BackgroundOxidative stress and redox-regulating enzymes may have roles both in lymphomagenesis and resistance to lymphoma therapy. Previous studies from the pre-rituximab era suggest that antioxidant enzyme expression is related to prognosis in diffuse large B-cell lymphoma (DLBCL), although these results cannot be extrapolated to patient populations undergoing modern treatment modalities. In this study we assessed expression of the oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and the antioxidant enzymes thioredoxin (Trx), manganese superoxide dismutase (MnSOD) and glutamate-cysteine ligase (GCL) via immunohistochemistry in 106 patients with DLBCL. All patients were treated with CHOP-like therapy combined with rituximab. Immunostaining results were correlated with progression-free survival, disease-specific survival and traditional prognostic factors of DLBCL.ResultsStrong 8-OHdG immunostaining intensity was associated with extranodal involvement (p = 0.00002), a high International Prognostic Index (p = 0.002) and strong Trx (p = 0.011) and GCL (p = 0.0003) expression. Strong Trx staining intensity was associated with poor progression-free survival (p = 0.046) and poor disease-specific survival (p = 0.015). Strong GCL immunostaining intensity predicted poor progression-free survival (p = 0.049). Patients with either strong Trx or strong nitrotyrosine expression showed significantly poorer progression-free survival (p = 0.003) and disease-specific survival (p = 0.031) compared with the other patients.ConclusionsThe redox state-regulating enzymes GCL and Trx are promising markers in the evaluation of DLBCL prognosis in the era of modern immunochemotherapy.
Although oxidative stress plays an important role in the biology of solid malignant tumors, little is known about oxidative stress in hematological malignancies. In this study, we evaluated the immunohistochemical expression and clinical correlations of oxidative stress markers and several essential antioxidant enzymes in B-cell lymphomas. Paraffin-embedded diagnostic tissue samples from 18 diffuse large B-cell lymphomas (DLBCL), 18 follicular lymphomas (FL), 19 Hodgkin lymphomas (HL), 7 chronic lymphocytic leukemias (CLL), 7 mantle cell lymphomas (MCL) and 7 mucosa-associated lymphoid tissue (MALT) lymphomas, together with samples from 6 reactive lymph nodes were stained for oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and antioxidant enzymes manganese superoxide dismutase (MnSOD), thioredoxin (Trx) and γ-glutamyl cysteine synthetase (γ-GCS). There was increased 8-OHdG reactivity in DLBCL compared to more indolent lymphomas and reactive lymph nodes. Positivity for Trx was most intense in HL. In DLBCL, positivity for 8-OHdG and nitrotyrosine associated with shorter survival (p = 0.032 and p = 0.026, respectively). This study showed increasing expression of oxidative stress markers and antioxidant enzymes in a series of lymph node samples evolving from reactive lymph nodes to indolent and aggressive lymphomas. These markers seem to have strong prognostic value, but this has to be verified in larger studies.
Central nervous system (CNS) relapse occurs in around 5% of diffuse large B-cell lymphoma (DLBCL) cases. No biomarkers to identify high-risk patients have been discovered. We evaluated the expression of lymphocyte-guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi-square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated with CNS involvement (P = 0.003 and P = 0.039). Immunoelectron microscopy revealed a nuclear CXCR4 staining in reactive lymph node, compared with cytoplasmic and membranous localization seen in CNS lymphomas. We found that CNS lymphoma presented a chemokine receptor profile different from systemic disease. Our findings give new information on the CNS tropism of DLBCL and, if confirmed, may contribute to more effective targeting of CNS prophylaxis among patients with DLBCL.
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