• chemokines
• cytokines
• dysplasia
• gallbladder cancer
• inflammation
• non‐steroidal anti‐inflammatory drugs

• Humans
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Female
• Male
• Middle Aged
• Case-Control Studies
• Aged
• Gallbladder Neoplasms/pathology
• Cholecystectomy
• Adult
• Inflammation
• Gallbladder/pathology
• Gallbladder/surgery
• Biomarkers/blood
• Precancerous Conditions/pathology
• Gallstones/surgery

• 15130011 Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias
• NIH HHS
• US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics
• 1212066 Fondo Nacional de Desarrollo Científico y Tecnológico
• NIH HHS
• Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias
• National Institutes of Health
• US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics
• Fondo Nacional de Desarrollo Científico y Tecnológico

• cholecystectomy
• gallbladder neoplasms
• health services research
• mortality
• universal health care
• women

• Humans
• Chile/epidemiology
• Gallbladder Neoplasms/mortality
• Gallbladder Neoplasms/epidemiology
• Female
• Male
• Middle Aged
• Gallstones/mortality
• Gallstones/epidemiology
• Adult
• Government Programs
• Aged

• 15130011 Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias
• 1212066 Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; the Office of Research on Women's Health, National Institutes of Health, National Cancer Institute, National Institutes of Health; the Fondo Nacional de Desarrollo Científico y Tecnológico

• environmental impact
• cancer
• environmental sciences
• oncology

• Bile duct dysplasia
• Cholangiocarcinoma
• Histomorphology
• Immunohistochemistry
• Molecular genetics

• cholesterol polyp
• gallbladder polyp
• intracholecystic papillary-tubular neoplasm
• polyp growth
• surveillance ultrasound

• FGFR
• GemCis
• HER2
• PD-L1
• gallbladder cancer
• immunotherapy

• ICPNs
• MUC
• immunohistochemistry
• intracholecystic papillary neoplasms
• p53
• whole-genome copy number
• β-catenin

• gallbladder
• maljunction
• mixed neuroendocrine non-neuroendocrine neoplasm
• pancreaticobiliary
• transdifferentiation

• Cholangiopancreatography, Endoscopic Retrograde
• Gallbladder Neoplasms/complications
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/therapy
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Staging
• Neuroendocrine Tumors/complications
• Neuroendocrine Tumors/pathology
• Neuroendocrine Tumors/therapy
• Pancreaticobiliary Maljunction/complications
• Phosphopyruvate Hydratase/blood

Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer.

The progression from biliary tract intraepithelial neoplasia (BilIN) to gallbladder carcinoma (GBC) remains unclear. Here the authors use genomics to analyze coexisting GBC lesions, low-grade and high-grade BilINs, revealing two distinct evolutionary paths for GBC development.

• Gallbladder adenoma
• Incidental gallbladder cancer
• Laparoscopy
• Surgery

• Adenoma
• Cholecystectomy
• Cross-sectional area
• Gallbladder neoplasms
• Predictive model

• Biliary cancers
• Gall bladder carcinoma
• Immunotherapy
• Molecular oncology
• Mutations
• Targeted therapy

• dysplasia
• gallbladder carcinoma
• gallbladder neoplasms
• pathological evaluation

A 13-year-old neutered female domestic shorthair rescue cat presented asymptomatically with raised hepatic enzymes following a routine pre-anaesthetic blood test. Cholangitis was suspected, and supportive treatment with 2 weeks of amoxicillin–clavulanic acid and 4 weeks of ursodeoxycholic acid and S-adenosylmethionine was trialled, with no improvement in biochemistry parameters. Clinicopathological investigations also revealed a markedly raised total bilirubin and abnormal bile acid stimulation test. Abdominal ultrasonography revealed pathological changes in the gallbladder, hepatomegaly with increased echogenicity and markedly thickened common bile duct walls. An exploratory laparotomy was performed revealing a grossly abnormal gallbladder with a small rupture at the dorsal fundus, which was managed via cholecystectomy. Pancreatic and hepatic biopsies were collected concurrently. Histopathology from the submitted samples revealed a gallbladder adenoma, chronic neutrophilic cholangitis and nodular hyperplasia of the pancreas. Culture of the gallbladder bile was negative but may be attributable to the initial treatment with antibiosis. At the time of writing, 5 months postoperatively, the cat had recovered well and remained asymptomatic and clinically healthy, but hepatic enzymes and bilirubin were only mildly reduced from the preoperative levels, despite the cat remaining clinically normal.

