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B. Gonzalez-Farre et al.
larly of the GCB subtype. Other genes frequently mutated in GCB-DLBCL but not in BL were GNA13 and TMEM30A associated with 6q14.1.14-16
We also compared our results with those of two recent studies on HGBCL (including double- and triple-hit lym- phomas).25,26 These cases also have recurrent mutations in histone modifier genes such as KMT2D, CREBBP and EZH2 (Online Supplementary Table S8). Intriguingly, HGBCL, NOS, mainly with MYC-translocations, shared mutations in genes frequently mutated in both BL and GC-DLBCL.25,26 All these observations suggest that BLL- 11q is a neoplasm closer to other GC-derived lymphomas rather than BL in which the 11q aberration together with other mutations may play a relevant role in their patho- genesis. While this manuscript was under revision, Wagener et al. published a mutational study of 15 BLL-11q cases. Similar to our findings, no mutations in ID3/TCF3 were identified and those cases carried frequent mutations in GC-DLBCL-associated genes such as GNA13, FOXO1 and EZH2. Intriguingly, that study did not find mutations in BTG2, KMT2D, KMT2C or CREBBP observed in our study.27 Collectively, these findings indicate that the genomic and mutational profiles of BLL-11q are different from those of BL and more similar to those of other GC- derived lymphomas.
In addition to the genetic differences, our BLL-11q cases differed clinically, morphologically and phenotypically from conventional BL and instead showed features more consistent with HGBCL or DLBCL. As in previous studies, all our patients were younger than 40 years, although occasional cases in older patients have been reported.4,5,27 Contrary to BL, most of our cases of BLL-11q presented with localized lymphadenopathy.4,5,27 These cases have a favorable outcome after therapy, although the optimal clinical management remains to be determined. Morphologically, our cases had a prominent “starry sky” pattern and high proliferation rate (>90%) but did not have the typical cytological features of BL since they were better classified as HGBCL with blastoid or intermediate features between HGBCL (8 cases) and DLBCL (2 cases) and only one had features of atypical BL. As previously reported,4 two of our cases displayed a follicular growth pattern, with an underlying meshwork of follicular den- dritic cells, raising the differential diagnosis with other pediatric lymphomas such as large B-cell lymphoma with IRF4 rearrangement.3 However, BLL-11q did not express IRF4/MUM1 and often exhibited a “starry sky” pattern with frequent mitotic figures, features that are not usual in large B-cell lymphoma with IRF4 rearrangement. We also identified different immunohistochemical stains that could help in the differential diagnosis from other lym- phomas entities. LMO2, a GC marker that is typically downregulated in BL and other lymphomas with MYC translocation,18 was detected in 46% of our BLL-11q cases. In addition, and contrary to BL, MYC expression with a diffuse and intense pattern was only detected in one of our cases while the other four positive cases either exhib- ited partial positivity or the intensity was weak contrary to the pattern seen in BL.
Negativity for MYC rearrangement is a crucial element for the recognition of these cases. The recommended technique for detecting MYC translocations in clinical practice is FISH analysis using break-apart probes, with the limitation that a subset of 4% of MYC-positive cases are not detected with this method but picked up using
MYC/IGH probes.28 The genetic feature that distinguishes BLL-11q is an alteration of the 11q arm that prototypically is characterized by an 11q23.2-q23.3 gain/amplification and 11q24.1-qter loss. Additionally, isolated cases have been recognized with single 11q24.1-qter terminal loss or 11q23 gain with 11q24-qter copy number neutral loss of heterozygosity.4,11 In our study we identified the presence of these 11q alterations using copy number arrays. We also confirmed the presence of 11q alterations by FISH analysis with a custom probe in all tested cases, suggesting that this approach may be useful in clinical practice to identify such cases (Online Supplementary Table S8). The specificity of this FISH approach was also confirmed by the fact that no false positive cases were observed in the 12 lymphoma cases in which the array showed a normal 11q pattern. Nevertheless, more studies on the clinical value of this probe are needed and, for the time being, confirmation of the finding by copy number array would be desirable. The specific 11q alteration observed in BLL- 11q should be distinguished from other 11q aberrations such as 11q gains of the 11q24 region that include ETS1 and FLI1, detected in DLBCL,29 or the 11q25 losses missing ETS1 and FLI1 described in some post-transplant lympho- proliferative disorders.30,31 On the other hand, although the 11q23 gain/11q24-qter loss of BLL-11q is mainly absent in other lymphoma entities, its detection should not be con- sidered as a unique feature to diagnose BLL-11q cases since some transformed follicular lymphomas may carry a similar 11q aberration pattern.22
In summary, BLL-11q is a GC-derived lymphoma with genomic and mutational profiles closer to those of HGBCL or GCB-DLBCL rather than BL in which the 11q aberration, together with other mutations, may play a rel- evant role in pathogenesis. These observations support a reconsideration of the “Burkitt-like” term for these tumors. Although, the most appropriate name is not easy to propose and requires broader discussion and consensus, we think that the term “aggressive B-cell lymphoma with 11q aberration” captures their pathological features. To identify these cases we suggest performing copy number arrays or FISH with the 11q probe in cases with BL, DLBCL, and HGBCL morphology, a GC phenotype and very high proliferative index (>90%), without MYC rearrangements, in young patients. The recognition of these tumors is clinically relevant because they have a favorable outcome after therapy, although further studies are needed to determine the optimal clinical management.
Funding
This work was supported by Asociación Española Contra el Cáncer (AECC CICPFI6025SALA), Fondo de Investigaciones Sanitarias Instituto de Salud Carlos III (Miguel Servet program CP13/00159 and PI15/00580, to IS), Spanish Ministerio de Economía y Competitividad, Grant SAF2015-64885-R (EC), Generalitat de Catalunya Suport Grups de Recerca (2017- SGR-1107 I.S. and 2017-SGR-1142 to EC), and the European Regional Development Fund “Una manera de fer Europa”. JER- Z was supported by a fellowship from the Generalitat de Catalunya AGAUR FI-DGR 2017 (2017 FI_B01004). EC is an Academia Researcher of the "Institució Catalana de Recerca i Estudis Avançats" (ICREA) of the Generalitat de Catalunya. This work was developed at the Centro Esther Koplowitz, Barcelona, Spain. The group is supported by Acció Instrumental d’Incorporació de Científics i Tecnòlegs PERIS 2016 (SLT002/16/00336) from the Generalitat de Catalunya.
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haematologica | 2019; 104(9)