Gallbladder cancer: Is significant attention to this pathology justified?

Abstract

The highest incidence rates of gallbladder cancer (GBC) are registered among the populations of South America (Bolivia: 7.6 per 100000 population), Asia (Bangladesh: 5.25 per 100000), and North Africa (Algeria: 2.65 per 100000). Recent studies demonstrate a significant association between GBC, cholelithiasis and extrahepatic gastrointestinal cancer, which allows for the development of a systemic approach to this problem and a more active search for pathophysiological predictors of such a relationship. Changes in the metabolism and ratio of primary and secondary bile acids, mutually regulated by the structure of the gastrointestinal microbiome, which modulate the function of farnesoid X receptor and Takeda G protein-coupled receptor 5 receptors, influence the differentiation and activity of key substrates of innate and adaptive immunity, and are mutually regulated by the structure of the microbiome, may be a key link explaining the association between GBC and other gastrointestinal oncological diseases. The results of such studies clearly have practical potential for developing original technologies for the gastrointestinal cancers prevention. In this regard, the study by Makdissi et al, published in World Journal of Gastroenterology, analyzing patients with gallbladder cancer in Brazil, provides a basis for developing new approaches to this well-known clinical problem.

Key Words: Gallbladder cancer; Bile acids; Gastrointestinal microbiota; Cholelithiasis; Epidemiology

Core Tip: Gallbladder cancer is characterized by high malignancy, a 5-year survival rate of less than 10%, and is extremely difficult to early diagnosis. Modern epidemiological studies highlight a strong association of gallbladder cancer with cholelithiasis, gastric cancer, hepatocellular carcinoma, pancreatic cancer and colorectal cancer. Investigation of the mechanisms of interaction between bile acids, gastrointestinal microbiota, the immune response, and metabolic pathways may be the primary pathogenetic paradigm for explaining this phenomenon and offers clear prospects for the development of new research directions to improve therapeutic and preventive technologies.

This editorial refers to "Gallbladder carcinoma in Brazil: Clinicopathological profile and survival outcomes from a high-volume cancer center" by Makdissi et al, 2026; https://doi.org/10.3748/wjg.v32.i7.113845.

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INTRODUCTION

Gallbladder cancer (GBC) is a malignant tumor originating from the gallbladder epithelium, characterized by local and vascular invasion, extensive regional lymphogenous and hematogenous metastasis[1]. GBC is relatively rare, but among all types of biliary tract cancer, it is the most common malignant tumor[2]. This neoplasm is characterized by high malignancy, with a 5-year survival rate of less than 10%[3].

NEW ASPECTS OF THE GBC EPIDEMIOLOGY

Interest in GBC is driven by several factors. First, there is the concept of the pathogenesis of biliary tract diseases, according to which cholelithiasis can lead to the development of cholecystitis and gallbladder polyps, which significantly increase the probability of developing GBC[4]. It should be emphasized that recently the direction of epidemiological studies has changed, which began to pay significant attention to the association of cholelithiasis not only with GBC and neoplasms of other localizations, but also with various metabolic disorders and cardiovascular diseases[5]. In a meta-analysis of 23 cohort studies conducted in Asia, Europe, and America, the presence of gallstones increased the risk of GBC by 7.3 times. Stone size greater than 1 cm and the number of gallstones were directly associated with biliary tract cancer[6]. Another meta-analysis (51 studies, including 13 million patients) demonstrated a significant increase in the risk of cancer in general [odds ratio (OR) = 1.43], gastrointestinal cancer (OR = 1.28), liver, pancreatic and biliary tract cancer (OR = 1.84) in patients with cholelithiasis[7]. In a study from China that examined 239799 people, the presence of gallstones was associated with a high risk of gastric cancer (OR = 2.54), liver and bile duct cancer (OR = 2.46), kidney cancer (OR = 2.04), and GBC (OR = 2.23)[8]. Monitoring of 86000 women and 44000 men over 32 years showed an increase in overall mortality from cancer of various localizations and cardiovascular diseases in the group of people with biliary pathology[9].

