Clinicopathological Prognostic Indicators Of 24 Patients With B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma
Authors: Miyamoto Ken-ichi , Maeshima Akiko Miyagi , Taniguchi Hirokazu , Nomoto Junko , Kitahara Hideaki , Fukuhara Suguru , Munakata Wataru , Maruyama Dai , Kim Sung-Won , Kobayashi Yukio , Tobinai Kensei 
Published: October 2019

Abstract

Background
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (iBL/DLBCL) by WHO classification 2008 is a rare subtype. Some cases of iBL/DLBCL have both MYC and BCL2 translocations (double hit translocation, DHT) by fluorescent in situ hybridization (FISH) or G-band staining, and DHT is an indicator of poor prognosis. Recently, detection method of c-MYC protein was developed. The staining might be an emerging tool to detect DLBCL cases with poor prognosis. Using this staining, double hit score (DHS) is defined as a sum of the numbers, whose count is 1 (positive) or 0 (negative) according to the status of MYC and BCL2 immunoreactivity, and those patients in whom DHS is 2 (DHS 2) have been reported to have a poor prognosis in DLBCL. However, the incidence of DHT and the significance of DHS in iBL/DLBCL has not been adequately studied. Herein we evaluated these parameters as potential prognostic indicators of iBL/DLBCL.

Patients and Methods
We retrospectively analyzed the clinicopathological features of 24 patients with iBL/DLBCL between 2000 and 2011. MYC split and IGH/BCL2 fusion by FISH analysis and MYC and BCL2 immunostaining were performed. Immunoreactivity of MYC was judged to be positive when MYC protein was expressed in more than 40% of the lymphoma cells. Survival analyses were performed using the Kaplan-Meier curves and compared using the log-rank test.

Results
The median age of the 24 patients with iBL/DLBCL was 47 years (range:16-79 years). All patients had received systemic chemotherapy regimens such as CHOP (n=9) or CODOX-M/IVAC (n=15), with or without rituximab. The iBL/DLBCL patients 60 years or older had received CHOP +/- R, and those patients younger than 60 years had received CODOX-M/IVAC +/- R according to our institution’s policy. The 4-year progression-free survival (PFS) and overall survival (OS) rates were 63 and 72%, respectively. Twelve patients (50%) had stage IV disease, 14 (58%) had high serum LDH levels, and 16 (66%) had extranodal presentation. IPI was low in 9 patients, low-intermediate in 4, high-intermediate in 3, and high in 7. The incidence of MYC, BCL2 immunoreactivity, and both (DHS 2) was 81%, 29%, and 14%, respectively. Three patients were not evaluated for MYC immunoreactivity. The incidence of MYC split, IGH/BCL2 fusion, and DHT was 55%, 30%, and 17%, respectively. Two patients were not evaluated for MYC split and 4 patients were not evaluated for IGH/BCL2 fusion. More patients with MYC immunoreactivity were found than those with MYC split, and 4 patients (21%) had MYC immunoreactivity despite lack of MYC split, and only one patient (5%) had MYC split without MYC immunoreactivity. All patients with IGH/BCL2 fusion had BCL2 immunoreactivity. The incidence of patients with Ki67 index more than 90% was 88%. Univariate analysis revealed that PFS was significantly shorter in patients aged ≥60 years (P =.042) and in those with high IPI scores (P <.0001), stage IV disease (P =.001), IGH/BCL2 fusion (P =.029), DHS 2 (P =.015), and DHT (P =.03). OS was significantly shorter in patients aged ≥60 years (P =.008) and in those with high IPI scores (P <.0001). MYC split positivity (55%) was not a significant prognostic indicator of OS (P =.669) or PFS (P=.728).

Conclusions
Immunoreactivity of MYC was more frequently observed than MYC split and its positivity with combination of IGH/BCL2 fusion or immunoreactivity of BCL2 provides clinical significance, thus, serving as a useful tool.

Disclosures:
Kobayashi: Ariad, Behringer, Ohtsuka, Onconova, Novartis: Research Funding.