CD19+, CD20+, CD10+, and BCL6+. However, BCL2 expression is a critical differentiating marker. Burkitt lymphoma is characteristically BCL2-negative, while DLBCL is frequently BCL2-positive. A high Ki-67 proliferation index is seen in both, but a Ki-67 nearing 100% is more typical of Burkitt lymphoma. While some DLBCL can have a high Ki-67, it is less consistently at the extreme levels seen in Burkitt lymphoma. Expression of MUM1/IRF4 is more commonly seen in DLBCL and typically negative in Burkitt lymphoma.
Genetic Differences: MYC translocations are present in Burkitt lymphoma in the vast majority of cases (approximately 95%). While MYC translocations can also occur in DLBCL, they are less frequent, occurring in approximately 10% of cases, particularly in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double/triple-hit lymphomas). The presence of a MYC translocation alone is not entirely specific for Burkitt lymphoma. However, the context of morphology and immunophenotype is crucial. Furthermore, DLBCL often harbors other genetic aberrations not typically seen in classic Burkitt lymphoma, such as BCL2 and BCL6 rearrangements in double-hit lymphomas.
Clinical Differences: While both present aggressively, the clinical context can sometimes offer clues. Endemic Burkitt lymphoma often presents with jaw involvement, which is less common in DLBCL. However, sporadic Burkitt lymphoma and DLBCL can have overlapping clinical presentations, often involving extranodal sites.
Key Differentiating Features: DLBCL vs. Burkitt Lymphoma
| Feature | Burkitt Lymphoma | Diffuse Large B-cell Lymphoma (DLBCL) |
|---|---|---|
| Cell Size | Intermediate-sized | Large |
| Pleomorphism | Monomorphic | Pleomorphic |
| Chromatin | Lacy | Vesicular |
| Nucleoli | Small, 1-few | Prominent, multiple |
| BCL2 | Negative | Frequently Positive |
| Ki-67 | Near 100% | High, but less consistently near 100% |
| MUM1/IRF4 | Negative | Frequently Positive |
| MYC Translocation | ~95% | ~10% (more common in double/triple-hit) |
| BCL2 Rearrangement | Rare | More frequent (especially double-hit) |
2. High-Grade Follicular Lymphoma
High-grade follicular lymphoma (FL grade 3B) can also enter the differential diagnosis of Burkitt lymphoma, particularly as it can present with a high proliferation rate and CD10 positivity.
Morphological Differences: High-grade follicular lymphoma, specifically grade 3B, exhibits a predominantly diffuse growth pattern and lacks the characteristic centrocytes seen in lower-grade follicular lymphoma. However, careful examination may reveal remnants of follicular architecture. The cells are typically large and can have cleaved or non-cleaved nuclei. While the cell size can overlap with DLBCL, and sometimes Burkitt lymphoma, the overall morphology and growth pattern differ from the monotonous sheets of cells seen in Burkitt lymphoma.
Immunophenotypic Differences: Like Burkitt lymphoma, high-grade follicular lymphoma is CD10-positive and BCL6-positive. However, follicular lymphoma, including high-grade variants, is typically BCL2-positive, which is a key distinction from Burkitt lymphoma. The Ki-67 proliferation index is high in grade 3B follicular lymphoma, but generally not as consistently close to 100% as in Burkitt lymphoma. Expression of markers like IRF4/MUM1 is generally less common in follicular lymphoma compared to DLBCL.
Genetic Differences: Follicular lymphoma is characterized by the t(14;18)(q32;q21) translocation involving BCL2 and IgH, leading to BCL2 overexpression. This translocation is not seen in Burkitt lymphoma. While MYC translocations can occur in high-grade follicular lymphoma, they are less common than in Burkitt lymphoma and often occur in the context of progression from lower-grade follicular lymphoma.
Clinical Differences: Follicular lymphoma, even high-grade, often has a less fulminant clinical course compared to Burkitt lymphoma. While aggressive, the pace of progression might be slightly slower than Burkitt lymphoma in some cases. Clinical history of prior low-grade follicular lymphoma favors high-grade transformation of follicular lymphoma.
