Gallbladder Cancer: A Complete Guide to Causes, Risks, Detection and Treatment

Table of Contents

• Key Points
• Overview: What Is Gallbladder Cancer?
• The Gallbladder and the Biliary Tract
• How Common Is Gallbladder Cancer?
• Who Is at Risk?
• How Gallbladder Cancer Develops: The Role of Inflammation
• The Metaplasia–Dysplasia–Carcinoma Pathway
• The Adenoma–Carcinoma Pathway
• Diagnosis and Its Challenges
• Treatment: Current Options and Their Limits
• Clinical Implications: What This Means for Patients
• Limitations of Current Knowledge
• Recommendations and Actionable Advice
• Frequently Asked Questions
• Source Information

Key Points

• Gallbladder cancer is the most common biliary tract cancer and is usually diagnosed late, often incidentally after gallbladder removal for gallstones.
• Chronic inflammation is the main driver, with most cancers following a metaplasia–dysplasia–carcinoma sequence and 5–10% an adenoma–carcinoma sequence.
• Gallstones are present in up to 90% of patients at diagnosis, but only about 1% of people with gallstones develop gallbladder cancer.
• Surgery is the only curative treatment, yet few cases qualify; most treatment given after surgery has a very low response rate, while targeted and immune therapies have emerged as promising alternatives to extend survival and quality of life.
• In a mouse model, ezetimibe prevented gallstone formation and the onset of metaplasia and dysplasia, suggesting a possible chemoprevention strategy.

Overview: What Is Gallbladder Cancer?

Gallbladder cancer (GBC) is the most common cancer of the biliary tract, the network of organs and ducts that produce and transport bile. It is also one of the most aggressive. The disease tends to be diagnosed late, when treatment options are few, and outcomes are poor at those advanced stages.

Early detection at a stage where surgery could cure the disease remains very difficult. Patients rarely notice symptoms early on. In fact, most gallbladder cancers are discovered incidentally — meaning they are found unexpectedly — when pathologists examine gallbladder tissue removed during a cholecystectomy (surgical removal of the gallbladder), usually performed because of symptomatic gallstones.

Longstanding chronic inflammation is an important driver of this cancer, regardless of whether gallstones are present (lithiasic inflammation) or absent (non-lithiasic inflammation). New molecular technologies have given researchers a much deeper understanding of how inflammation triggers tumors and how these tumors progress.

Surgical removal is the only treatment with curative intent for gallbladder cancer, but very few cases are suitable for this operation. Most adjuvant therapy (treatment given after surgery) produces a very low response rate. These unmet needs have driven efforts to find reliable biomarkers — measurable biological signals — for screening, therapy selection and prognosis.

The Gallbladder and the Biliary Tract

The gallbladder is a small, pear-shaped organ that sits on the undersurface of the liver. It stores and concentrates bile, a digestive fluid. Bile drains from the gallbladder through the cystic duct, which joins the common hepatic duct to form the common bile duct.

Anatomically, the gallbladder wall is unusual. It has a discontinuous muscle layer and lacks a muscularis mucosa (a thin layer of muscle found in most of the digestive tract). About 30% of the gallbladder's surface is attached directly to the liver; the remaining surface is covered by peritoneum, the membrane that lines the abdominal cavity.

Biliary tract cancers (BTC) include cholangiocarcinoma (cancer of the bile ducts, subdivided into intrahepatic, perihilar and extrahepatic types) and gallbladder cancer. When a tumor arises at the neck of the gallbladder, it can look identical to a hilar or mid-common-bile-duct cholangiocarcinoma, making the two difficult to tell apart. However, gallbladder cancer is more aggressive, and patient outcomes are often poorer than for perihilar cholangiocarcinoma.

About 95% of gallbladder cancers arise from epithelial cells (the cells lining body surfaces) with features of cholangiocytes, the cells that line the bile ducts. The most common histological type (the type identified under a microscope) is adenocarcinoma, which accounts for more than 90% of cases. Less common subtypes include squamous, undifferentiated, mucinous and neuroendocrine carcinomas.

How Common Is Gallbladder Cancer?

In 2020, an estimated 115,949 new cases of gallbladder cancer were diagnosed worldwide. This ranked the disease 25th out of 36 cancers tracked across 185 countries.

