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The diagnostic gray zone between Burkitt lymphoma and diffuse large B-cell lymphoma is also a gray zone of the mutational spectrum

Leukemia volume 29, pages 1789–1791 (2015)Cite this article

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The current WHO classification recognizes the existence of aggressive B-cell lymphomas that share morphological, immunophenotypic and gene expression profile-based features intermediate between Burkitt lymphomas (BLs) and diffuse large B-cell lymphomas (DLBCLs) and created the provisional category of ‘B-cell lymphoma, unclassifiable, with features intermediate between BL and DLBCL (BCL-U)’.1 From a clinical perspective, however, the introduction of the diagnostic BCL-U category appears problematic, because current therapeutic concepts differ significantly between BL and DLBCL. Moreover, many patients with BCL-U have a dismal prognosis. Translocations of the MYC oncogene are common in BCL-U, usually in the context of a complex genetic background, and 35–50% of BCL-U lymphomas, next to MYC aberrations, harbor additional translocations involving BCL2 and/or BCL6. These cases are referred to as ‘double hit’/’triple hit’ (DH/TH) lymphomas. However, neither MYC translocations nor a ‘double hit’/triple hit’ genetic constellation are unifying genetic features of BCL-U, as ~10% of DLBCL carry MYC translocations or show DH/TH features as well.1 Nonetheless, according to current concepts, these B-cell non-Hodgkin lymphomas (B-NHLs) are categorized as DLBCL on the basis of their morphological features, although there is evidence that these genetic alterations may predict inferior outcome amongst DLBCL patients.2

The mutation frequency of ID3 and/or TCF3 (ID3/TCF3) was comparably high in BL and BCL-U (65% vs 67%). However, the rate of biallelic mutations in ID3 or a mutation in TCF3 was higher in BL (70%) than in BCL-U (37.5%; Supplementary Table 2, Supplementary Figure 3). The frequency of ID3 mutations was lower in the DL-DH/TH (22%) and DL-MYC (37%) subgroups, whereas only one DL (GCB) without a MYC rearrangement (3.5%) carried an ID3 mutation. Initial investigations suggested that ID3 mutations that occur in up to 65% of BL might constitute a discriminatory marker to distinguish between bona fide BLs and non-BLs.3, 4, 5 However, the recent report by Gebauer et al.12 already demonstrated the presence of ID3 mutations in 25% of BCL-U cases. In our study, the frequency of ID3 mutations even reached 67% in the BCL-U subgroup thus showing a similar frequency compared with the BL cohort (65%). We even detected ID3 mutations in some GCB DLBCL cases carrying MYC translocations. Of note, all BCL-U cases with MYC (‘single hit’) translocations carried concomitant ID3 mutations, albeit with a lower rate of biallelic mutations. The presence of additional mutations characteristic of DLBCL in many of these cases argues against the idea that these B-NHL might represent ‘true’ BLs. It must therefore be concluded that ID3 mutations do not exclusively occur in BL cases and that the presence or absence of this mutation is not helpful in discriminating BL from non-BL cases.

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Acknowledgements

We wish to thank Heike Brückner, Eva Bachmann and Tina Grieb for their excellent technical support. This study was supported by the German Ministry for Education and Science (BMBF) in the framework of the ICGC MMML-Seq (01KU1002A-J) Network and by the Robert-Bosch-Stiftung, Stuttgart, Germany.

Author Contributions

SM, GO and AR designed the research, prepared the figures and wrote the paper. SM, SW, TN, MR, AS and EB performed the experiments. SM, JP and AR analyzed and interpreted the data. AR, GO, MR, EG and SM reviewed and classified the cases.

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  1. G Ott and A Rosenwald: Co-senior authors.

Authors and Affiliations

  1. Institute of Pathology, University of Würzburg, Würzburg, Germany

    S Momose, S Weißbach, J Pischimarov, T Nedeva, M Rudelius, E Geissinger & A Rosenwald

  2. Comprehensive Cancer Center Mainfranken (CCC MF), Würzburg, Germany

    S Momose, S Weißbach, J Pischimarov, T Nedeva, M Rudelius, E Geissinger & A Rosenwald

  3. Department of Human Genetics, University of Würzburg, Würzburg, Germany

    E Bach

  4. Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

    A M Staiger & G Ott

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Correspondence to A Rosenwald.

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Momose, S., Weißbach, S., Pischimarov, J. et al. The diagnostic gray zone between Burkitt lymphoma and diffuse large B-cell lymphoma is also a gray zone of the mutational spectrum. Leukemia 29, 1789–1791 (2015). https://doi.org/10.1038/leu.2015.34

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