• Gallbladder
• adenoma
• cholecystectomy
• neoplasia

 Primary neuroendocrine tumors of the gallbladder (GB-NETs) are rare, accounting for 0.5% of all NETs and 2.1% of all gallbladder cancers. Among GB-NETs, mixed neuroendocrine–non-neuroendocrine neoplasms of the gallbladder (GB-MiNENs) are extremely rare.

We present the case of a 66-year-old woman who was referred to us for the management of a gallbladder tumor (incidentally found during abdominal ultrasonography indicated for gallbladder stones). The patient had no history of abdominal pain or fever, and the findings on a physical examination were unremarkable. Blood tests showed normal levels of tumor markers. Imaging studies revealed a mass of approximately 10 mm in diameter (with no invasion of the gallbladder bed) located at the fundus of the gallbladder. A gallbladder cancer was suspected. Therefore, an open whole-layer cholecystectomy with regional lymph nodes dissection was performed. The postoperative course was uneventful, and she was discharged on postoperative day 6. Pathological findings showed GB-MiNENs with invasion of the subserosal layer and no lymph node invasion (classified T2aN0M0 pStage IIA according to the Union for International Cancer Control, 8th edition staging system). Analysis of the neuroendocrine markers revealed positive chromogranin A and synaptophysin, and a Ki-67 index above 95%. Fourteen months after the operation, a local recurrence was detected, and she was referred to another hospital for chemotherapy.

 GB-MiNENs are extremely aggressive tumors despite their tumor size. Optimal therapy should be chosen for each patient.

• Gallbladder cancer
• Mixed adenoneuroendocrine carcinoma
• Mixed neuroendocrine–non-neuroendocrine neoplasms

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) of the gallbladder are rare with no established therapeutic strategies. We report a case of recurrent gallbladder MiNEN from a population with a low incidence of gallbladder carcinomas, a review of the current therapeutic options, and recent updates on the nomenclature proposed by the World Health Organization in 2017.

• Gallbladder neoplasms
• Mixed neuroendocrine-non-neuroendocrine neoplasm
• Neuroendocrine tumors

• Chile Biliary Longitudinal Study
• etiology
• gallbladder cancer
• gallbladder dysplasia
• gallstones
• incidence

• Aged
• Blood Pressure
• Body Weights and Measures
• Cardiovascular Diseases/epidemiology
• Chile
• Diabetes Mellitus/epidemiology
• Female
• Gallbladder Neoplasms/diagnostic imaging
• Gallbladder Neoplasms/epidemiology
• Gallbladder Neoplasms/ethnology
• Gallstones/diagnostic imaging
• Gallstones/epidemiology
• Gallstones/ethnology
• Humans
• Inflammation Mediators/blood
• Longitudinal Studies
• Middle Aged
• Obesity/epidemiology
• Research Design
• Risk Factors
• Socioeconomic Factors
• Tooth Loss/epidemiology

• Dual-energy computed tomography
• differential diagnosis
• gallbladder polyps

• Cholecystectomy
• Diagnostic imaging
• Gallbladder diseases
• Gallbladder neoplasms
• Polyps

• Biliary tract cancer
• Biomarker
• Diagnosis
• Gallbladder cancer
• Molecular pathogenesis
• Next-generation sequencing
• Prognosis

• Gallbladder polyp (GBP)
• adenoma
• cholesterol
• malignancy
• predictive factors

Mixed neuroendocrine-non-neuroendocrine tumors (MINEN) of the gallbladder are extremely rare; indeed, the English expert literature reports a mere handful of case reports and case series on this topic. According to the WHO classification of 2010, MINEN are considered to be tumors consisting of two major components, neuroendocrine and non-neuroendocrine, each of which hosts at least 30% of the total cellular population. To date, the etiology and pathogenesis of MINEN have not been precisely determined and the non-specific symptoms generally result in late diagnosis (mainly in the terminal stages of the condition) and contribute to the generally poor prognosis. As far as the management of the disease is concerned, radical surgery plays a crucial role; however, the significance of surgical debulking and biological therapy applying somatostatin analogues has not yet been determined.

A 56-year-old female was referred to our department for a rapidly progressing tumor in the subhepatic area along with the infiltration of S5 and S6 liver segments. With regard to preoperative findings, the tumor appeared as operable, although, during the surgery, an extensive involvement of the hepatoduodenal ligament by the tumor through the lymph nodes was revealed. Due to acute perioperative bleeding from the necrotic tumor, we decided to perform modified resection. Histologically, the tumor was confirmed as MINEN of gallbladder, where the neuroendocrine component was dominant over the non-neuroendocrine component. Six weeks after the discharge, the patient underwent a follow-up CT revealing large recurrence of the disease. Thereafter, the patient was started on systemic therapy with etoposide and carboplatin in combination with somatostatin analogues. Thirteen months after the surgery, the patient is in good clinical condition, and while a recently performed PET/MRI scan revealed a hepatic lesion and hilar lymphadenopathy in full regression, there was a spread of small peritoneal and pleural metastases. The patient remains in the follow-up care.