Globally, gallbladder cancer is more common in women than in men. In the Americas, the incidence rate ratio between women and men is about 2 to 1. In the United States, the age-adjusted incidence rate is 1.9 per 100,000 women compared with 1.1 per 100,000 men — roughly 1.9 in every 100,000 women and 1.1 in every 100,000 men. In Chile, the rates are much higher: they range from 8.3 to 18.8 per 100,000 women compared with 3.2 to 5.8 per 100,000 men.

Risk increases with age. In Delhi, India, the age-adjusted incidence rate climbs from less than 1 per 100,000 in people under 30 years of age to a peak of 43.7 per 100,000 in women and 24.0 per 100,000 in men aged 70–74 years. The average age at diagnosis is about 20 years younger in India than in Western countries.

Regions with a higher human development index, higher income, higher tobacco use, higher rates of overweight or obesity, and higher prevalence of hypercholesterolemia (high blood cholesterol) tend to have higher gallbladder cancer incidence and mortality.

Global Trends Over Time

Between 1980 and 2017, gallbladder cancer incidence fell in men in 3 of 45 countries (7%) and rose in 5 of 45 countries (11%). In women, incidence fell in 13 of 45 countries (29%) and rose in 4 of 45 countries (9%).

Mortality (death rates) declined in a larger share of countries. Deaths fell among men in 8 of 44 countries (18%) and among women in 18 of 44 countries (41%).

These averages hide important differences between populations. In the United States, incidence increased among Black individuals and among people under 45 years of age — both by 1.8% per year — from 1999 to 2003. Between 1980 and 2017, mortality rose among men in Ecuador (2.3% per year) and Germany (1.2% per year), and among women in the Netherlands (2.9% per year) and the United Kingdom (2.6% per year). Mortality also appears to have increased in Colombian and Canadian men between 2010 and 2016.

Geographic Hotspots

Although gallbladder cancer is rare in most countries, its distribution around the world is remarkably uneven. Nearly 40% of the countries with the highest incidence rates — 15 of the 38 countries with rates of at least 1.3 per 100,000 — are in South America, South Asia and Southeast Asia. Indigenous populations in South America, Northern India and East Asia have particularly high rates.

In the United States, the highest rates occur among Native American, Hispanic and other non-white populations. The proportion of biliary tract cancers caused by gallbladder cancer is higher among American Native and Alaskan Native individuals than in any other population. This disparity varies by region: Alaskan Native and American Native individuals in the Southwest have the highest incidence compared with non-Hispanic White individuals.

India illustrates the geographic variation vividly. About 10% of the world's gallbladder cancers are estimated to occur there. In Delhi, in the north, the incidence is nearly ten times higher than in Chennai, in the south. Even after migrating to a low-risk region, people born in a high-risk region of India had a slightly increased risk compared with those born in a low-risk region (odds ratio 1.4, 95% confidence interval 1.0–1.8). In Chile, age-standardized incidence rates are about two to three times higher in south-central Chile than in the north. Environmental factors, along with population-specific risk factors, may explain these patterns.

Who Is at Risk?

Native American individuals carry a disproportionately high burden of both gallbladder cancer and gallstones, a major risk factor for the cancer. Gallstones are present at diagnosis in up to 90% of patients with gallbladder cancer, especially in high-risk areas and populations. Gallstones are strongly associated with increased gallbladder cancer risk and are typically diagnosed years before the cancer develops.

Populations with high gallbladder cancer incidence tend to have high gallstone prevalence, although the link is weaker than you might expect. For example, in several East Asian countries, gallbladder cancer incidence is elevated even though gallstone disease is uncommon. This pattern suggests a cause unrelated to gallstones in those countries, such as pancreatobiliary maljunction (a congenital abnormality where the pancreatic and bile ducts join outside the intestinal wall).

Environmental exposures also vary by region. Mustard oil, used mainly in the high-risk region of northern India and in Nepal, has been associated with gallbladder cancer.

Do Gallstones Actually Cause Gallbladder Cancer?

Some researchers have questioned whether gallstones truly cause gallbladder cancer, since the two conditions share many risk factors. But a technique called Mendelian randomization — which uses genetic variants to test whether an exposure causally affects an outcome — supports a causal role.

