BCL6 Rearranged Indolent B-Cell Lymphomas Show Mutational Profile Similar to Marginal Zone Lymphomas

Introduction

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. It is a neoplasm of germinal center (GC) B cells with hallmark BCL2 rearrangements (BCL2-R). A distinct subgroup of indolent B cell lymphomas (iBCL), histologically revealing a follicular growth pattern but lacking BCL2-R and with BCL6 rearrangements (BCL6-R) has been described. Historically they have been classified as FL and included under the FL entity in the WHO classification. However, recent studies on diffuse Large B cell lymphomas (DLBCL) (1, 2) have described BCL6-R in ~20% of DLBCL, with a subset of cases showing concurrent gene mutations commonly found in marginal zone lymphomas (MZL) rather than those characteristic of FL or GCB DLBCL. Systematic studies elucidating the clinicopathologic and genetic features of the BCL6-R iBCL are currently lacking thus generating controversy over their appropriate classification and management.

Methods

The MSKCC cytogenetic lab database was searched from 01/2006 to 07/2021 and a cohort of 131 iBCL with BCL6-R (71 with BCL6-R only and 60 with both BCL6-R & BCL2-R) was obtained (Table 1). The clinical, morphologic, immunophenotypic, and molecular results (50 cases had molecular data) were reviewed. These were compared to 70 BCL2-R conventional FL (cFL; all having molecular data) and 54 BCL2-R and BCL6-R negative iBCL (17 had molecular data).

Results

BCL6-R iBCL showed distinct histological, immunophenotypic, genetic and clinical features. They showed a significantly higher number of Grade 3 FL diagnosis and CD10 negative phenotype. The most commonly mutated genes in BCL6-R only group were KMT2D (48%) and TNFAIP3 (40%); in the BCL6-R & BCL2-R group, KMT2D (72%) and BCL2 (56%); and in the cFL group KMT2D (83%), BCL2 (81%) and CREBBP (66%). Unsupervised clustering (K-Means) performed to cluster the samples based on the mutational status of about 50 genes revealed that majority of the BCL6-R only cases clustered separately from cFLs. They clustered with majority of BCL2-R and BCL6-R negative cases and revealed frequent mutations in TNFAIP3, BCL10, B2M, NOTCH2, SPEN (Fig 1). Majority (2/3) of the BCL6-R & BCL2-R cases clustered with cFL and showed mutations commonly seen in FL (Fig 1). The overall survival (OS) was significantly inferior in the BCL6-R cases (BCL6-R only as well as both BCL6-R & BCL2-R cases) in comparison to cFL even though progression free survival was shortest for cFL.

Conclusion

BCL6-R only iBCL are biologically distinct, cluster separately from cFL based on mutational profile, and demonstrate an MZL-like mutational profile similar to that is described for the BN2 group of DLBCL (1). These findings suggest that they are a distinct entity, different from cFL and possibly precursor lesions for BN2 DLBCL.

In contrast, majority of the BCL6-R & BCL2-R cases cluster with cFL and show mutations commonly seen in FL. Finally, presence of BCL6-R was associated with a worse OS.

References:

1. Schmitz, R., et al. Genetics and pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018 Apr 12;378(15):1396-1407.
2. Chapuy, B., et al. Molecular Subtypes of Diffuse Large B Cell Lymphoma are Associated with Distinct Pathogenic Mechanisms and Outcomes. Nat Med. 2018 May;24(5):679-690.