The occurrence of mixed neuroendocrine-non-neuroendocrine neoplasms is extremely rare. Radical surgery remains the only potentially effective approach to the cure of this disease. The role of biological therapy and debulking in the management of the disease has not yet been precisely defined. In our experience, both of these methods have the potential to positively influence overall survival rates and the postoperational quality of life of patients.

• Gallbladder cancer
• MINEN
• Mixed neuroendocrine-non-neuroendocrine tumors
• Somatostatin analogues

Gallbladder cancer (GBC) is diagnosed often incidentally after cholecystectomies, with a rate of 0.1–3%.

To review the clinical and morphological aspects of GBC and pre-neoplastic lesions in patients who underwent cholecystectomy.

A total of 5026 patients who underwent cholecystectomy between January 1, 2012 and December 31, 2017 were included in the study. Histological changes (acute cholecystitis, adenomyomatosis, xanthogranulomatous cholecystitis (XGC), polyps, antral metaplasia, intestinal metaplasia (IM), dysplasia, cancer, and others) in gallbladders (GB) from 5029 patients who underwent cholecystectomy for cholelithiasis were analysed.

Gallbladder cancer was more common in women than in men (14/4 = 3.5). A significant relation was found between cholelithiasis and GBC (p = 0.031). Of the patients with GBC, six had stage 1a (T1a + T1b), five had stage 1b (T2N0), two had stage 2 (T3N0), three had stage 2b (T1-3 N1), one had stage 3 (T4 N0), and one had stage 4 (T3N1M1). The IM was more common in females than in males (K/E = 3.3). A significant relationship was found between cholecystitis and IM (p < 0.001). A significant association was observed between IM and adenomyomatosis hyperplasia (p = 0.016).

In this study, it was observed that adenomyomatous hyperplasia and adenomatous polyp were associated with metaplastic changes in the GB pathologies, including XGC and follicular cholecystitis. It is thought that metaplasia-dysplasia may be associated with GBC. However, further studies on GB carcinogenesis are needed.

• cholecystectomy
• cholelithiasis
• laparoscopic
• metaplasia

There is limited literature about the clinicopathological characteristics and outcomes of rare histologic variants of gallbladder cancer (GBC).

Using SEER database, surgically managed GBC patients with microscopically confirmed adenocarcinoma, adenosquamous/squamous cell carcinoma and papillary carcinoma were identified from 1988 to 2009. Patients with second primary cancer and distant metastasis at presentation were excluded. The effect of clinicopathological variables on overall survival (OS) and disease specific survival (DSS) were analyzed using univariate and multivariate proportional hazards modeling. All associations were considered statistically significant at an alpha error of 0.01.

Out of 4738 cases, 217 adenosquamous/squamous (4.6%), 367 papillary (7.7%), and 4154 adenocarcinomas (87.7%) were identified. Median age was 72 years. Higher tumor grade (grade 2, 3, 4 versus grade 1), higher T stage (T2, T3, T4 versus T1), lymph node positivity (N1 versus N0) and adenosquamous/squamous histology (versus adenocarcinoma) had worse OS and DSS (p < .001). Papillary GBC had better OS and DSS than adenocarcinoma (HR = 0.7; p < .001). Radical surgery (versus simple cholecystectomy) had better OS (HR = 0.83, p = 0.002) in multivariate analysis. OS rates at 3 and 5 years were 0.56 and 0.44 for papillary, 0.3 and 0.22 for adenocarcinoma, and 0.14 and 0.12 for adenosquamous/squamous histology, while DSS rates at 3 and 5 years were 0.67 and 0.61 for papillary, 0.38 and 0.31 for adenocarcinoma, and 0.17 and 0.16 for adenosquamous/squamous subtypes respectively.

Papillary GBC had better survival outcomes while adenosquamous/squamous GBC had worse survival outcomes compared to gallbladder adenocarcinoma.