The second factor that emphasizes the importance of studying GBC is its high malignancy. Although GBC is not a common oncological neoplasm and ranks 22^nd globally in primary incidence, with an age-standardized rate (ASR) of 1.2 per 100000 population, the mortality ASR accounts for more than two-thirds of the incidence rate and is equal to 0.83 per 100000 population. According to the GLOBOCAN 2022 database, the highest incidence rates of GBC are registered among the population of South America (Bolivia: 7.6 per 100000; Chile: 5.7 per 100000; Peru: 2.6 per 100000), Asia (Bangladesh: 5.25 per 100000; Nepal: 4.36 per 100000; Republic of Korea: 2.62 per 100000) and North Africa (Algeria: 2.65 per 100000; Libya: 2.22 per 100000)[10]. There are differences in the GBC incidence depending on the region of the country. For example, in India, the GBC incidence ASR is 10 times higher in the northern part of the country compared to the southern states (8.9 cases per 100000 in Delhi vs 0.8 cases per 100000 population in Chennai)[11]. In terms of GBC mortality, Bolivia (6.33 per 100000), Bangladesh (4.17 per 100000), Chile (3.61 per 100000) and Nepal (3.27 per 100000) are leading[10].

An analysis of epidemiological data shows that cholelithiasis and GBC are associated with oncological pathologies in other locations and metabolic diseases. In this regard, a Brazilian study by Makdissi et al[12], published in World Journal of Gastroenterology, that followed 364 patients with gallbladder adenocarcinoma diagnosed from 2020 to 2024 provides a rationale for a systematic interpretation of the data obtained and a search for pathogenetic mechanisms underlying this pattern. We think that the mutual regulation of bile acid metabolism and the intestinal microbiome may be a key link explaining the association between GBC and other oncological diseases of the digestive system.

PATHOPHYSIOLOGICAL ASPECTS OF THE ASSOCIATION OF GBC WITH GASTROINTESTINAL NEOPLASMS

It is well known that bile acids play an important role in the physiological processes of fat absorption, cholesterol secretion, and cholesterol gallstone formation. The primary human bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver, secreted into the intestine, and undergo bacterial biotransformation to form secondary bile acids, including deoxycholic acid and lithocholic acid. The importance of the microbiome in bile acid metabolism has been well known for a long time[13]. Bile acids are key molecules shaping the microbial ecology in the intestine through their antimicrobial activity and by activating host signaling pathways[14,15]. In turn, microbes alter the size and composition of the bile acid pool. Thus, a feedback mechanism between bile acid metabolism and the intestinal microbiome is formed[16,17].

Recent studies highlight the active interactions between the gastrointestinal microbiota, bile acids, the immune response, and metabolic pathways. Dysbiosis, defined as a condition characterized by reduced microbial diversity and the dominance of pathogenic strains, alters bile acid metabolism, increases intestinal permeability, modulates immune dysregulation, and stimulates liver inflammation[18]. It has been suggested that intestinal dysbiosis, manifested by the prevalence of Fusobacterium nucleatum, Escherichia coli, and Bacteroides fragilis, along with the action of secondary bile acids, promotes the development of colorectal cancer by inducing chronic inflammation, oxidative stress, and damaging the host’s DNA[19]. Changes in the metabolism and ratio of primary and secondary bile acids that modulate the function of farnesoid X receptor and Takeda G protein-coupled receptor 5 receptors, affecting the differentiation and activity of key substrates of innate (macrophages, natural killer cells) and adaptive immunity (CD8+ T cells, regulatory T cells, Th1/Th17 cells) are of great importance in modern meta-analyses devoted to the pathophysiology of liver cancer[20,21] and colorectal cancer[22].

The discussion of the genetic aspects of biliary pathology deserves attention. A classic study of 43141 pairs of twins was published in 2005, which showed that genetic factors make a significant contribution to the development of cholelithiasis compared with phenotypic influence[23]. Our work on examining the health of various ethnic groups in Siberia demonstrated that among Caucasoids in Evenkia and Khakassia, the prevalence of cholelithiasis was 8.8% and 7.2%, respectively, while among indigenous peoples, these numbers were 1.5% in Evenkia and 3.4% in Khakassia. We think that the biosynthesis of bile acids in the liver corresponds to national nutritional traditions and is genetically determined[24].