• One study found an odds ratio of 2.0 (95% CI 1.4–2.8) for gallstones and gallbladder cancer in Chile, and 5.0 (95% CI 2.2–11.3) in Europe.
• Another study found an odds ratio of 4.5 (95% CI 3.5–5.8) for self-reported gallstones and 2.0 (95% CI 1.5–2.7) for objectively diagnosed gallstones in India.

An odds ratio above 1.0 means the exposure is linked to higher risk; for example, an odds ratio of 2.0 means roughly double the odds.

A transcriptomic analysis (a study of which genes are switched on or off) examined 10 patients with gallbladder cancer and 30 patients with gallstones. The gallstone group was divided into three subgroups of 10 patients each, based on how long it had been since their gallstone diagnosis: 1–3 years, 5–10 years, or more than 10 years before surgery. Patients whose gallstones had been diagnosed only 1–3 years earlier had the fewest number of differentially expressed genes in gallbladder tissue compared with cancer tissue — meaning their tissue looked most similar to cancer tissue. The authors suggest that worsening symptoms shortly after a gallstone diagnosis might signal an increased risk of gallbladder cancer. Patients diagnosed more than 10 years before cholecystectomy showed the next highest similarity, supporting a role for chronic trauma and inflammation in gallstone-related cancer development.

Other Contributing Factors

Despite the evidence for causality, only about 1% of people with gallstones develop gallbladder cancer — about 1 in 100. This strongly suggests that additional factors are involved. Genetics may play a part: a genome-wide association study in an Indian population identified three germline variants (inherited gene changes) in the ABCB1 and ABCB4 genes that were later also found in Chilean and European populations.

Exposure to aflatoxin B1, a potent liver carcinogen produced by certain molds, has also been linked to gallbladder cancer. Studies found odds ratios of 2.7 (95% CI 1.7–4.3) in China and 9.4 (95% CI 2.8–37.2) in Chile when comparing people with gallbladder cancer to those with gallstones but no cancer. Some parts of the United States, including the Southwest, have climates that make crops prone to contamination with Aspergillus flavus, a mold that is a primary producer of aflatoxin B1.

Aflatoxin exposure also appears to be high in areas of Nepal near the high-risk region of northern India, which may contribute to elevated rates in these Asian populations. Marginalized populations have higher aflatoxin exposure, potentially because they consume more non-commercially produced food. High aflatoxin exposure has been documented in indigenous and low-socioeconomic-status populations in Mexico and Africa, raising the question of whether aflatoxin might increase gallbladder cancer risk in indigenous populations in the United States and elsewhere.

Additional reported risk factors include:

• Polypoid gallbladder lesions (growths projecting into the gallbladder)
• Metabolic syndrome
• Parity (number of pregnancies)
• Bile duct abnormalities
• Primary sclerosing cholangitis (a chronic liver and bile duct disease)
• Family history of gallstones
• Salmonella enterica serovar Typhi infection (the bacterium that causes typhoid fever)
• Exposure to heavy metals
• Diet
• Chemical exposures such as organochlorines (a class of industrial chemicals and pesticides)

How Gallbladder Cancer Develops: The Role of Inflammation

Chronic inflammation is the main process driving gallbladder cancer. Inflammation creates a permissive environment — one that allows and encourages malignant transformation and tumor progression.

Current understanding recognizes two major histogenic pathways (routes by which normal tissue becomes cancer), both driven by long-standing inflammation, whether gallstones are present or not.

1. Most gallbladder cancers appear to develop when gallstones are present, following a metaplasia–dysplasia–carcinoma sequence. Here, the gallbladder lining undergoes progressive changes under chronic inflammation, leading to carcinoma in situ (cancer confined to the surface layer) and finally invasive adenocarcinoma.
2. About 5–10% of gallbladder cancers appear to develop through an adenoma–carcinoma sequence, which is less often linked to gallstones but still involves chronic inflammation that favors adenoma (a benign growth) formation and the buildup of molecular changes.

Both models are supported by morphological (structural) and molecular evidence, though understanding of the underlying mechanisms remains limited. Recent next-generation sequencing (NGS) and multi-omics studies — technologies that read large amounts of genetic and molecular data at once — have revealed key cancer-driving mutations, subtypes based on the tumor microenvironment, and important oncogenic (cancer-promoting) pathways.

The Metaplasia–Dysplasia–Carcinoma Pathway

Most gallbladder cancers — 70–90% — arise in the setting of cholelithiasis (gallstones), which is considered the major risk factor. Gallstones, most of which consist mainly of cholesterol, form when environmental and genetic factors disrupt critical metabolic processes, producing gallbladder hypomotility (poor emptying) and altered bile acid composition.

