Gallbladder cancer (GBC) is the most common cancer of the biliary tract, characterized by a very poor prognosis when diagnosed at advanced stages owing to its aggressive behaviour and limited therapeutic options. Early detection at a curable stage remains challenging because patients rarely exhibit symptoms; indeed, most GBCs are discovered incidentally following cholecystectomy for symptomatic gallbladder stones. Long-standing chronic inflammation is an important driver of GBC, regardless of the lithiasic or non-lithiasic origin. Advances in omics technologies have provided a deeper understanding of GBC pathogenesis, uncovering mechanisms associated with inflammation-driven tumour initiation and progression. Surgical resection is the only treatment with curative intent for GBC but very few cases are suitable for resection and most adjuvant therapy has a very low response rate. Several unmet clinical needs require to be addressed to improve GBC management, including discovery and validation of reliable biomarkers for screening, therapy selection and prognosis. Standardization of preneoplastic and neoplastic lesion nomenclature, as well as surgical specimen processing and sampling, now provides reproducible and comparable research data that provide a basis for identifying and implementing early detection strategies and improving drug discovery. Advances in the understanding of next-generation sequencing, multidisciplinary care for GBC, neoadjuvant and adjuvant strategies, and novel systemic therapies including chemotherapy and immunotherapies are gradually changing the treatment paradigm and prognosis of this recalcitrant cancer.
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The authors thank D. Check for creating the bar chart figure of gallbladder disease prevalence and gallbladder cancer incidence. The work of J.K. is supported by general funds from the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The work of J.C.R. and P.G. is supported by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement No. 825510 (ESCALON), and from Agencia Nacional de Investigación y Desarrollo (ANID) Fondecyt 1221345 and Millennium Science Initiative Program: Millennium Institute on Immunology and Immunotherapy (ICN09_016/ICN 2021_045; former P09/016-F).
M.J. receives research funding (to Institution) from Merck, EMD Serono, Novartis, Eli Lilly, AstraZeneca, Genentech, Transthera, Meclun, BMS, Incyte, QED, Taiho, Servier, Oncosil, Basilea, Nucana; and to self or as advisory board/Data and Safety Monitoring Board member from Incyte, Zymeworks, Mundi Pharma, Nucana, MORE health and Origimed. Peer grant funding is provided from Department of Defense and NIH. S.K.M. receives research funding (to Institution) from BMS, QED/HELSINN, Natera. The other authors (J.C.R., P.G., J.K. and V.K.K.) declare no competing interests.
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- Muscularis mucosa
Thin muscle layer that separates mucosa from submucosa in most segments of the digestive tract with the exception of the gallbladder.
- Histogenic sequence
Sequence of histopathological entities that progress from preneoplastic to invasive neoplastic gallbladder lesion.
Related to the formation of stony concretions (calculi) in the body, most often in the gallbladder or urinary system.
Not associated with stones.
- Pancreatobiliary maljunction
A congenital anomaly in which the pancreatic and common bile ducts join together outside the duodenal wall.
- Mendelian randomization analysis
A method that uses germline genetic variation associated with the exposure but not the outcome to mimic randomization.
- Aflatoxin B1
Considered the most potent carcinogen of the aflatoxins, a family of toxins that are products of fungal infection of agricultural crops.
- Polypoid gallbladder lesions
Intraluminal projecting lesions attached to the surface by a stalk.
- Primary sclerosing cholangitis
Progressive fibrosing inflammatory disorder of the intrahepatic and extrahepatic bile ducts.
Stones in the gallbladder.
- Fluke-related cholangiocarcinoma
Cases of cholangiocarcinoma associated with chronic exposure to parasitic flatworms (flukes).
- Loss of heterozygosity
(LOH). Allelic imbalance caused by the loss of one of the two alleles present at a particular locus in a heterozygous somatic cell.
- Microsatellite instability
(MSI). Genomic alteration characterized by deletions and/or insertions in microsatellite regions of the genome; correlated with deficiency of the DNA mismatch repair system.
- Tumour mutational burden
(TMB). Approximate number of gene mutations occurring in the genome of a cancer cell, expressed as the number of mutations per megabase (muts/Mb).
- Hot tumour
Immunogenic tumour that shows signs of inflammation and is infiltrated by tumour-specific CD8+ T lymphocytes, making it more responsive to immunotherapy treatment using checkpoint inhibitors.
- Rokitansky–Aschoff sinuses
Pseudodiverticula into the gallbladder wall present in the muscle layer or even in the perimuscular connective tissue.
- Mirizzi’s syndrome
Extrinsic compression of the common hepatic or bile duct by a large stone in the neck of the gallbladder.
- Xanthogranulomatous cholecystitis
Severe chronic inflammation of the gallbladder with abundant foamy cells and granuloma formation resulting in thickening of the gallbladder wall.
- Gallbladder fossa
Place in the liver undersurface where the gallbladder is normally embedded with absence of liver capsule.
- Radiological response rates
A score that attempts to provide objective measurements via imaging of tumour response to therapy.
Nanoparticle albumin-bound paclitaxel to increase the delivery to tumour cells.
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Roa, J.C., García, P., Kapoor, V.K. et al. Gallbladder cancer. Nat Rev Dis Primers 8, 69 (2022). https://doi.org/10.1038/s41572-022-00398-y