Overexpression of MYC and BCL2 Predicts Poor Prognosis in Patients with Extranodal NK/T-cell Lymphoma, Nasal Type

Background: Recently double-hit lymphoma or double protein expressor lymphoma has been identified as a distinct group of diffuse large B cell lymphoma with poor prognosis. However, the expression status, clinical and prognostic effect of combined overexpression of MYC and BCL2 in extranodal NK/T-cell lymphoma, nasal type (ENKTL) are not known. Materials and methods: Paraffin-embedded lymphoma samples from 53 patients with newly diagnosed ENKTL were studied using immunohistochemistry for MYC and BCL2, and fluorescent in situ hybridization (FISH) for MYC and BCL2 were done on 5 tissue sections with highest percentages of both MYC and BCL2 positive lymphoma cells. Results: The median percentage of MYC-positive lymphoma cells and BCL2-positive lymphoma cells were 20% (range, 5%-45%) and 70% (10%-95%), respectively. Using median scores as cutoffs, we assigned each patient an IHC double-hit score (DHS) that ranged from 0 to 2. Using this DHS, 15 patients (28.3%) had a DHS of 0, 24 patients (45.3%) had a DHS of 1, and the remaining 14 patients (26.4%) had a DHS of 2. FISH analysis was performed on 5 tissue sections with DHS of 2, and none of them had MYC or BCL2 rearrangement. The DHS was not associated with patients' age, gender, disease stage, LDH level, B symptoms, performance status, or local tumor invasiveness. However, patients with tumor localized in extranasal sites seemed to have higher expression of BCL2 and higher DHS than nasal lesions (p=0.014 and 0.042, respectively). In univariate survival analysis, either high expression of MYC or BCL2 was significantly correlated with inferior PFS and OS (p<0.05). According to the DHS, patients with ENKTL could be divided into three significantly different risk groups for PFS and OS (3-year PFS rate for DHS of 0, 1, and 2 was 60%, 41%, and 21%, respectively, p=0.008; 3-year OS rate for DHS of 0, 1, and 2 was 79%, 49%, and 33%, respectively, p=0.015). In multivariate survival analysis, it was found that DHS was an independent prognostic factor for both PFS and OS (p=0.006 and 0.011, respectively). Conclusions: Our study demonstrated that DHS can help identify patients with newly diagnosed ENKTL who are at a high risk for a poor clinical outcome, which needs to be validated in prospective clinical trials with patients treated uniformly.