Specifically, decreased bile acid production and increased secretion of hepatic and intestinal cholesterol into the bile result in cholesterol-supersaturated bile. This favors the precipitation of solid cholesterol crystals and gallstone formation.

Cholelithiasis is often asymptomatic, but about a quarter of cases — roughly 1 in 4 — can produce symptoms over decades through repeated acute episodes. These episodes involve total or partial blockage of the cystic duct and massive inflammatory destruction of the gallbladder lining. Continuous cycles of mucosal damage and repair, combined with the chemical pro-inflammatory effect of lithogenic (stone-forming) bile, create a long-standing chronic inflammatory response that disrupts cellular homeostasis (the cell's stable internal balance).

This chronic condition, called chronic cholecystitis (persistent gallbladder inflammation), is characterized by overexpression of cyclooxygenase-2 (COX-2), an enzyme involved in inflammation, and high infiltration of immune cells. These include T cells, B cells, COX-2/iNOS-positive macrophages, iNOS-positive granulocytes and mast cells. Histological changes such as metaplasia (one cell type changing into another) and dysplasia (abnormal, precancerous cell growth) — both considered precursor lesions of gallbladder cancer — are common in this setting.

What Studies in Animals Show

Studies using mouse models of cholelithiasis have linked chronic cholecystitis with the histological and structural changes seen in the gallbladder lining. A new mouse model of gallbladder preneoplasia (precancerous change) showed that metaplasia and dysplasia are strongly associated with gallstone-mediated inflammation.

The timing of immune cell infiltration mattered. High infiltration of polymorphonuclear neutrophils (PMN) and F4/80+ macrophages early on correlated with hyperplasia (overgrowth of cells) and metaplasia. In contrast, increased infiltration of adaptive immune cells (CD4+ and CD8+ T cells) correlated with the development of dysplasia.

Notably, inhibiting gallstone formation with ezetimibe, a cholesterol-lowering drug, prevented the excessive inflammatory response and the onset of metaplasia and dysplasia. This provides preclinical evidence for targeting gallstones as a chemoprevention strategy — using medication to prevent cancer — in high-risk populations.

Genetic Damage Accumulates Step by Step

Sequential histological changes are accompanied by cumulative molecular alterations, which appear even in histologically normal gallbladder epithelia from patients with chronic cholecystitis. NGS-based mutational profiling showed that about 30% of chronic cholecystitis samples — 7 of 23 — had cancer-driver somatic alterations (mutations or copy loss) in the genes TP53, CDKN2A, PIK3R2 and CHD1.

Chronic inflammation is known to damage DNA through oxidative stress generated by elevated levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) — unstable molecules that harm cells. DNA damage activates various response pathways, including the p53-mediated tumor suppression pathway. This pathway acts as a major barrier against tumor formation by controlling processes such as apoptosis (programmed cell death), senescence (cellular aging) and cell-cycle arrest in damaged cells.

Sustained inflammation-related DNA damage may cause genomic instability and early p53 dysfunction. That dysfunction, in turn, enhances chronic inflammation and hyperactivates inflammatory mediators and pro-oncogenic signaling pathways, ultimately leading to neoplastic transformation of inflamed tissues.

In gallbladder carcinogenesis, TP53 alterations are the earliest genetic events. They are detectable in chronic cholecystitis and accumulate as precursor lesions progress from metaplasia to invasive cancer. Loss of p53 function contributes similarly to many other inflammation-related cancers, including intestinal-type Helicobacter pylori-associated gastric adenocarcinoma (stomach cancer), fluke-related cholangiocarcinoma and ulcerative colitis-associated colorectal cancer.

More broadly, genetic abnormalities affecting DNA repair pathways appear to be frequent in gallbladder cancer. These include somatic mutations in direct DNA repair genes (predominantly ATM and BRCA2) and caretaker genes (predominantly TP53). Inefficient DNA repair leads to genome instability and the accumulation of mutations — a critical driver of cancer initiation and progression.

Accordingly, loss of heterozygosity (LOH) — the loss of one copy of a gene — is detected in chronic cholecystitis and progressively accumulates through the histogenic sequence. Tumor suppressor genes (genes that normally restrain cancer) affected by allelic loss include FHIT, APC, CDKN2A, CDH1, RB1, TP53 and DCC.

