Aquaporin-9 expression as an independent adverse prognostic marker in diffuse large B-cell lymphoma: an...

Aquaporins (AQPs) are membrane channel proteins implicated in tumor biology, but their clinicopathological and prognostic relevance in diffuse large B-cell lymphoma (DLBCL) remains insufficiently characterized. This study evaluated the immunohistochemical expression of AQP1, AQP2, AQP8, and AQP9 and their associations with clinicopathological features and survival outcomes in DLBCL. In this retrospective cohort study, formalin-fixed, paraffin-embedded tissue samples from 164 DLBCL cases diagnosed at Mansoura University Oncology Center between 2011 and 2022 were analyzed using tissue microarray-based immunohistochemistry. Associations between marker expression and clinicopathological variables were assessed using appropriate comparative tests. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. A sensitivity Cox analysis was additionally performed to assess whether the association of AQP9 with overall survival persisted after adjustment for rituximab exposure. Positivity for AQP1, AQP2, AQP8, and AQP9 was detected in 9.8% (16/164), 1.8% (3/164), 0.6% (1/164), and 11.6% (19/164) of cases, respectively. AQP1 positivity was associated with higher International Prognostic Index (IPI) risk category (P = 0.007) and lower hemoglobin levels (P = 0.012), but not with significant differences in survival. AQP9 expression was significantly associated with inferior OS, with a median OS of 20.7 months in AQP9-positive cases versus 78.6 months in AQP9-negative cases (log-rank P = 0.002). In multivariable analysis, AQP9 remained an independent adverse predictor of mortality (HR 2.44, 95% CI 1.35-4.40; P = 0.003). This association remained significant in a sensitivity model additionally adjusting for rituximab exposure (HR 2.26, 95% CI 1.25-4.09; P = 0.007). None of the evaluated markers significantly predicted DFS. AQP9 expression identifies a subgroup of DLBCL patients with significantly poorer overall survival and may provide prognostic information beyond conventional clinical risk stratification. In contrast, AQP1 was associated with adverse baseline features but had no significant impact on survival, while AQP2 and AQP8 were rarely expressed. Larger multi-center studies are warranted to validate the prognostic role of AQP9 in DLBCL.