Biological determinism and the stage-dependent role of surgical approach in gallbladder cancer: A 20-year cohort study and meta-analysis.

BACKGROUND: Gallbladder cancer (GBC) is a lethal malignancy for which the substantial survival benefit of guideline-mandated R0 resection is fundamentally constrained by the advanced stage at which most patients present. The determinants of long-term survival and the optimal surgical approach, particularly for incidental GBC (IGBC), remain insufficiently defined. We aimed to address these gaps in a large, contemporary cohort. METHODS: We retrospectively analyzed 416 consecutive patients who underwent surgery for GBC at a national tertiary center (2003-2022). The primary endpoints of overall survival (OS) and disease-free survival (DFS) were assessed using Kaplan-Meier analysis and multivariable Cox regression. A prospectively registered systematic review and meta-analysis (PROSPERO: CRD42024501216) was performed to contextualize the role of surgical approach in IGBC. RESULTS: The cohort was characterized by a predominance of advanced-stage disease (68% stage III-IV), with an R0 resection rate of 44.0%. Perioperative morbidity was 12.7% and 30-day mortality was 0.7%. Compared to conventional GBC, IGBC was diagnosed at significantly earlier stages, resulting in a lower recurrence rate (20.0% vs. 34.7%, P = 0.044) and improved median OS (56.5 vs. 32.0 months). Multivariable analysis confirmed that survival was overwhelmingly dictated by adverse tumor biology (e.g., poor differentiation, nodal involvement, M1 status). R0 resection emerged as the sole, powerful, modifiable protective factor for both OS (HR 0.27) and DFS (HR 0.23). The meta-analysis demonstrated a significant, stage-dependent survival benefit for a primary laparoscopic approach in IGBC, particularly for T2 tumors. CONCLUSION: The prognosis of GBC is fundamentally determined by tumor biology at presentation. Within this paradigm of biological determinism, achieving an R0 resection is the most critical surgical intervention to improve survival. For appropriately selected patients with IGBC, a laparoscopic approach confers a survival advantage, reinforcing the dual importance of strategies that facilitate both earlier detection and guideline-adherent oncologic resection.