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Diffuse large B-cell lymphoma (DLBCL) is regarded as a heterogeneous group of lymphomas. The aims of this study were to determine the clinical significance and prognostic value of different immunophenotypic profiles in localized-stage head and neck DLBCL treated with curative radiotherapy. We included 102 localized-stage head and neck DLBCL patients in this study. We classified DLBCL patients into germinal center B-cell (GCB) and non-GCB groups by immunohistochemical analysis. Statistical analysis was used to correlate the GCB and non-GCB subgroups, CD5 and Ki67 expression, B-ALPS (a modified International Prognostic Index for early stage lymphoma), chemotherapy regimen, and sex. Multivariate analysis was performed using the Cox proportional hazard regression model to compare cause-specific survival (CSS) and relapse-free rate (RFR) distributions. The cell of origin classification (GCB or non-GCB subtypes) was an independent predictor of CSS (p = 0.040) and RFR (p = 0.023). In the non-GCB group, chemotherapy with rituximab was an independent predictor of CSS. In conclusion, this study shows that the prognosis of the non-GCB group was significantly poorer than that of the GCB group, and that rituximab improved CSS in localized-stage head and neck DLBCL, especially in the non-GCB group.