Carcinoma of gallbladder and extrahepatic biliary tract (ORPHA:56044)
Carcinoma of the gallbladder (GBC) is the most common and aggressive form of biliary tract cancer (BTC; see this term) usually arising in the fundus of the gallbladder, rapidly metastasizing to lymph nodes and distant sites.
Epidemiology
Annual incidence rates vary from 1/100,000 to 1/ 4,350 between different ethnic groups and geographical regions. It is rare in developed Western countries but has a high incidence in Japan (1/19,000), northern India, Chile and certain regions of Eastern Europe.
Clinical description
GBC is a rare neoplasm occurring more often in females (3-4:1 female to male ratio) with an average age of onset of 65 years. Most patients are asymptomatic until the disease is advanced but presenting symptoms include abdominal pain (usually in the upper right quadrant), nausea, vomiting, jaundice, anorexia and weight loss. Gallstones are often present in patients with GBC. GBC is extremely aggressive and invasion of the lymph nodes, liver and other organs occurs rapidly in many cases.
Etiology
The exact etiology is unknown. Genetic susceptibility elicited by chronic inflammation of the gallbladder leading to dysplasia and malignant change is one possibility. Risk factors associated with GBC include a history of gallstones, cholelithiasis, porcelain gallbladder, bacterial infections, high caloric diet and an anomalous pancreaticobiliary junction. A family history of GBC is also a risk factor supporting the hypothesis that genetic and environmental factors both play a role in disease susceptibility. The APOB gene is the only gene identified so far with a direct link to GBC. Mutations in the genes KRAS, INK4a, p53 and EGFR have all been implicated in the pathogenesis of GBC.
Diagnostic methods
Diagnosis is based on laboratory tests and imaging studies. Blood tests measuring liver enzymes and tumor marker levels are conducted. There is often an increase in CEA and CA 19-9 tumor markers, especially at an advanced stage. Ultrasound and computed tomography (CT) scans show any masses or enlargement of the gallbladder. Tumor masses are usually found in the neck and body of the gallbladder. The TNM staging system is used to stage GBC and to determine the treatment and prognosis given. Patients are then given a stage based on the International Union Against Cancer (UICC) staging system. Histopathologically most GBCs are adenocarcinomas with various histopathological subtypes. Less frequently there can be squamous cell carcinoma, sarcoma, lymphoma (see this term) or melanoma.
Differential diagnosis
GBC is often misdiagnosed as other types of adenocarcinoma and other benign gallbladder diseases such as chronic cholecystitis and adenomyomatosis.
Management and treatment
The only curative treatment is complete surgical resection. If obstructive jaundice is present then biliary drainage with stenting is necessary. For T1 tumors a simple or radical (in T1b tumors) open cholecystectomy is recommended and is usually curative. Unfortunately GBC is rarely discovered at such an early stage. T2 tumors are best managed with an en bloc resection of the liver bed. T3 tumors require a selective radical resection depending on the organs affected. T4 tumors are considered unresectable or associated with high surgical morbidity. Chemotherapy can be given to those with unresectable T3 or T4 tumors or metastatic disease in hopes of improving survival and quality of life. Gemcitabine combined with cisplatin therapy is the standard treatment for unresectable biliary tract cancers. Less toxic molecular-targeted agents are now being tested as possible future treatments.
Prognosis
As GBC is often detected only at an advanced disease stage, the prognosis is poor with 5-year survival rates of approximately 20%.

                            Last update: 
                            September 2012


                            - Expert reviewer(s): 
                            Dr Junji FURUSE