Key Differentiating Features: High-Grade Follicular Lymphoma vs. Burkitt Lymphoma
| Feature | Burkitt Lymphoma | High-Grade Follicular Lymphoma (Grade 3B) |
|---|---|---|
| Growth Pattern | Diffuse sheets | Predominantly Diffuse (may have follicular remnants) |
| BCL2 | Negative | Typically Positive |
| BCL2 Translocation | Absent | Typically Present (t(14;18)) |
| MYC Translocation | ~95% | Less common |
| Clinical Course | Highly Aggressive | Aggressive, but potentially less fulminant than BL |
3. B-cell Acute Lymphoblastic Leukemia/Lymphoma (B-ALL)
B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) can be morphologically similar to Burkitt lymphoma, especially in cases presenting as lymphoma with bone marrow involvement.
Morphological Differences: B-ALL lymphoblasts are typically small to intermediate in size and can resemble Burkitt lymphoma cells. However, the chromatin in B-ALL is often described as finer or more condensed (“blastic” chromatin) compared to the lacy chromatin of Burkitt lymphoma. Nucleoli may be less prominent in B-ALL. Cytoplasm in B-ALL is typically scant and less basophilic than in Burkitt lymphoma. The “starry sky” appearance is less prominent or absent in B-ALL.
Immunophenotypic Differences: Immunophenotyping is crucial for distinguishing B-ALL from Burkitt lymphoma. B-ALL lymphoblasts express markers of immaturity, such as terminal deoxynucleotidyl transferase (TdT) and CD34, which are characteristically negative in Burkitt lymphoma. While both can be CD10-positive, the constellation of markers is different. B-ALL typically expresses CD19, CD20 (often weaker), CD10, CD34, and TdT, while Burkitt lymphoma is CD19+, CD20+, CD10+, BCL6+, and TdT- and CD34-. BCL2 can be positive in B-ALL.
Genetic Differences: While MYC translocations are characteristic of Burkitt lymphoma, they are not typical of B-ALL. B-ALL is associated with a different spectrum of genetic abnormalities, including translocations involving BCR-ABL1, MLL rearrangements, and hyperdiploidy.
Clinical Differences: The clinical presentation can be very helpful. B-ALL often presents with significant bone marrow involvement (by definition, leukemia if >25% blasts in marrow), peripheral blood involvement, and systemic symptoms related to bone marrow failure. While Burkitt lymphoma can involve the bone marrow, it is less frequently the predominant presentation, and a purely leukemic presentation is rare. Central nervous system involvement can be seen in both.
Key Differentiating Features: B-ALL vs. Burkitt Lymphoma
| Feature | Burkitt Lymphoma | B-cell Acute Lymphoblastic Leukemia/Lymphoma (B-ALL) |
|---|---|---|
| Chromatin | Lacy | Finer, Condensed (“Blastic”) |
| Cytoplasm | Basophilic, Vacuolated | Scant, Less Basophilic |
| TdT | Negative | Typically Positive |
| CD34 | Negative | Typically Positive |
| Bone Marrow | Involvement less common as primary | Frequent involvement, often primary |
| Peripheral Blood | Typically not involved | May have circulating blasts |
| MYC Translocation | ~95% | Uncommon |
4. Burkitt-like Lymphoma with 11q Aberration
“Burkitt-like lymphoma with 11q aberration” is a recently described entity that morphologically resembles Burkitt lymphoma but lacks the typical MYC translocation. This entity is important to consider in the differential diagnosis, especially in cases with Burkitt-like morphology that are MYC-negative by FISH or cytogenetics.
Morphological Differences: Morphologically, these lymphomas are very similar to classic Burkitt lymphoma, exhibiting intermediate-sized cells, lacy chromatin, and high proliferation rates.
Immunophenotypic Differences: Immunophenotypically, they are also very similar to Burkitt lymphoma, typically CD19+, CD20+, CD10+, BCL6+, BCL2-negative, and high Ki-67.
Genetic Differences: The defining feature is the lack of MYC translocation and the presence of aberrations involving chromosome 11q. These aberrations are heterogeneous but often involve gains or amplifications of the 11q region. The genes targeted by these 11q aberrations are still being fully characterized, but they are thought to play a role in driving lymphomagenesis in a manner similar to MYC overexpression in classic Burkitt lymphoma.
