Prognostic Significance of Tumor Budding, Tumor–Stroma Ratio, and Annexin A1 in Gallbladder Cancer

Objective Gallbladder cancer (GBC) is a rare, aggressive malignancy with poor survival outcomes. The tumor microenvironment (TME), which includes stromal content, immune infiltration, and tumor budding, influences tumor progression and prognosis. ANXA1 is a multifunctional protein that mediates crosstalk within the TME to regulate cancer cell behavior and stromal dynamics; however, its prognostic role in GBC remains unclear. Patients and Methods We retrospectively analyzed 131 patients who underwent surgery for primary GBC. Tumor–stroma ratio (TSR), local immune responses [Klintrup-Mäkinen (KM) grade, stromal tumor-infiltrating lymphocytes (TILs), and Crohn-like lymphoid reaction (CLR)], tumor budding, and ANXA1 expression were evaluated using hematoxylin and eosin-stained slides and immunohistochemistry. Associations with clinicopathological features, disease-specific survival (DSS), and progression-free survival (PFS) were assessed using Kaplan–Meier analysis and Cox regression models. Results High-grade tumor budding was observed in 23% of tumors, and a stroma-high phenotype was identified in 29%. ANXA1 expression was positive in 80.9% of the tumors. Stroma high status and high-grade tumor budding were identified as independent predictors of poor DSS, whereas high-grade tumor budding independently predicted poor PFS. Low KM grade, stromal TILs, CLR, and ANXA1 expression were not independently associated with survival. Conclusions High-grade tumor budding and stroma-rich phenotypes were independent adverse prognostic factors for GBC, whereas stromal TILs were associated with favorable outcomes. Although ANXA1 is expressed in GBC and linked to aggressive features, it does not independently predict survival. A comprehensive assessment of TME components may improve prognostic stratification and guide personalized management strategies for GBC.