DIAGNOSIS AND RISK FACTORS FOR GBC

Current diagnosis of GBC is challenging. The guidelines of the Japanese Hepato Biliary-Pancreatic Surgery Society emphasize that symptoms of gallbladder neoplasm appear late and that in most patients, GBC is discovered incidentally during ultrasound or cholecystectomy[25]. The first step in diagnosis is biochemical blood analysis and ultrasound, which is the dominant method for this pathology[26]. Subsequent steps include multiphase contrast-enhanced computed tomography, magnetic resonance cholangiography and endoscopic ultrasound[25]. Gallbladder biopsy with histological examination is the gold standard for confirming the diagnosis of GBC, allowing us to establish whether the tumor is malignant, determine the type and stage of the disease, which is crucial for developing an individualized treatment plan. A study of 28 patients who underwent percutaneous transhepatic core needle biopsy revealed the presence of GBC in 4 patients and benign tumors in 24 patients. No significant complications of this procedure were observed in the patients[27]. A modern comparative study of the diagnostic performance of ultrasound-guided percutaneous transhepatic biopsy (PTGB) and endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) for the detection of gallbladder tumors demonstrated the same sensitivity and specificity of both methods (94.2% and 94.2% for PTGB and 97.8% and 98.0% for EUS-FNA). However, EUS-FNA was associated with a significantly lower rate of adverse reactions (2.04%) compared to PTGB (15.38%)[28].

Due to the complexity of early diagnosis of GBC, it is necessary to pay attention to the key risk factors for this pathology, which include female gender (in women, GBC may occur on average 3 times more often than in men)[29], the presence of gallstone disease (stone sizes greater than 2 cm increase the risk of GBC by 2.4 times, and the duration of cholelithiasis for more than 20 years – by 6.2 times)[30], age over 65 years[31], obesity[32], genetic predisposition[29], bacterial infection of the biliary tract[33] and adenomatous polyps of the gallbladder[34]. Modern meta-analyses confirm that risk factors for biliary tract cancer are obesity (OR = 1.7) and infection of bile ducts (OR = 31.7)[35], as well as advancing age (OR = 1.09), female gender (OR = 1.9), elevated alkaline phosphatase (OR = 1.7), polyps larger than 10 mm (OR = 8.6) and open cholecystectomy (OR = 9.20)[36].

Since gallbladder polyps are an important predictor of GBC, we considered it appropriate to draw attention to European guidelines for the management of patients with this pathology. Ultrasound and, if necessary, endoscopic ultrasound can be used as diagnostic methods for polyps. Cholecystectomy is recommended for patients with gallbladder polyps 10 mm or larger, provided that the patient has no somatic contraindications to surgery and consents to it. Cholecystectomy is indicated in patients with a polyp 6-9 mm in diameter and one or more risk factors (age over 60 years, history of primary sclerosing cholangitis, Asian ethnicity, broad-based polypoid lesion). In patients with a polyp 6-9 mm in diameter and no risk factors, or with a polyp 5 mm in diameter and risk factors, follow-up ultrasound of the gallbladder is recommended after 6 months, 1 year, and 2 years. Follow-up should be stopped after 2 years if there is no polyp growth[31,37].

CONCLUSION

The problem of association between GBC, cholelithiasis and extrahepatic gastrointestinal cancer poses new challenges for epidemiological research and allows for a more active search for pathophysiological predictors of such an association. Clearly, the study of cholelithiasis and GBC is not a closed chapter and holds promising prospects for further development. The assertion that cholelithiasis and gallbladder polyps should be considered precancerous conditions deserves more attention. One possible direction for future research in the prevention of gastrointestinal cancer (and, possibly, metabolic diseases) may be the stimulation of bile acid biosynthesis in the liver, modulation of the intestinal microbiome, and the search for opportunities to regulate the interaction of the pool and composition of cholates with the structure of the microbiome.