The expression of many of these genes is regulated by epigenetic mechanisms (changes that affect gene activity without altering the DNA sequence), particularly hypermethylation of their promoter regions — a chemical "switch" that silences genes. The number and magnitude of epigenetic alterations increase during gallbladder carcinogenesis and affect genes involved in communication between cells and their environment.

Inflammation Recruited by the Tumor Itself

Once a tumor is established, tumor cells can recruit inflammatory immune cells into their local microenvironment. Crosstalk between tumor and stromal cells (the supportive tissue around a tumor) then drives invasion and metastasis (spread to other parts of the body).

This cancer-elicited inflammation differs from the earlier pro-tumorigenic inflammation, but it results in a profoundly immunosuppressive microenvironment — a setting where the immune system is held back from attacking the tumor. The molecular mechanisms underlying these two inflammatory conditions, and their effect on gallbladder cancer, are only beginning to be clarified.

The Adenoma–Carcinoma Pathway

Gallbladder cancer can also develop from adenomatous precursor lesions — growths that are not yet cancer — most of which occur in the context of non-lithiasic inflammation (inflammation without gallstones). This pathway accounts for 5–10% of gallbladder cancers and remains poorly characterized compared with the stepwise metaplasia–dysplasia–carcinoma model.

The 2019 World Health Organization (WHO) classification of tumors of the digestive system recognized the intracholecystic papillary-tubular neoplasm (ICPN) as one of the precursor lesions of gallbladder carcinoma. An ICPN is an exophytic preinvasive neoplasm — a growth that projects outward from the mucosa into the gallbladder cavity rather than spreading within the wall.

Unlike the flat premalignant lesions seen in cancers that arise via metaplasia–dysplasia, ICPNs are infrequently associated with cholelithiasis. However, they occur at a relatively high frequency — about 30% — in people with pancreaticobiliary maljunction (PBM).

PBM is a congenital malformation in which the junction of the pancreatic and bile ducts lies outside the duodenal wall. This condition causes bile stasis (poor bile flow) and chronic reflux of pancreatic juice into the biliary tract and gallbladder. There, activated proteolytic pancreatic enzymes modify bile composition and generate strong cytotoxic substances (such as lysolecithin) that damage the gallbladder lining and trigger a constant, excessive inflammatory state.

This process promotes oxidative stress and DNA damage. Evidence of this damage comes from the overexpression of 8-hydroxy-2'-deoxyguanosine and γ-H2AX (a biomarker for DNA double-strand breaks) in the gallbladder lining of patients with PBM. Together, these events may facilitate the formation of adenomatous lesions and their eventual malignant transformation into invasive carcinoma.

Genetic Changes in PBM-Related Gallbladder Cancer

Genetic changes underlying cancer development in patients with PBM-related gallbladder cancer include high frequencies of mutations in several genes:

• TP53 — 50%
• EGFR — 20.6%
• RB1 — 17.6%
• ERBB2 — 17.6%

However, the molecular pathology of ICPN lesions has not been studied extensively. To date, only one study has evaluated the mutational profile of ICPNs, in a total of 7 patients, 4 of whom had an associated invasive carcinoma. That study showed ICPNs are genetically distinct from gallbladder cancers that arise through the metaplasia–dysplasia–carcinoma sequence.

Somatic mutations in STK11, CTNNB1 and APC were frequent — 43%, 29% and 14%, respectively — and were proposed as major driver genes for ICPNs. Genomic alterations in these genes have also been reported in advanced gallbladder cancer, suggesting that some of those tumors arose following an adenoma–carcinoma sequence. Identifying the molecular determinants that drive this pathway remains an open research question.

Diagnosis and Its Challenges

Screening and early diagnosis remain major challenges because patients rarely have specific symptoms. Most lesions are flat and arise against a background of chronic inflammation and gallbladder wall thickening caused by gallstones. This makes both clinical and imaging diagnosis difficult.

The consequences are significant. Without reliable early warning signs, most tumors are detected only after they have advanced — or incidentally, when a gallbladder is removed for other reasons. Standardizing the nomenclature (naming system) for preneoplastic and neoplastic lesions, along with surgical specimen processing and sampling, now provides reproducible and comparable research data. This standardization forms a basis for identifying and implementing early detection strategies and improving drug discovery.

