Lymphomas with Concurrent T(14;18) and 8q24 Translocations Are Under- Reported and Clinical Outcome Depends on the MYC Partner

Background: Lymphomas with concurrent t(14;18) and 8q24 translocations (BCL2+/MYC+) are associated with a poor overall survival (OS). Recently, Savage et al. (Ann Oncol 19: 4, 2008, a186) reported that 4% (6/163) of patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) have BCL2+/MYC+ rearrangements and have a variable clinical outcome. We identified the clinical and cytogenetic characteristics of a larger cohort of patients with BCL2+/MYC+ rearrangements to determine correlations with outcome.

Methods: Cases of non-Hodgkin lymphoma (NHL) with concurrent 18q21 and 8q24 breakpoints were identified by karyotype and/or fluorescence in-situ hybridization (FISH) analysis. Histological diagnoses were determined according to the World Health Organization. All MYC rearrangements were confirmed by FISH using a commercial MYC break-apart probe. OS was calculated from the MYC+ biopsy date to last follow up date or death.

Results: 55 of 1480 NHL samples (4%) were identified and confirmed to have BCL2+/MYC+ rearrangements. The histological diagnoses were follicular lymphoma (FL)(1), DLBCL(17) and high-grade B cell lymphoma unclassifiable (HGBCL) (37). The HGBCL included cases that were considered intermediate between DLBCL and Burkitt lymphoma (BL), Tdt⁺ lymphoblastic lymphoma (LBL) and surface immunoglobulin (IG)⁺ acute lymphoblastic leukemia (sIG⁺ ALL). All HGBCL cases with available Bcl-2 protein staining were positive in contrast to 5/14 DLBCL cases that were Bcl-2 protein negative despite having t(14;18). By karyotype, 31/55 had MYC translocations involving the IG loci (11 t(8;14), 11 t(8;22), 3 t(2;8) and 6 complex t(8,14,18)). The remaining MYC rearrangements involved different chromosome partners, the most common being t(8;9) (q24;p13) (12/31). The other MYC partners included 1p36, 3p25, 3q27, 4p13, 5q13, 12p11 and 13q31. There was a high correlation between the MYC partner and the resulting histology. 28/31 of the IG/MYC translocations were associated with HGBCL. 14/17 of DLBCL cases had non-IG/MYC translocations and those with IG/MYC translocations were either Bcl-2 protein-negative (2) or had a complex t(8;14;18)(1). HGBCL histology, Bcl-2 protein expression and the presence of an IG/MYC partner all correlated with a poor outcome. HGBCL was associated with a median OS of 3 months compared to 3 y for DLBCL (p<0.0001). In contrast to the DLBCL patients, the HGBCL patients were older (median age 62 y vs 54 y), more often developed transformation from antecedent indolent lymphoma (44% vs 30%) and were less likely to complete anthracycline-based chemotherapy (76% vs 94%). Bcl-2 protein-negative biopsies were associated with median OS of 5.7 years vs 5 months for Bcl-2 protein⁺ cases (p = 0.05). An IG/MYC partner correlated with a median OS of 3 months compared to 7 months for non-IG/MYC partner (p=0.02). Thus, a favorable outcome was associated with DLBCL morphology, a non-IG/MYC rearrangement and Bcl-2 protein-negative biopsy. IG/MYC⁺ and Bcl-2 protein⁺ biopsies were associated with HGBCL and a median OS of < 4 months (p = 0.02).

Conclusion: NHL with BCL2+/MYC+ rearrangements are under-recognized due to lack of routine karyotyping or FISH analysis of all high-grade lymphomas. Comprehensive analysis of BCL2 and MYC status should be performed on all HGBCL in the new WHO (2008) classification. The presence of an IG-related MYC partner correlates with a poor prognosis. The favorable survival associated with the few Bcl-2 protein-negative cases suggests that the anti-apoptotic effect of Bcl-2 protein explains the negative impact on prognosis when NHL have concurrent t(14;18) and MYC translocations. Thus, Bcl-2 targeted therapy should be ideally suited for the more frequent Bcl-2 protein⁺ cases.