About Gallbladder Cancer
Carcinoma gall bladder has an unusual geographic distribution. While it is uncommon in Europe and the United States, it is more frequent in Chile, Bolivia and Israel (Orth and Berger, 2000). The incidence of carcinoma gall bladder in India ranges from 1.01 per 100000 for males to 10.1 per 100000 for females (ICMR 1996) but the actual number may be much more in the endemic zones of Western Bihar and Eastern Uttar Pradesh where it is the third commonest malignancy of the alimentary tract (Shukla et. al. 1985). Due to its non specific clinical presentation, it is seldom diagnosed preoperatively except in advanced cases. Survival depends on the ability to achieve a curative resection depending upon the stage of the disease. The overall surgical resection rates range from 10% to 30% only thereby indicating a poor prognosis. The aetiology of carcinoma gall bladder is poorly understood. Chronic cholecystitis and gallstones, choledochal cysts, female gender, age and exposure to carcinogens are some of the factors implicated in the causation of gall bladder cancer but a definite cause - effect relationship has yet to be established for any of these factors (Dixit et al 2001). The following article will discuss the evidence in support of the various aetiological factors and the management of patients with gallbladder cancer.
Cholelithiasis is frequently associated with carcinoma gallbladder in up to 40%-100% patients and is the most common associated factor independent of age or sex (Hart et al, 1971). The risk of carcinoma gall bladder in patients with gall stones may be increased 4 to 7 times (Nervi et al, 1988) and patients with gallstones >3cm in diameter have a much higher risk (Diehl 1983). Gallstones were found in 45% of our cases of carcinoma gallbladder (Shukla et al, 1985). Carcinoma gallbladder is known to develop in patients with gallbladder preserving therapies for cholelithasis. However, the mode of carcinogenesis is not clear. Experimental studies have demonstrated chronic irritation of gallbladder mucosa by using different materials such as gallstones, pebbles, pitch, linonin, glass beads etc. (Piehler et al, 1978). It has been shown that chronic trauma and inflammation can induce epithelial dysplasia, carcinoma in situ and invasive cancer (Kijima et al, 1989, Dowling & Kelly, 1986) but a cause and effect relation has not been unequivocally proved. Furthermore, one would expect squamous carcinoma to develop as a result of chronic irritation whereas it is adenocarcinoma which is the commonest histological type of carcinoma gallbladder seen in over 90% of cases. In about 10-40% of patients, carcinoma gallbladder is not associated with gallstones. Moreover only a small proportion (1-3%) of all cholelithasis patients develop carcinoma gallbladder (Piehler et al, 1978). Certain ethnic and racial groups have a higher incidence of carcinoma gallbladder in population where cholelithiasis is uncommon (Strom et al 1995) suggesting that other environmental and/or genetic factors may also have a contributory role in gallbladder carcinogenesis. Comfort et al followed patients with silent gallstones for 10-25 years and only 1% of them developed carcinoma gallbladder. In another prospective study none of the 123 patients with gallstones who were followed from 1000 patient years developed carcinoma. Therefore there is insufficient clinical data to irrefutably support this association, yet, the frequent association suggests common antecedents.
Chronic Cholecystitis:
Approximately 50% patients of carcinoma of the gallbladder have a history suggestive of chronic cholecystitis (Silk et al, 1989). It has been reported that carcinoma gallbladder may develop in 10% of patients with xanthogranulomatous cholecystitis, (Houstan et al, 1994, Benbow 1989) a variant of chronic cholecystitis but in our own series there has been a low association between xanthogranulomatous cholecystitis and carcinoma gallbladder suggesting that this is a coincidental finding (Dixit et al, 1998).
Procelain gallbladder:
There is a 20% risk of developing carcinoma gallbladder in patients with calcified or porcelain gallbladder making this an absolute indication for cholecystectomy (Berk et al, 1973).
