High Grade Non-Hodgkin’s Lymphoma with Tandem t(14;18) and c-MYC Rearrangement Is a Pathological Lymphoma Entity with Aggressive Clinical Presentation and Very Poor Prognosis.

Translocation t(14;18)(q32;q21) is a hallmark of follicular lymphomas (FL) and reported in 10% to 40% of diffuse large B cell lymphomas (DLBCLs). It leads to Bcl-2 over expression, a protein that opposes to mitochondrial apoptotic pathways and chemotherapy-induced cell death. c-MYC (8q24) rearrangement is a hallmark of Burkitt’s lymphoma (BL) but observed in 7% to 15% of DLBCLs. c-MYC (8q24) induces over expression of c-MYC protein which promotes cell cycle and tumour proliferation. Among 70 DLBCL expected for c-MYC and t(14;18) translocation, we identified a series of 16 patients with DLBCL characterized by a tandem t(14;18) translocation and c-MYC rearrangement.

Patients were 10 males, 6 females with a median age of 59 years old (36–73). At the time of diagnosis, all patients presented with poor features: B symptoms in 81%, ECOG PS > 2 in 81%, elevated LDH in 100% , stage IV in 100 % with at least one extra nodal localisation (bone marrow involvement in 87,5% and CNS involvement in 44%) and age-adjusted IPI = 3 in 81%. Lymphoma cells in blood smear was found in 50% of the cases. Three patients had a prior history of FL. All patients but one were treated with chemotherapy regiments: R-CHOP like (n=8) or Burkitt regiments (n=7). Five patients reached complete response, 7 partial response and 4 patients progressed. Five patients underwent ASCT (n=3) or allogenic bone marrow transplantation (n=2) upfront. However, disease response was dramatically short precluding planned hematopoietic-cell transplantation in most cases. Despite salvage chemotherapy, all patients progressed with a median time to progression from diagnosis of 4 months (1–10) and median overall survival of 5 months (1–16).

Morphological and immunophenotypic findings were consistent with the diagnosis of DLBCL with a germinal-center (GC) profile(CD10 + and CD10−/BCl6+/Mum1−) in all cases.

Combination of t(14;18) translocation and MYC rearrangement was identified by conventional cytogenetic and/or FISH analysis in all cases. Conventional cytogenetic found 3 patients with t(8;14), 3 patients with t(8;22) and one with t(2;8) translocation. We also identified a new MYC translocation variant that has never been reported in DLBCL before : t(8;9)(q24;p13) translocation in combination with t(14;18)(q32;q21) translocation. All cases assessed by cytogenetic analysis had a complex karyotype. FISH analysis for BCL6 was positive for only 3 patients.

Our series shows that DLBCL with a tandem t(14;18) and c-MYC rearrangement is a particular sub-type of GC-DLBCL with aggressive initial clinical presentation and a disastrous overall survival. We conclude that patients with DLBCL with unusual aggressive clinical and biological presentation should be investigated for tandem translocation. These patients require innovative strategies and targeted therapies.