Systematic review of gallbladder disorders: Molecular pathogenesis, biomarkers, diagnostic approaches, and emerging...

Gallbladder cancer (GBC) is the most aggressive and lethal malignancy of the biliary tract, characterized by rapid disease progression, early invasion, and poor survival rates. The unfavorable prognosis is primarily attributed to delayed diagnosis, nonspecific clinical manifestations, and limited effective therapeutic options. Although GBC is relatively uncommon worldwide, its incidence demonstrates considerable geographic variation, with particularly high prevalence observed in South Asian countries, especially northern India, Chile, and certain regions of East Asia. Chronic gallstone disease, persistent inflammation, and environmental factors significantly contribute to disease development.

This review aims to provide a comprehensive and critical synthesis of the molecular pathogenesis of gallbladder cancer, evaluate the current evidence and clinical readiness of diagnostic, prognostic, and predictive biomarkers, and critically assess established and emerging therapeutic strategies, with particular emphasis on their translational limitations, evidence gaps, and implications for precision medicine.

Relevant peer-reviewed literature published in recent years was critically analyzed, focusing on epidemiology, risk factors, genetic and epigenetic alterations, dysregulated signaling pathways, tumor microenvironment, biomarkers, and novel therapeutic strategies. Because of substantial clinical and methodological heterogeneity among the included studies, the findings were synthesized qualitatively and narratively rather than by formal statistical meta-analysis.

Chronic inflammation caused by gallstones, cholecystitis, and biliary infections remains the principal etiological factor in gallbladder carcinogenesis. Several genetic alterations, including mutations in TP53, KRAS, PIK3CA, and CDKN2A, along with HER2/ERBB2 amplification and epigenetic modifications, play critical roles in tumor initiation and progression. Dysregulation of multiple signaling pathways, including EGFR, PI3K/Akt/mTOR, MAPK, Wnt/β-catenin, Notch, Hedgehog, and NF-κB pathways, contributes to cellular proliferation, invasion, angiogenesis, and metastasis. Conventional serum biomarkers such as CA19-9 and CEA remain clinically useful but have limited sensitivity and specificity when used alone. Emerging approaches, including circulating tumor DNA, circulating tumor cells, extracellular vesicles, microRNAs, and other liquid-biopsy biomarkers, show potential for diagnosis, prognosis, and disease monitoring; however, their clinical utility remains limited by small cohorts, methodological heterogeneity, lack of standardized assays, and insufficient prospective validation. Established therapeutic approaches, including surgery, chemotherapy, and guideline-supported systemic treatment, remain central to GBC management, while immune checkpoint inhibitors, molecularly targeted therapies, and nanotechnology-based strategies represent either biomarker-selected, broader biliary tract cancer-derived, or investigational approaches with varying levels of clinical evidence. The review therefore highlights the distinction between established clinical practice and emerging strategies requiring further GBC-specific validation.

The available evidence indicates that GBC management is progressing from conventional clinicopathological assessment toward molecularly informed and biomarker-guided strategies. However, important gaps remain in the clinical validation of emerging biomarkers, standardization of liquid-biopsy assays, prospective evaluation of predictive biomarkers, and generation of GBC-specific evidence for therapies frequently evaluated within broader biliary tract cancer populations. Future research should prioritize multicenter validation, longitudinal biomarker assessment, and integration of molecular, immune, and clinical characteristics to establish which emerging approaches can be translated into routine GBC practice.