Gallbladder polyp:
Even though a definitive evidence similar to the adenoma carcinoma sequence in colonic cancer is lacking in carcinoma gallbladder, recent studies suggest that polyps greater than 10mm in diameter have a strong malignant potential. In one study all the adenomas showing malignant change were larger than 12mm in diameter (Kozuka et al, 1982). If diagnosed in asymptomatic patients, cholecystectomy is recommended even in the absence of stones (Aldridge & Bismuth, 1990). However, for polyps < 10mm in diameter cholecystectomy is only recommended in the presence of stones and/or symptoms.
Recent studies have suggested that anomalous pancreaticobiliary duct junction (APBDJ) is a risk factor for carcinoma gallbladder (Kimura et al 1985, Chijiwa et al 1995, Mishra et al 1998). Gallbladder carcinoma occurred in 25% of the 65 patients with an anomalous union of the 2 duct systems as compared with 1.9% among 635 consecutive patients with a normal duct union. Anomalous duct union is seen in approximately 17% patients with carcinoma gall bladder as compared with less than 3% among patients with other hepatobiliary disorders. It is thought that this anomalous junction allows the free reflux of pancreatic juice into the gallbladder, the stasis of which damages the gallbladder mucosa and causes precancerous changes (Mori, 1993). Choledochal cysts are also associated with malignant transformation if they are left or incompletely excised during surgery.
Inflammatory bowel disease: Though the association of sclerosing cholangitis with long standing ulcerative colitis is well known, carcinoma gallbladder has been uncommonly reported in patients with chronic inflammatory bowel disease (O’Connor 1986). Polyposis coli also has been rarely associated with carcinoma gallbladder (Willson et al, 1987).
Chemical Carcinogen: Methylcholanthrene, a known chemical carcinogen is derived from deoxycholic acid which aroused suspicion about the possible role of bile acids as precursors of carcinogenic aromatic hydrocarbons in gallbladder carcinogenesis. Recently many studies have shown bile acids as co-mutagens as they can cause dysplastic changes in colonic and gastric mucosa. We have found a significantly high concentration of secondary bile acid in patients with carcinoma of the gallbladder (Shukla et al, 1993). Chemicals such as O-aminoazotoluene, aflatoxin B and various other nitrosamines have been implicated in carcinogenesis in experimental studies (Klamer & Max, 1983). This observation is further supported by the high risk of carcinoma gallbladder occurring in rubber, automobile, wood finishing and metal fabricating industry workers who are exposed to nitrosamines (Kelly & Chamberlain 1982).
The role of dietary factors in gallbladder carcinogenesis is now well defined. The regions of Eastern UP, and Western Bihar where carcinoma gallbladder is highly prevalent lie downstream of the river Ganges which is the main source of drinking and irrigation water. It also receives untreated domestic sewage and industrial effluents and it is possible that certain environmental pollutants may act as carcinogens. We have shown the protective effect of vegetables on gallbladder carcinogenesis while consumption of red meat was associated with increased risk of gallbladder cancer (Pandey et al, 2002). Other studies have also shown protective effect of fat and protein rich diet and consumption of fiber, vitamin C and vitamin E (Tominaga et al, 1979, Zatonski et al, 1992).
Increased frequency of carcinoma gallbladder in females suggests a possible role of hormonal factors (Silk et al 1989, Plesko et al 1985). An increased risk has also been seen in women taking oral contraceptive pills. Khan et al (1999) reported post menopausal status to be a risk factor for carcinoma gall bladder. Singh et al (1997) reported a high risk of carcinoma gallbladder in women having early menarche, late marriage, late pregnancy and prolonged reproductive phase. Epidemiological studies have demonstrated a strong association between carcinoma gallbladder, obesity and oestrogens. V. FAMILIAL AND GENETIC FACTORS Several members of two Spanish American families were affected by carcinoma of the gallbladder. Trajber et al (1982) reported carcinoma gallbladder in two siblings from Brazil. Recently Pandey et al (1995) have shown increased frequency of carcinoma gallbladder in patients with A+ and AB+ blood groups. Allele specific mutations in pathogenesis of carcinoma gallbladder were reported in 25 patients by Wistuba et al (1995).