Clinical Differences: Clinically, Burkitt-like lymphoma with 11q aberration presents aggressively, similar to classic Burkitt lymphoma. The prognosis appears to be similar to that of classic Burkitt lymphoma, although more data is still being gathered on this relatively newly recognized entity.
Key Differentiating Features: Burkitt-like Lymphoma with 11q Aberration vs. Classic Burkitt Lymphoma
| Feature | Classic Burkitt Lymphoma | Burkitt-like Lymphoma with 11q Aberration |
|---|---|---|
| MYC Translocation | Typically Present (~95%) | Absent |
| 11q Aberration | Absent | Typically Present |
| Morphology | Burkitt-like | Burkitt-like |
| Immunophenotype | Burkitt-like | Burkitt-like |
| Prognosis | Aggressive, similar to 11q type | Aggressive, similar to classic BL |
Diagnostic Approach to Differential Diagnosis
Establishing the correct diagnosis in cases suspected of Burkitt lymphoma requires a multi-faceted approach:
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Histopathological Evaluation: Careful morphological assessment of the lymphoma cells on hematoxylin and eosin (H&E) stained slides, evaluating cell size, shape, chromatin, nucleoli, cytoplasm, and growth pattern. Assessment of the “starry sky” appearance and mitotic index.
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Immunohistochemistry: A comprehensive panel of immunohistochemical stains is crucial. This should include:
- B-cell markers: CD19, CD20, CD79a, PAX5
- Germinal center markers: CD10, BCL6
- Differentiation markers: BCL2, MUM1/IRF4
- Proliferation marker: Ki-67
- Markers to exclude other entities: TdT, CD34, and potentially others depending on the differential (e.g., Cyclin D1 to exclude mantle cell lymphoma if morphology is less typical).
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Cytogenetic and Molecular Studies:
- FISH for MYC translocation: Essential to detect the hallmark MYC translocation.
- Cytogenetics (karyotyping): Can detect MYC translocations and other chromosomal abnormalities, including complex karyotypes.
- Molecular genetic studies (NGS): Next-generation sequencing can identify mutations and copy number alterations, including those in MYC, BCL2, BCL6, and other genes, and can be helpful in complex cases or to identify Burkitt-like lymphoma with 11q aberrations or other atypical variants.
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Clinical Correlation: Integrate clinical information, including patient age, clinical presentation (e.g., site of involvement, rapidity of growth, presence of B symptoms), EBV and HIV status, and LDH levels, to refine the differential diagnosis.
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Flow Cytometry: Useful, especially when dealing with fluid samples (pleural effusion, ascites, CSF) or for rapid assessment of fresh tissue. Can help assess cell size, immunophenotype, and proliferation markers.
Conclusion
The differential diagnosis of Burkitt lymphoma encompasses several aggressive B-cell lymphomas that share overlapping features. Accurate differentiation relies on a combination of careful morphological assessment, comprehensive immunohistochemical analysis, and cytogenetic/molecular studies, integrated with clinical context. Distinguishing Burkitt lymphoma from DLBCL, high-grade follicular lymphoma, B-ALL, and Burkitt-like lymphoma with 11q aberration is critical for guiding appropriate therapy and ultimately improving patient outcomes in this highly aggressive lymphoma. A multidisciplinary approach involving pathologists, hematologists, and oncologists is essential to navigate the diagnostic complexities and ensure optimal management of patients with suspected Burkitt lymphoma.
Figure 1: Burkitt Lymphoma Morphology.
Microscopic view of Burkitt lymphoma lymphoblasts showing high proliferation and “starry sky” appearance, crucial features in distinguishing it from other lymphomas.
Figure 2: Burkitt Lymphoma Histopathology.
Histopathology of Burkitt Lymphoma demonstrating sheets of intermediate-sized lymphocytes, highlighting the cellular uniformity that aids in differential diagnosis.
References
[References from original article – same as provided before]
Disclosure: Brittney Graham declares no relevant financial relationships with ineligible companies.
Disclosure: David Lynch declares no relevant financial relationships with ineligible companies.