• Chemokines
• Cytokines
• Gallbladder cancer
• Inflammation
• Risk stratification

• Polypoid lesions of gallbladder
• cholecystectomy
• diagnosis and management
• gallbladder cancer
• gallbladder polyps
• risk factor
• surgery intervention

• Adenomatous polyp
• Carcinoma
• Gallbladder
• Texture analysis
• Ultrasound

• Adult
• Aged
• Aged, 80 and over
• Diagnosis, Differential
• Female
• Gallbladder/diagnostic imaging
• Gallbladder Diseases/diagnostic imaging
• Gallbladder Neoplasms/diagnostic imaging
• Humans
• Male
• Middle Aged
• Polyps/diagnostic imaging
• Retrospective Studies
• Risk
• Sensitivity and Specificity
• Ultrasonography/methods

• Gallbladder dysplasia
• Malignant transformation
• Port site implantation
• Tumour seeding
• Wound implantation

• Cholelithiasis
• Gallbladder cancer
• Mutation
• Sonic hedgehog gene

The management of incidentally detected gallbladder polyps on radiological examinations is contentious. The incidental radiological finding of a gallbladder polyp can therefore be problematic for the radiologist and the clinician who referred the patient for the radiological examination. To address this a joint guideline was created by the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), European Association for Endoscopic Surgery and other Interventional Techniques (EAES), International Society of Digestive Surgery – European Federation (EFISDS) and European Society of Gastrointestinal Endoscopy (ESGE).

A targeted literature search was performed and consensus guidelines were created using a series of Delphi questionnaires and a seven-point Likert scale.

A total of three Delphi rounds were performed. Consensus regarding which patients should have cholecystectomy, which patients should have ultrasound follow-up and the nature and duration of that follow-up was established. The full recommendations as well as a summary algorithm are provided.

These expert consensus recommendations can be used as guidance when a gallbladder polyp is encountered in clinical practice.

• Management of gallbladder polyps is contentious

• Cholecystectomy is recommended for gallbladder polyps >10 mm

• Management of polyps <10 mm depends on patient and polyp characteristics

• Further research is required to determine optimal management of gallbladder polyps

• Cholecystectomy
• Gallbladder
• Neoplasms
• Polyps
• Ultrasonography

• Gallbladder cancer
• Intestinal metaplasia
• Neuroendocrine carcinoma
• Neuroendocrine tumor

• Cancer metabolism
• Electrolyte abnormalities
• Hypokalemia
• Hyponatremia
• Hypoosmolality
• Hypotonicity
• Osmoregulation
• Osmotic stress

• Carcinogenesis
• Drinking Water/adverse effects
• Electrolytes/adverse effects
• Electrolytes/metabolism
• Neoplasms/chemically induced
• Neoplasms/epidemiology
• Water Purification
• Water-Electrolyte Imbalance/chemically induced
• Water-Electrolyte Imbalance/epidemiology

• Choledochal cyst
• Gallbladder cancer
• Intracholecystic papillary neoplasm

• Chronic inflammation
• Gallbladder cancer
• Gallstones
• Metaplasia
• Salmonella Typhi
• TP53

• Autoimmune Diseases/complications
• Bacterial Infections/complications
• Gallbladder Neoplasms/etiology
• Gallstones/complications
• Humans
• Inflammation/complications

• ZIA CP010218-01 Intramural NIH HHS

• Aged
• Aged, 80 and over
• Asian People/genetics
• China
• Female
• Flap Endonucleases/genetics
• Gallbladder Neoplasms/enzymology
• Gallbladder Neoplasms/ethnology
• Gallbladder Neoplasms/genetics
• Gallstones/enzymology
• Gallstones/ethnology
• Gallstones/genetics
• Gene Frequency
• Genetic Predisposition to Disease/ethnology
• Genetic Predisposition to Disease/genetics
• Genotype
• Haplotypes
• Humans
• Linkage Disequilibrium
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Population Surveillance/methods
• Risk Factors

• Complex epithelial lesion
• FAP
• Gallbladder carcinogenesis

• biliary tract cancer
• targeted therapy
• egfr
• vegf
• trial

• Antineoplastic Agents/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols
• Biliary Tract Neoplasms/drug therapy
• Biliary Tract Neoplasms/pathology
• Disease-Free Survival
• Humans
• Molecular Targeted Therapy/trends
• Neoplasm Staging
• Prognosis

Gallbladder cancer (GBC) is an uncommon disease in the majority of the world despite being the most common and aggressive malignancy of the biliary tree. Early diagnosis is essential for improved prognosis; however, indolent and nonspecific clinical presentations with a paucity of pathognomonic/predictive radiological features often preclude accurate identification of GBC at an early stage. As such, GBC remains a highly lethal disease, with only 10% of all patients presenting at a stage amenable to surgical resection. Among this select population, continued improvements in survival during the 21st century are attributable to aggressive radical surgery with improved surgical techniques. This paper reviews the current available literature of the 21st century on PubMed and Medline to provide a detailed summary of the epidemiology and risk factors, pathogenesis, clinical presentation, radiology, pathology, management, and prognosis of GBC.