Letter to the Editor: Gallbladder cancer deserves attention: From epidemiologic awareness to organized referral pathways and translational research

Abstract

We read with interest the editorial by Tsukanov et al published in the World Journal of Gastroenterology regarding the relevance of gallbladder cancer (GBC). Although emerging evidence points to the roles of bile acids, the microbiota, and immune regulation in GBC carcinogenesis, findings from our Brazilian cohort highlight the ongoing impact of late diagnosis and fragmented referral pathways. Most patients presented with advanced disease at the time of diagnosis and were ineligible for curative-intent treatment. We believe that improving GBC outcomes requires integrating translational research with structured clinical pathways, specialized multidisciplinary care, and timely access to specialized treatment.

Key Words: Gallbladder cancer; Gallbladder neoplasms; Biliary tract neoplasms; Early diagnosis; Referral pathways; Multidisciplinary care; Prognosis

Core Tip: Gallbladder cancer (GBC) remains a highly lethal disease. Although insights into bile acids, microbiota, and immune regulation may enhance our understanding of carcinogenesis, late diagnosis and a lack of access to specialized care continue to contribute to the poor outcomes observed in patients with GBC. In turn, data from our Brazilian cohort highlight the need to combine biological insights with organized clinical pathways to improve survival.

TO THE EDITOR

We read with great interest the editorial by Tsukanov et al[1] “Gallbladder cancer: Is significant attention to this pathology justified?”, which discussed the relevance of gallbladder cancer (GBC) as a highly lethal malignancy and emphasized the potential links among cholelithiasis, bile acid metabolism, gastrointestinal microbiota, immune regulation, and gastrointestinal carcinogenesis[1]. We appreciate the authors’ thoughtful discussion of our study “Gallbladder carcinoma in Brazil: Clinicopathological profile and survival outcomes from a high-volume cancer center”, and we agree that GBC deserves greater scientific, clinical, and public health attention[2].

Our Brazilian cohort reinforces this need from a real-world clinical perspective. In our study, 364 patients with histologically confirmed gallbladder adenocarcinoma were treated at a high-volume cancer center between 2010 and 2024. Most patients presented with advanced disease: 72.3% were diagnosed at stage IV, reflecting the well-recognized tendency of GBC to remain clinically silent or cause nonspecific biliary symptoms until the disease is advanced. Accordingly, median overall survival was only 11.5 months, and the 5-year overall survival rate was 15.4%. Although incidental GBC accounted for 54.1% of cases and was associated with better outcomes than non-incidental GBC, only 13.5% of patients ultimately underwent curative-intent surgery. These findings illustrate a central paradox in GBC care: The disease is uncommon enough to be overlooked, yet sufficiently aggressive that late recognition frequently narrows or eliminates the window for curative treatment[2].

Closer clinical and imaging assessment is warranted in patients with gallbladder polyps measuring at least 10 mm, interval growth or suspicious morphology[3], anomalous pancreaticobiliary junction, selected patterns of gallbladder wall calcification, or longstanding symptomatic gallstone disease, particularly among older adults and populations from high-incidence regions[4]. Risk assessment should also consider established epidemiological factors, including obesity, smoking, prior biliary tract infections, and multiparity in women[4]. However, current evidence does not support population-wide screening for GBC[5]. Instead, risk-adapted ultrasonographic surveillance or prophylactic cholecystectomy may be appropriate for selected gallbladder abnormalities according to established guidelines, whereas regional screening strategies in high-incidence areas require prospective evaluation.

Most GBCs are sporadic; however, familial aggregation and pathogenic germline variants in cancer-predisposition genes have been reported across biliary tract cancers. Evidence remains insufficient to support a GBC-specific screening program for unaffected relatives, but genetic counseling and germline testing may be considered in younger patients and in those with multiple primary malignancies, a strong family history, or features suggestive of a hereditary cancer syndrome[6,7].

We agree with Tsukanov et al[1] that cholelithiasis, bile acid metabolism, and the microbiome represent promising areas for mechanistic research[1]. Contemporary reviews have highlighted the biological plausibility of a carcinogenic pathway involving chronic inflammation, altered bile acid signaling, dysbiosis, and immune modulation[5]. However, from the standpoint of clinical implementation, these translational hypotheses must be integrated with pragmatic health-system interventions. Patient outcomes are determined not only by tumor biology, but also by late-stage presentation, incomplete initial staging, non-standardized histopathological assessment of cholecystectomy specimens, and delayed referral to specialized hepatobiliary centers[2,5].

This issue is particularly relevant in countries outside the highest-incidence regions, including Brazil. Global data confirm marked geographic heterogeneity, with particularly high incidence in selected regions of South America and Asia, including Bolivia, Chile, Peru, Bangladesh, Nepal, and northern India[8-10]. Nevertheless, our findings suggest that even outside the highest-incidence belts, GBC can impose a substantial clinical burden when referral pathways are fragmented[2]. The high proportion of incidental diagnoses in our cohort also underscores the importance of systematic pathological examination of cholecystectomy specimens[5]. Patients with incidental GBC staged as pT1b or higher who are medically fit and have no evidence of metastatic or unresectable disease should be promptly referred to specialized hepatobiliary centers for consideration of completion radical re-resection. Completion re-resection generally includes an R0-directed hepatic resection of the gallbladder bed and regional portal lymphadenectomy, aiming to retrieve at least six lymph nodes for accurate pathological staging[11,12] (Figure 1).

Figure 1 Integration of biological mechanisms and clinical pathways in gallbladder cancer care.

Therapeutic advances further support the need for organized care. Complete oncologic resection remains the only potentially curative treatment, whereas systemic therapy for advanced biliary tract cancer has historically offered limited survival. The ABC-02 trial established gemcitabine plus cisplatin as the historical first-line backbone, whereas TOPAZ-1 and KEYNOTE-966 subsequently demonstrated overall survival benefits from adding durvalumab or pembrolizumab, respectively, to gemcitabine-cisplatin in advanced biliary tract cancer[13-15]. However, the clinical impact of these advances depends on timely diagnosis, multidisciplinary treatment selection, equitable access to systemic therapy, and molecular profiling to identify actionable alterations and clinical trial opportunities[5].

Three complementary features warrant greater attention to GBC. First, the disease has disproportionate lethality relative to its incidence. Second, curative treatment is highly time-sensitive and depends on early recognition and appropriate referral. Third, GBC provides a biologically relevant model to investigate the interface among gallstones, chronic inflammation, bile acids, microbiota, genetics, and carcinogenesis. Future efforts should combine multicenter clinical registries, standardized surgical and pathological quality indicators, molecular and genomic profiling, and translational studies focused on bile acid-microbiome-immune interactions[1,5].

GBC should no longer be viewed solely as a rare malignancy, but rather as a disease in which survival depends on the successful integration of biological discovery with coordinated clinical care.

In conclusion, we strongly agree that GBC should not be considered a closed chapter. The next step is to transform epidemiologic concern into structured clinical pathways and research networks capable of improving early diagnosis, surgical access, systemic treatment selection, and ultimately patient survival. In this context, significant attention to GBC is not only justified, but essential if emerging biological insights are to be translated into meaningful improvements in patient outcomes.