NF- B Activation Through the Alternative Pathway Correlates with Chemoresistance and Poor Survival in Extranodal NK/T-cell Lymphoma, Nasal Type

Abstract

OBJECTIVE: Nuclear factor-kappaB (NF-kappaB) activation has been identified in a variety of solid tumors and lymphoid malignancies. The aim of our study was to determine the expression status and clinical significance of NF-kappaB in extranodal natural killer (NK)/T-cell lymphoma, nasal type. METHODS: Tumor specimens from 23 patients with previously untreated NK/T-cell lymphoma initially treated with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) or CHOP-based chemotherapy were examined by immunohistochemistry for three NF-kappaB subunits (p65, p50 and p52), which are involved in either the canonical or alternative pathway. RESULTS: None of the cases could be detected with p65 or p50 nuclear staining. On the other hand, 15 (65.2%) cases had p52 nuclear staining, suggesting NF-kappaB activation through the alternative pathway. All major clinical characteristics were balanced between NF-kappaB p52-positive and -negative patients. The objective response rate achieved in NF-kappaB-positive patients was significantly lower than that in negative patients (33.3% vs. 87.5%, P = 0.027). At a median follow-up of 25 months, 8 (53.3%) of 15 NF-kappaB-positive patients had died compared with none of 8 NF-kappaB-negative patients (P = 0.041). In a multivariate analysis, NF-kappaB status and stage were identified to be independent prognostic factors. CONCLUSIONS: Our results suggest that NF-kappaB activation through the alternative pathway is frequently observed in NK/T-cell lymphoma and associated with chemoresistance and poor survival.