Gallbladder Cancer Vijay K Shukla, Manoj Pandey
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Etiopathogenesis of Gallbladder Cancer1

Manoj Pandey
Primary carcinoma of the gallbladder (GBC) is the most common malignant lesion of the biliary tract and 5th commonest lesion of the digestive tract.1,2 The disease is seen regularly in large hospitals and a sizeable experience has been recorded in literature. The first description of the carcinoma of the gallbladder was given by M deStoll in 17773 in two autopsy specimen, since then various reports have developed a characteristic pattern of late diagnosis and ineffectual treatment. With the recent development in imaging modalities the detection rate of the GBC has increased, however, the overall outcome still remains bleak.
 
INCIDENCE
Burdette (1957)4 calculated the incidence of the GBC to be 2.5/100,000 population of United States. Lam (1940)5 estimated that carcinoma of the gallbladder claimed 6,500 lives during 1936. His assumption was based on the hypothesis that two-third of all cancer deaths due to hepatico-biliary malignancy were caused by gallbladder cancer. Arminsky (1949)6 found an incidence rate of 0.43 percent while Strauch (1964)7 reported rate of 1.41 percent among the patients undergoing cholecystectomy. Kelly and Chamberlain (1982)8 found 110 cases among 10,500 cholecystectomies performed between 1954 and 1980, an incidence of 1.1 percent, at Akron City Hospital, Ohio. Piehler and Crichlow (1978)9 in a collective review reported 1,091 instances of carcinoma of the gallbladder in 57,170 biliary operations, an incidence of 1.9 percent. At MD Anderson Hospital carcinoma of the gallbladder represented 0.08 percent of all hospital admission over a period of 36 years.10 Glenn and Hays (1954)11 reported that in patients over the age of 65 years, operated for cholelithiasis, about 10 percent would be found to have carcinoma. Moertel (1982)12 stated that approximately 6,600 new cases of carcinoma of the gallbladder are diagnosed each year in United States matched by equal number of deaths each year, a figure similar to observed by lam (1940).5 Shukla et al, (1985)1 reported an incidence of 4.4 percent of all malignancies and 0.03 percent of total hospital admissions 2from Varanasi, India.
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Figure 1.1: Highest and lowest incidence of gallbladder cancer among males(Based on data from Perkin DM, Whelan SL, Ferlay J, Raymond L, Young J (Eds.). Cancer incidence in five continents Vol VII, IARC Sci Pub No 143, Lyon, France, 1997).
Chao and Greager (1991)13 reported an incidence of 2.5/100,000 population and found carcinoma of the gallbladder in 1-3 percent of cholecystectomy specimens. All these studies were either autopsy series or prospective evaluation. The true picture of overall incidence emerged only after the publication of prospective data by International Agency for Research on Cancer (IARC) obtained from the cancer registries world over and compiled. This showed the incidence of gallbladder cancer among women in Chile to be the highest at 27/100,000 followed by Poland 23/100,000, Japan 5/100,000 and Israel 13/100,000 (Figs 1.1 and 1.2). United States had a low incidence of 1/100,000.14
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Figure 1.2: Highest and lowest incidence of gallbladder cancer among females (based on data from Perkin DM, Whelan SL, Ferlay J, Raymond L, Young (Eds). Cancer incidence in five continents Vol III, IARC Sci Pub Sci Pub No. 143, Lyon, France, 1997)
The figures from Indian cancer registry (1989)15 showed the highest incidence from New Delhi 10/100,000 followed by Bhopal and Bombay. At Varanasi, the gallbladder cancer represented 17.6 percent of all malignancies and 3.14 percent of total admissions in a single surgical unit16,17 an almost four fold rise over the 1985 figures.1 This apparent increase is probably due to increased use of newer imaging modalities leading to increased detection or special interest of this unit in GBC rather than true rise in incidence or perhaps a selection bias. Absence of a hospital or population based registry in this area make these figures unrealistic.
 
Age
When seen by age, the patients at New York Hospital who underwent operations on biliary tract were found to have carcinoma of the gallbladder 4at a rate of 0.3 percent when less than 50 years of age and 8.8 percent when over 65 years.9, 11,18 Other investigators have found incidence of carcinoma of the gallbladder in patients over 70 years who underwent operations on biliary tree to be 10-17 percent.11,19,20 Shukla et al, (1985)1 reported mean age of the patients to be 50 years (Range 40-60 years). The mean age of 1,728 patients from 29 series, reported upon since 1960 was 65.2 years with incidence of carcinoma of the gallbladder of 0.1, 1.5, 8.9, 19.6, 37.0 and 32.0 percent in third, fourth, fifth, sixth, seventh and eighth decades respectively.9 In the Arminky’s series of 1388 cases (1949) 15 percent were of more than 70 years of age.6 Gradiser and Kelly (1970) 21 reported average age of 70 years ranging from 52-86 years, an observation similar to that of earlier series. Perpetuo etal,10 (1978) reported peak incidence in 7th decade, while Guo et al, (1981)22 found peak incidence in 7th and 8th decade of life. Maringhini et al, (1987)23 in an epidemiological study in Rochester, Minnesota, compared 2358 residents suffering from cholelithiasis between 1950 and 1970 with population developing malignancies and found the median age for cholelithiasis to be 63 years among men and 57 years among women while median age for gallbladder cancer among men was 79.6 years and 72.3 years among women. Mean age of patients with carcinoma of the gallbladder in the study of Beltz and Condon (1974)24 from Iowa City was 67 years. Kelly and Chamberlain (1982)8 in their review of carcinoma of the gallbladder from Arkon City Hospital, Ohio reported peak incidence between 75-79 years, followed by 70-74 years and 80-84 years, 70 percent of their patients were between 75-84 years old. Yamaguchi and Enjoji (1988)25 reported mean age of 65 years ranging from 36-91 years in their series of 103 cases. In the study of department of epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven, Netherlands, along with IARC within the frame work of program for studying the risk factors in relation to cancer, Surveillance on Environmental Aspects in Relation to Cancer in Humans (SEARCH), information collected on the age of presentation of gallbladder cancer showed mean age of presentation to be 65.4 years.26
 
