Clinicopathological Features and Prognosis of B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma with t(14;18) and 8q24 Translocation in the Rituximab Era
Authors: Niitsu Nozomi , Takahashi Naoki , Kohri Mika , Asou Norio , Tamaru Jun-ichi , Sakai Jun , Nakamura Shigeo , Miura Ikuo , Okamoto Masataka 
Published: October 2019

Abstract
Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases in terms of morphology, immunohistochemistry and molecular features. The t(14;18)(q32;q21) translocation juxtaposes the BCL2 gene, normally located at 18q21, with the IGH locus on 14q32. The t(14;18)(q32;q21) occurs in about 80-90% of follicular lymphomas and about 25-30% of de novo DLBCLs. On the other hand, the t(8;14)(q24;q32) translocation juxtaposes the c-MYC protooncogene, which is located at 8q24, to the immunoglobulin heavy chain (IGH) gene, located at 14q32, resulting in deregulated expression of c-MYC. t(8;14)(q24;q32) has been found in 80-90% of Burkitt lymphoma cases and in 5-15% of DLBCL cases. B-cell lymphoma having both t(14;18) and 8q24, so called double hit lymphoma (DHL), is rare. The pathological diagnosis in most cases of DHL is B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCLU). Patients with DHL have elevated serum LDH levels, advanced stage, bone marrow involvement, extranodal involvement and the presence of B symptoms. In the present study, we evaluated the clinicopathological characteristics and prognoses of patients with BCLU with DHL.
Patients and Methods: A total of 368 patients with DLBCL and BCLU were treated from 2007 to 2013. Chromosomal data were available in 195 of the 368 patients. Pathologic evaluation of the materials from each patient was performedat several central review meetings by six hematopathologists in the ALTSG pathology review board. Patients were treated with cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone (CyclOBEAP) regimen or CHOP regimen. Rituximab was administered to all patients. The median follow-up period was 44 months (range, 12-61 months).
Results: t(14;18) + 8q24 dual translocation was seen in 18 (9.2 %) of the 195 patients with DLBCL and BCLU. There were 12 males and 6 females, with a median age of 62 (range, 47-76) years. Stage III/IV was found in 56%, bone marrow infiltration was found in 39％, central nervous system (CNS) infiltration was found in 17％, and high risk of international prognostic index (IPI) was found in 67％. Among the 18 patients with the DHL, extranodal sites of disease were bone marrow (7 patients), CNS (3 patients), pleural effusion (5 patients), and gastrointestinal tract (3 patients). Furthermore, 8 patients had at least two extranodal localizations. Immunophenotyping analysis (CD20, CD5, CD10, BCL2, BCL6, MUM1, Ki-67) was performed and showed BCLU with a germinal center type in all cases. Ki-67 staining ranged from 30-90%. All lymphoma cells were positive for CD20 and negative for CD5. CD10, BCL2, BCL6, and MUM1 were positive in 89%, 75%, 88%, and 19%, respectively. The 4-year overall survival (OS) rate was 72% among the patients with dual translocation (n=18) and 75% among the patients in the other chromosomal abnormalities group (n=177). The 4-year progression-free survival (PFS) rate was 52% among the patients with the dual translocation and 71% among the patients in the other chromosomal abnormalities group. The 4-year OS rate of the stage I/II and stage III/IV groups was 100% and 47%, respectively (P=0.016). We next examined the survival curve of patients in whom data on serum LDH levels were available. The 4-year OS rates of the high (>2N) and low LDH groups (<2N) were 33 and 100%, respectively (p=0.0002). According to the IPI, the 4-year OS of patients with L or L-I risk and those with H-I or H risk was 100% and 50%, respectively (p=0.03).
Conclusions: Among patients with DHL, there was one subgroup that had a good prognosis. We elucidated the clinicopathological condition of especially the subgroup of DTL with poor prognosis, and prognostic improvement of this disorder is expected in the future by considering a new treatment strategy for these subgroups.

Disclosures
Niitsu: Chugai pharmaceutical: Research Funding. Takahashi:Chugai pharmaceutical: Research Funding. Kohri:Chugai pharmaceutical: Research Funding. Asou:Chugai pharmaceutical: Research Funding. Sakai:Chugai pharmaceutical: Research Funding. Miura:Chugai pharmaceutical: Research Funding. Okamoto:Chugai pharmaceutical: Research Funding.