Treatment: Current Options and Their Limits

Surgical resection (removal of the tumor and surrounding tissue) is the only treatment with curative intent for gallbladder cancer. The central problem is that very few cases are suitable for resection.

Advanced gallbladder cancer is usually resistant to conventional cytotoxic therapy (chemotherapy that kills cancer cells). Drugs commonly used include:

• Gemcitabine
• Cisplatin
• 5-fluorouracil (5-FU)
• Oxaliplatin
• Capecitabine

Most adjuvant therapy after surgery has a very low response rate. Targeted therapy and immunotherapy (treatments that attack specific molecular targets or help the immune system fight cancer) have emerged as promising alternatives to extend survival and quality of life.

Advances in next-generation sequencing, multidisciplinary care, neoadjuvant strategies (treatment given before surgery), adjuvant strategies (treatment given after surgery) and novel systemic therapies — including chemotherapy and immunotherapies — are gradually changing the treatment paradigm and prognosis for this stubbornly difficult cancer.

Clinical Implications: What This Means for Patients

This research has several practical implications for people living with or at risk of gallbladder cancer.

First, early detection is the single most important factor in survival. Because symptoms are rare, patients who fall into high-risk groups — particularly those with long-standing gallstones, PBM or a family history of biliary disease — should discuss screening approaches with their doctors.

Second, not all gallbladder inflammation carries the same risk. The research shows that gallstones diagnosed shortly before worsening symptoms (within 1–3 years) may signal elevated risk, and that inflammation lasting more than 10 years also increases risk through chronic damage.

Third, the molecular discoveries open the door to personalized treatment. Identifying mutations in genes like TP53, EGFR, ERBB2, RB1, STK11, CTNNB1 and APC could one day guide which targeted therapies a patient receives.

Fourth, chemoprevention may become possible in high-risk populations. The mouse-model finding that ezetimibe prevented metaplasia and dysplasia by blocking gallstone formation is a proof of concept that deserves further study.

Limitations of Current Knowledge

The authors are candid about what remains unknown. Several key limitations stand out.

• Understanding of mechanisms is still limited. Although both carcinogenic models (metaplasia–dysplasia–carcinoma and adenoma–carcinoma) are supported by morphological and molecular evidence, the underlying mechanisms are not fully worked out.
• Adenoma–carcinoma pathway is poorly characterized. Because it accounts for only 5–10% of cases, it has been studied far less than the more common pathway. Only one study has profiled ICPN mutations, and it included just 7 patients.
• Only about 1% of people with gallstones develop cancer — about 1 in 100 — so additional contributing factors, including genetic susceptibility, remain to be identified.
• The link between gallstones and cancer is controversial. Because the two conditions share many risk factors, some researchers question whether gallstones are truly causal; however, Mendelian randomization studies support causality.
• Geographic correlation is imperfect. In several East Asian countries, gallbladder cancer incidence is high while gallstone prevalence is low, suggesting other causes such as pancreatobiliary maljunction may be at work.
• The relationship between the two types of inflammation — the inflammation that initiates tumors and the inflammation that tumors themselves recruit — is only beginning to be clarified.

Recommendations and Actionable Advice

Several unmet clinical needs must be addressed to improve gallbladder cancer management: discovering and validating reliable biomarkers for screening, therapy selection and prognosis. Until then, the following practical steps may help patients:

1. Know your risk profile. Gallstones, especially long-standing ones, are the strongest known risk factor. If you have gallstones, particularly with worsening symptoms, discuss your risk with a physician.
2. Report changing symptoms promptly. Because tissue from patients whose gallstones were diagnosed within the past 1–3 years most closely resembled cancer tissue, new or worsening symptoms after a recent gallstone diagnosis deserve attention.
3. Ask about standardized pathology review. Standardized processing and sampling of gallbladder specimens improves the reliability of diagnosis and is now recommended.
4. Seek multidisciplinary care. Advances in multidisciplinary management, next-generation sequencing and novel systemic therapies are gradually improving outcomes, and access to specialists matters.
5. Consider biomarker testing for advanced disease. Molecular profiling may reveal actionable mutations that guide targeted therapy or immunotherapy choices.
6. Discuss geographic and environmental exposures. In high-risk regions, exposure to aflatoxin B1, mustard oil and other environmental factors may be relevant, and food safety measures may reduce risk.