Sex
Carcinoma of the gallbladder is predominantly a disease of elderly females. Of 2,998 patients from 51 series reported over last 20 years there were 2,292 females (75%) and 706 males (25%), a female to male ratio of 3.2: 1.9 Shukla etal, (1985)1 in their series of 315 patients found a female to male ratio of 2.5: 1, while Adson (1973)27 reported a male female ratio of 1:3. In the series of Yamaguchi and Enjoji (1988)25 there were 83 females and 20 males, a male female ratio of 1:4. Kelly and Chamberlain (1982)8 observed a male female ratio of 1:3.2 at Arkon City Hospital, Ohio. Perpetuo etal, (1978)105in their review observed a male female ratio of 1:5.2. In the study by IARC under SEARCH program gallbladder cancer was found to be commonest among women (56%) with cancer of the ampulla of the Vater coming second with 30 percent.
 
Geographical Distribution
Carcinomas of the gallbladder exhibit a marked geographical variation with highest incidence being reported from Chile (27/100,000). The diseases exist in endemic pockets in South America, Eastern Europe, Scandinavia, Middle East, Southeast Asia and East Asia (Fig. 1.3). Besides exhibiting an intercontinental variation the disease exhibit intercontinental variations. In South America the disease is common in Chile while in Brazil and Venezuela exhibit a lower or negligible incidence. In Eastern Europe, Poland has a very high incidence (23/100,000) while other eastern European countries show a negligible incidence. In Middle East highest incidence is reported from Israel (7.5/100,000 for males and 13.8/100,000 for females) while the disease is non-existent in Arabian countries. In south East Asia, India again shows a high incidence of 10/100,000 among females while neighboring countries have a very minimal incidence (Fig. 1.4).28
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Figure 1.3: Global distribution of carcinoma of the gallbladder
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Figure 1.4: Distribution of gallbladder carcinoma in India
The variation also occurs within the country. In United States of America clustering of elevated mortality rates are found in southwest, north central and Appalachia.29 In India a high incidence has been observed in New Delhi (14/100,000 females) and Bhopal (10/100,000) cancer registries, beside, Kashmir and Gangetic planes of eastern Uttar Pradesh and western Bihar while the disease is a rare in South India with Madras (Chennai) and Bangalore cancer registries showing zero incidence during 1988 and 1989 (Fig. 1.4).157
 
Etiology
Although the carcinoma of the gallbladder was described over two countries ago3 its etiology is still obscure. Several causative factors have been proposed.
 
