MYC rearrangement + BCL6 rearrangement

High-grade B-cell lymphomas are subclassified based on morphologic and genetic features. There are differences in the nomenclature and definition of these lymphomas in the WHO-5 and ICC classifications. Distinguishing HGBLs from other mature B-cell lymphomas and B-LBL/ALL is critical so that patients receive appropriate treatment.

In this review, we provide an update of HGBL and its subgroups, focusing on their clinicopathologic features, diagnosis, molecular genetic features, and pathogenesis. Our diagnostic approach and caveats for differential diagnosis are also discussed with an emphasis on the differential diagnosis with B lymphoblastic leukemia/lymphoma.

The patient was assigned Stage IEA, IPI = 0 and received chemotherapy. This case depicts a very uncommon occurrence of fully localized LBL in a patient of an unusually young age and clinical presentation for this type of lymphoma.

Furthermore, because one IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

She was treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab chemotherapy. Rituximab was discontinued owing to largely absent CD20 expression. Interim positron emission tomography-CT after three cycles revealed a complete response, and the patient completed six cycles of therapy.

Our virtual MTB approach identified potential molecularly targeted treatment options alongside targetable genomic signatures for both prDLBCL/HGBL-MYC/BCL2 and prHGBL, NOS-MYC/BCL6. These results underline the potential of MTB consultations in difficult-to-treat lymphomas early in the treatment sequence.

Whereas R-CHOP or polatuzumab vedotin + R-CHP are now both standard treatments for DLBCL, in primary mediastinal B-cell lymphoma, dose adjusted EPOCH-R has become the standard of care based on prospective trials demonstrating that this treatment can obviate the need for mediastinal radiation in most patients.12,13 In the case of traditional Burkitt lymphoma, the Magrath regimen of R-CODOX-M/IVAC is frequently used for young/fit patients although there are also prospective data supporting the use of dose adjusted EPOCH-R for Burkitt lymphoma.14,15 For double/triple hit lymphoma, more intensive chemotherapy regimens are frequently recommended for fit patients including dose adjusted R-EPOCH, R-hyperCVAD, and R-CODOX-M/R-IVAC based on prospective single-arm trials and/or retrospective experience.16,17 In the case of HGBL, NOS, it is generally assumed that one of these intensive regimens should be used, as outcomes with R-CHOP are generally unsatisfactory, but comparative data are lacking. In conclusion, as outlined in the 2016 WHO classification and carried forward to updated classifications, HGBL remains an imperfectly described disease with lack of consensus diagnostic or treatment recommendations. In general, aggressive treatment regimens are recommended, if feasible, and future research is needed to study a larger number of cases with advanced molecular techniques and to prospectively assess different treatment regimens to improve outcomes for patients with these high-risk lymphomas.

Marginal zone lymphoma and LPL may undergo a variety of transformation events, most commonly to DLBCL, which is usually, although not always, directly clonally related to the underlying low-grade lymphoma. Multiparameter analysis including broad-based sequencing studies can assist in the diagnosis and classification of these uncommon cases.

Aggressive B‑cell lymphomas with MYC and BCL2 rearrangements form a molecularly distinct group and are listed as definite entities in both classifications. This is in contrast to the more heterogeneous group of aggressive B‑cell lymphomas with MYC and BCL6 rearrangements that are recognized as a provisional entity in the ICC, while they fall into the DLBCL, NOS, or the HGBL, NOS, groups in the WHO-HAEM5.

The t(3;8) translocation is a common cause of apparent double hit MYC and BCL6 FISH results but, as expected from a rearrangement leading only to MYC overexpression, this group have a similar survival to MYC single hit cases. However, large B cell lymphomas with separate MYC and BCL6 rearrangements which are negative for t(3;8) are associated with inferior survival, independently of established clinical prognostic factors.

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BCL6 -DHL patients show aggressive clinical characteristics similar to BCL2 -DHL patients and more aggressive than DLBCL patients. The major difference between BCL6 -DHL and BCL2 -DHL was immunophenotype, with BCL6 -DHL having less often MYC and BCL2 double expression and GCB type. R-EPOCH, but not R-CHOP, improved the survival of BCL6 -DHL patients, similar to BCL2 -DHL patients.

The phenotypic and genotypic characteristics of HIV-associated aggressive B-NHL are similar to those of the general population, except for the low frequency of BCL2 rearrangements in DLBCL. MYC and BCL2 co-expression in DLBCL, and MUM-1 expression in BL have negative prognostic impact in HIV-infected individuals.

While detection of a translocation in sequencing data can be limited by factors such as poor biopsy quality, a translocation partner was identified for the majority of tumors with LR and LG patterns, with all but 1 translocation preserving the MYC gene. These results support that LR and LG patterns should be interpreted as a positive MYC FISH result.

FISH strategies for diffuse large B-cell lymphoma (DLBCL) and HGBCL are discussed in detail for these diseases. Advances in integrative analysis of mutations, structural abnormalities, copy number, and gene expression signatures allow a more nuanced view of the heterogeneity of DLBCL, NOS as well as definitions of HGBCL and point to where the future may be headed for classification of these diseases.

No abstract available

Loss of 6p22 ( HLA ) previously described in PCNSL, was detected in 12.5% of the T-LBCL cases. Conclusion Although these data warrant further investigation, we identified that T-LBCL is a poor-risk type of DLBCL with mainly ABC subtype and peculiar genetic characteristics.

Our study shows that most HGBCLs with t(3;8)(q27;q24) BCL6/MYC also have a BCL2 rearrangement. Clinically, these are aggressive lymphomas, with most patients responding poorly to therapy and dying of disease within one to two years. Two patients in our study achieved complete remission, one with a BCL2 rearrangement and one without.

Concurrently, provincial guidelines were introduced recommending treatment with dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone and rituximab (DA-EPOCH-R) for appropriately fit patients aged 75 years (y) or younger with HGBL-DH/TH harboring BCL2 rearrangements with DLBCL morphology (HGBL-DH/TH- BCL2 -DLBCL). Introduction of a provincial, population-based recommendation to use DA-EPOCH-R for appropriately fit patients aged 75y or younger is associated with improved real-world outcomes of HGBL-DH/TH- BCL2 -DLBCL. The similarity between TTP and OS within each era suggests the high failure rate of conventional salvage therapy irrespective of frontline treatment, prompting further investigation of novel second-line therapies in this poor-prognosis population. Targeted capture sequencing to identify MYC translocation partners is underway, and the influence of the MYC partner on outcomes in both eras will be presented.

The patient was refractory to R-CHOP and high-dose methotrexate and was placed in comfort care. Intravascular distribution pattern of DHL has not been previously described and raises consideration for intravascular large B-cell lymphoma. This case underscores the importance of characterizing MYC, BCL2, and BCL6 rearrangement status for accurate subclassification of aggressive B-cell neoplasms and highlights the morphologic variation that can be observed in DHL.

The incidence of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements was low in DLBCLs, and no significant correlation between gene abnormality and protein overexpression was shown. The correct diagnosis of DHL depends on molecular genetic detection.

DH/TH status and DH status alone were associated with poorer OS and DSS (both p<0,05) among all pcDLBCLs, without reaching statistical significance in pcDLBCL-LT and pcDLBCL-NOS groups. In conclusion, MYC, BCL2 and BCL6 cytogenetical testing could be useful in identifying a putative subset of more aggressive pcDLBCLs, although this observation has to be confirmed by further studies.