Patients should remember that this remains a difficult cancer with limited options — but the pace of discovery, especially in genomics and immunotherapy, is changing the outlook.

Frequently Asked Questions

What is gallbladder cancer?

Gallbladder cancer is the most common cancer of the biliary tract, the network of organs and ducts that produce and transport bile. It is aggressive and usually diagnosed late, when treatment options are few. Most cases are found incidentally when a gallbladder is removed for gallstones. About 95% arise from epithelial cells, and more than 90% are adenocarcinomas.

Who is at risk for gallbladder cancer?

Risk is higher in women, older adults, and certain populations, including Native American, Hispanic, and indigenous groups in South America, Northern India, and East Asia. Gallstones are present in up to 90% of patients at diagnosis. Other reported risks include metabolic syndrome, bile duct abnormalities, primary sclerosing cholangitis, family history of gallstones, Salmonella Typhi infection, and aflatoxin B1 exposure.

Do gallstones cause gallbladder cancer?

Gallstones are strongly associated with gallbladder cancer, and Mendelian randomization studies support a causal role. For example, one study found an odds ratio of 2.0 in Chile and 5.0 in Europe. However, only about 1% of people with gallstones develop gallbladder cancer, so other factors such as genetics and environmental exposures are also involved.

What are the symptoms of gallbladder cancer?

Early gallbladder cancer rarely causes symptoms, which is why most cases are found incidentally after gallbladder removal for gallstones. When symptoms do occur, they may include worsening symptoms shortly after a gallstone diagnosis. The text notes that patients whose gallstones were diagnosed 1–3 years before surgery had tissue that most closely resembled cancer tissue, suggesting new or worsening symptoms deserve attention.

How is gallbladder cancer treated?

Surgery is the only treatment with curative intent, but few cases are suitable for resection. Advanced disease is usually resistant to conventional chemotherapy. Drugs commonly used include gemcitabine, cisplatin, 5-fluorouracil, oxaliplatin, and capecitabine. Targeted therapy and immunotherapy are emerging options to extend survival and quality of life. Most adjuvant therapy after surgery has a very low response rate.

What does it mean if I have gallstones and worsening symptoms?

A transcriptomic analysis of 10 gallbladder cancer patients and 30 gallstone patients found that those whose gallstones were diagnosed 1–3 years before surgery had tissue that most closely resembled cancer tissue. The authors suggest that worsening symptoms shortly after a gallstone diagnosis might signal an increased risk of gallbladder cancer. Discuss any new or worsening symptoms with your doctor promptly.

Can gallbladder cancer be prevented?

There is no proven prevention, but a mouse model of gallbladder preneoplasia showed that inhibiting gallstone formation with ezetimibe prevented excessive inflammation and the onset of metaplasia and dysplasia. This provides preclinical evidence for targeting gallstones as a chemoprevention strategy in high-risk populations. Food safety measures may reduce aflatoxin exposure in high-risk regions. Discuss risk reduction with your doctor.

When should a patient with gallbladder cancer or a gallbladder mass found after gallbladder removal seek a second opinion?

A second opinion is worth seeking when gallbladder cancer is diagnosed incidentally after cholecystectomy, because most cases are found this way and surgical removal is the only treatment with curative intent, yet few cases are suitable for resection. Standardized pathology review of gallbladder specimens improves diagnostic reliability, and molecular profiling may reveal mutations in genes such as TP53, EGFR, ERBB2, RB1, STK11, CTNNB1 and APC that could guide targeted therapy or immunotherapy choices. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Gallbladder cancer - review

Authors: Juan C. Roa, Patricia García, Vinay K. Kapoor, Shishir K. Maithel, Milind Javle, Jill Koshiol

Affiliations: Department of Pathology, Millennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hepato-pancreato-biliary (HPB) Surgery, Mahatma Gandhi Medical College & Hospital (MGMCH), Jaipur, Rajasthan, India; Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA; Department of Gastrointestinal Medical Oncology, UT M.D. Anderson Cancer Center, Houston, Texas, USA; Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA

Publication details: Nature Reviews Disease Primers, volume 8, article 69 (2022). DOI: 10.1038/s41572-022-00398-y. Available via HHS Public Access (PubMed Central), author manuscript.

Note: This patient-friendly article is based on peer-reviewed research.