Primary bile acids are degraded to the secondary bile acids by anaerobic organisms in the large bowel, some of which are thought to be implicated in colonic carcinogenesis (Lowenfels, 1978). Fox et al (1998) identified the presence of Helicobacter species in bile and gallbladder tissue from patients with cholelithiasis and cholecystitis but its relevance in carcinoma of the gallbladder is not yet established. A study from one centre has clearly shown significantly higher secondary bile acid in carcinoma of the gallbladder with positive culture (Shukla et al, 1993). Among the different microbial agents salmonella typhi has been implicated frequently. Mellemgaard et al (1988) reported a six fold higher risk for hepatobiliary cancer among typhoid carriers but the exact mechanism of carcinogenesis is yet to be established. We found that 10.7% of our cholelithiasis patients were typhoid carriers. There was an 8.5 times higher risk of carcinoma in culture positive carriers as compared to culture negative carriers (Pandey et al, 1995, Shukla VK et al, 2000).
The fatty acid saturation index is found to be decreased in patients with recurrent cancer as compared to cancers without recurrence (Wood et al, 1985). The erythrocyte stearic and oleic acid ratio (Erythrocyte saturation index) changes in patients with cancers as compared to cholelithiasis, a finding which is however, not specific for neoplasia (Pandey et al, 1995, Kelly et al, 1990).
Lipid peroxidation and cytochrome P-450
Free radicals, which are highly reactive chemical intermediates, are being implicated in a wide range of neoplastic transformations. Lipid peroxidation is a free radical mediated chemical reaction which damages polyunsaturated fatty acids and results in liberation of genotoxic and tumorigenic peroxidation products (Southorn et al, 1988). Increased concentration of a lipid peroxidation product 4-hydroxynoneal (HNE) was reported in the bile of patients with carcinoma of the gallbladder (Shukla et al 1994). NADP cytochrome P- 450 acts as an electron donor and thus promotes generation of free radicals which initiate lipid peroxidation (Rosen & Rauchkan 1982). Significantly higher levels of this enzyme have been associated with carcinoma of the gallbladder (Singh et al 1998).
Heavy metals as environmental pollutants have been implicated in carcinogenesis. In our study significantly higher biliary concentration of cadmium, chromium and lead was seen in patient with carcinoma gallbladder as compared to those with gallstones alone (Shukla et al, 1998). Recently metallothionein, a low molecular weight, metal binding protein which also acts as a free radical scavenger has been shown to play a protective role against heavy metal toxicity. We have observed significantly higher metallothionein expression in carcinoma gallbladder (70.3%) as compared to controls and cholelithiasis (Shukla et al, 1998). Metallothionein expression has also been shown to be associated with resistance to anticancer drugs (Kelly et al, 1988).
Early carcinoma gallbladder has no specific clinical presentation and preoperative diagnosis is rarely possible. Most of these patients are asymptomatic while a few present with clinical features suggestive of benign disease such as right upper abdominal pain interspersed with occasional attack of nausea and vomiting. In one study (Cunningham et al, 2002), 48.2% of patients of carcinoma gallbladder had a preoperative diagnosis of symptomatic cholelithiasis. About 1% of patients operated for acute cholecystitis are found to have carcinoma gallbladder. Jaundice, presence of a lump and features of malignant cachexia such as anorexia and weight loss are a feature of extensive disease as is the presence of repeated attacks of vomiting which suggests gastric outlet obstruction due to tumour infiltration. The presence of a hard nodule in the liver and ascites indicates disseminated disease. In 15-20% of patients, carcinoma gallbladder is discovered either intraoperatively or postoperatively on histology, which in only 20% of the patients is the disease confined to gallbladder at diagnosis. The majority of the patients thus have locoregionally advanced or metastatic disease on first presentation.
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