The highest incidence rates of gallbladder cancer worldwide are found in cultures indigenous to the Andes Mountains of South America. In North America, high incidence rates are found among native American Indians and Mexican Americans. Gallbladder cancer occurs in women almost three times more often than in men across all populations studied (123).

As with other biliary tract tumors, chronic inflammation is a common denominator of associated risk factors. The most common of these risk factors is cholelithiasis, especially large gallstones (123,124). Other conditions leading to gallbladder inflammation, such as chole-cystoenteric fistula and chronic infection with typhoid bacillus bacteria, have also been noted as risk factors for the development of cancer. As with other GI malignancies, a progression from adenoma to carcinoma has been demonstrated within adenomatous polyps of the gallbladder

(125). Gallbladder polyps have been noted in 3% to 6% of the population undergoing US. The vast majority are cholesterol polyps and have no malignant potential. However, about 1% of cholecystectomy specimens contain adenomatous polyps which have malignant potential

(126). Yang et al. reviewed a series of 182 gallbladder polyps found in cholecystectomy specimens

(127). Preoperative ultrasound was 93% sensitive in diagnosing a polypoid lesion of the wall of the gallbladder. Most of the polyps were non-neoplastic, benign cholesterol polyps (93%); however, 13 (7%) were discovered to harbor a malignancy. Furthermore, malignant potential appears to be proportional to size, among other risk factors. Yeh et al., in a series of 123 patients with polypoid lesions of the gallbladder, the likelihood of an associated malignancy correlated with size >1 cm, age >50 years, and the presence of multiple lesions (128). The conservative recommendation based on these studies is prophylactic cholecystectomy for polypoid lesions greater than 0.5 cm in size, although the likelihood of malignancy in polyps even up to 1 cm appears to be quite low. This is in contrast to gallbladder polyps arising in the setting of PSC, which are more often neoplastic (129). The authors' practice is to generally recommend cholecystectomy for polyps >1 cm; polypoid lesions <0.5 cm have a much lower likelihood of harboring a malignancy and should be followed with serial ultrasounds for evidence of growth or any change in character (125-127).

A gallbladder that demonstrates a calcified wall, otherwise known as "porcelain gallbladder" is also a condition associated with an increased risk of developing a gallbladder cancer (Fig. 6). The deposition of calcium into the wall is most likely the result of chronic inflammation. Porcelain gallbladder has been reported in approximately 0.5% to 1.0% of cholecystectomy specimens (130,131). The risk of malignancy in porcelain gallbladder has previously been considered extremely high (10-50%), although more recent studies have shown a much lower incidence (<10%) and that varies according to the type of mural calcification seen (131,132). Nevertheless, the current recommendations are for cholecystectomy for patients with porcelain gallbladder, which in most cases, can be done laparoscopically.

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