Know it, to control it

Gall Bladder Stones and Gall Bladder Cancer

Gallstones are the most common risk factor for gall bladder cancer. Gallstones are pebble-like collections of cholesterol and other substances that form in the gallbladder and can cause chronic inflammation. At least 3 out of 4 people with gallbladder cancer have gallstones when they are diagnosed.

Gall bladder stones are very common, but gall bladder cancer is quite rare, and most people with gallstones never develop gallbladder cancer.
Prevalence of gallbladder cancer shows great geographical variation. It is rare in the West, higher incidence rates have been reported from various countries in central and South America, central and Eastern Europe, India and Japan.

Gall bladder cancer arises primarily in individuals older than 50 years and is approximately three times more common in women than in men. Most often, gall bladder cancer is diagnosed at a late stage of disease progression, which results in a dismal 5-year survival rate of 1% to 5%.
In the early stages of the disease, symptoms are extremely uncommon and if they do occur, are usually due to the co-existence of cholecystitis, cholelithiasis (gallstones) or complications of associated benign biliary disease.

Review of literature reveals that although genetic factors, malignant transformation of benign neoplasms of the gallbladder, congenital abnormalities, bacterial infections, occupation, xanthogranulomatous cholecystitis, chronic inflammatory bowel disease and previous biliary surgery have all been noted in association with carcinoma of the gallbladder, gallstones remain the sole major known risk factor with an 8.3x higher risk than the general population.

The early precursor lesions which give rise to adenocarcinoma and their progression of the gallbladder have been proposed. The development is thought to be through a sequence of epithelial hyperplasia to atypical hyperplasia or dysplasia to carcinoma in situ and finally to infiltrating adenocarcinoma. On the other hand, dysplasia and ultimately adenocarcinoma of the gallbladder was considered to arise from the metaplastic epithelium which is commonly found in chronically inflamed gallbladders where chronic irritation is believed to be the major promoting factor for neoplastic transformation.

Chronic inflammation is considered a major factor in carcinogenesis, causing DNA damage, tissue proliferation, and cytokine and growth factor release. Another result of chronic inflammation is deposition of calcium within the gallbladder wall, causing the gallbladder to develop a bluish hue and become fragile—the “porcelain gallbladder.” While less than 1% of gallbladder specimens demonstrate this change, it is frequently (~25%) associated with gallbladder cancer. Only specimens with stippled calcification on imaging are considered potentially “premalignant” as transmural calcification is less likely to develop malignancy.

Further, there is a strong relationship between gallstone size and gallbladder carcinoma; larger gallstones being associated with an increased risk of carcinoma: the relative risk for gallbladder carcinoma in people with stones of > 3cm in diameter is 9.2 compared to stones of < 1 cm.

More than 30% of all gallbladder carcinomas are associated with large (> 3 cm) stones and the annual rate of gallstone growth is 2 mm. This increased risk is most likely attributable to greater local epithelial irritation. Gallstones and biliary duct stones are hypothesized to cause chronic inflammation leading to dysplasia.

The exact mechanism of cholelithiasis causing or predisposing gallbladder cancer remains debatable. It has been suggested that chronic mucosal damage due to mechanical forces exerted by the gallstone may be involved. Between 0.5 to 1.5% of patients who undergo a simple cholecystectomy for presumed cholelithiasis are discovered incidentally to have gallbladder cancer.

Given the association between chronic cholecystitis and gallbladder cancer, can routine prophylactic cholecystectomy be an effective way to prevent malignancy? When the prevalence of metaplasia in routine cholecystectomy specimens was examined, it was found that an increased prevalence of dysplastic changes, gallbladder wall thickening, and microlithiasis was seen in specimens with metaplastic features.

Microlithiasis is mostly asymptomatic, while macrolithiasis produces symptomatic cholecystitis and therefore performing a cholecystectomy for all symptomatic cholecystitis patients may not be treating the population at the greatest risk, as opposed to treating those with incidentally discovered microlithiasis on abdominal imaging.

An annual ultrasound examination in high risk populations with a CA-19.9 tumour marker (a blood test) is recommended to pick up early cancerous changes in pre-existing gall –stones. In case Ultrasound abdomen shows a polyp in the gall bladder a CAT Scan is recommended.