Cholelithiasis
The commonest factor implicated in gallbladder carcinogenesis is gallstones.9 The frequency of gallstones in the United States general population, as evident by Framingham study is 11 percent.30 Gallstones were found to be associated with GBC in 40-100 percent of cases in various series. The frequent association of cholelithiasis with the carcinoma of the gallbladder remains undisputed, however, the controversy over the cause or effect relationship still exist. Piehler and Crichlow (1978)9 examined 2,352 patient of GBC in 37 series and found the incidence of cholelithiasis among GBC patients to be 73.9 percent. Hart et al, (1972)31 documented a higher incidence of stones in carcinoma patients than in general population of United States at all age levels. Adson (1973)27 reported an association of cholelithiasis in 75 percent of his patients. McLaughlin (1964)20 reported an incidence of 100 percent in untreated cholelithiasis. Hart et al, (1972)31 pointed out that:
  1. A causal relationship of gallstones in the etiology of gallbladder cancer has not been proved since gallstones could accompany or result from gallbladder cancer
  2. Gallstones may be related to previous inflammatory disorders of the gallbladder and therefore the inflammatory process rather than gallstones may lead to carcinoma.
  3. The frequency of gallbladder cancer among all patients with gallstones is relatively low (1.5-3%) and
  4. Not infrequently patients with GBC have neither a previous history nor present findings of gallstones.
There is difficulty in obtaining true estimates on frequency of gallstones in GBC due to low reliability of retrospectively obtained information regarding history of gallbladder diseases. In the series of Hart et al, (1972)31 74 percent of females and 26.7 percent of the males had a previous history of gallstone disease, while on pathological examination of resected specimen gallstones were found in 69 percent of males and 83 percent of females, suggesting a high incidence of silent gallstones among male carcinoma patients. Black et al, (1977)32 found gallstones in 41 out of 56 patients of southwestern American Indian origin, an incidence of 73.2 percent. In the series from MD Anderson Hospital 51 (88%) patients had gallstones.10 Shieh et al, (1981)33 from Waterburg Hospital Health Center reported gallstones 8 in 66 percent of their patients, while it was associated with 78 percent patients of GBC at Akron City Hospital.8 Klammer and Max (1983)34 found gallstones associated with GBC in 14 out of 20 of their patients. Maringhini et al, (1987)23 in an epidemiological study followed 2583 patients with documented cholelithiasis for a mean 13.3 years. The incidence of GBC in their cohort was significantly greater than expected for man (153 compared with 18 per 100,000 person years), but not for women (69 compared with 35 per 100,000 person years). In absolute terms the overall incidence was not impressive only 5 (0.19%) patients developed gallbladder cancer. They calculated an overall cumulative incidence of GBC to be 1 percent for 20 years after the initial diagnosis of gallstones in those who do not undergo cholecystectomy. Data from Fukuoka in Japan shows association of gallstones in 62 percent of GBC patient.25 In the Roswell Park Memorial Institute series, 68 percent of patients with GBC had gallstones.35 A similar incidence of 68.9 percent was noted by Chao and Greager (1991) from Illinois.13 Shirai et al, (1992)36 in another study from Niigata, Japan reported an incidence of 67 percent among the patients with early carcinoma of the gallbladder (mucosal (m) or submucosal (sm) lesions). The gallstones were found to be associated with subclinical GBC in 28 out of 31 patients in Fukuoka, Japan.37 deAretxabla et al, (1992)38 reported associated gallstones in 53 out of 54 potentially resectable gallbladder cancer in Chile, an area of high incidence of GBC. The points, which point to a causal association is:
  1. Presence of gallstones in the vast majority of patients with GBC.
  2. A similar male, female ratio in GBC patients and in those with cholelithiasis.
  3. Similar high frequency (70-80%) of gallstones in both sexes with GBC, despite the high frequency of gallstones in females in general population.
  4. A similarly high frequency of gallstones among women with GBC of all ethnic groups despite the marked difference in the incidence of both gallstones and GBC, when estimated separately in each ethnic group.
  5. The long period of previous abdominal complaints in the vast majority of patients with GBC.30
The argument against stones as possible cause of carcinogenesis is that 25 percent of all carcinoma develop without documented cholelithiasis.9 Comfort et al, (1948)39 followed silent gallstone patients from 10 to 20 years with only 1 percent patients developing carcinoma. When the results of Comfort et al, (1948)39 and Wenekert (1976)40 were clubbed together the incidence of carcinoma in silent gallstone patients dropped to 0.4 percent In another randomized trial 123 patients with gallstones were followed for more than 1,000 person years, none of the patient developed carcinoma.419 The clinical data does not establish a causative role for the gallstone in carcinogenesis, although the association is quite frequent to suggest a common antecedent or at least a facilitative role. The controversy over the cause and effect still exist.
 
Chronic Cholecystitis and Porcelain Gallbladder
The observation of Piehler and Crichlow (1978)9 that 40-50 percent of the patients with GBC had a history of antecedent chronic cholecystitis led to the belief that chronic cholecystitis per se is a causative factor in pathogenesis, however, the frequent association of the stones predates isolation of the effect of inflammation in carcinogenesis. Adson (1973)27 commented that 1/5th of the patients with GBC have symptoms similar to that of calculus disease of gallbladder inflammation while one-third are asymptomatic. He further stated that calculus, inflammation and cancer all produces the symptoms by same mechanism beside these conditions simultaneously coexist. Black et al, (1977)32 followed 1163 patients operated for gallbladder diseases at Gallup Indian Medical Center and 27 (2.3%) were found to have carcinoma. Among these 82 percent presented with upper abdominal pain, similar to chronic cholecystitis or calculus disease.
In a 36-year review of GBC at MD Anderson Hospital by Perpetuo et al, (1978)10 pain was commonest presenting feature in 98 percent of the patients. At Waterbury Hospital Health Center, Connecticut, 75 percent of all patients have symptoms suggestive of cholecystitis. The duration of these symptoms varied from 1 day to 21 years. The shortest duration was in a patient admitted with acute cholecystitis and longest in those who had underwent cholecystectomy for either inflammatory or calculus disease in past.33 The most striking feature of this study was that a preoperative diagnosis of cancer was established in only one (2%) case, while 64 percent were diagnosed at laparotomy and 14.6 percent on histology of resected specimen. Kelly and Chamberlain (1982)8 found pain in right upper quadrant (RUQ) in 74 percent while nausea and vomiting were present in 51 percent of their patients. In the series of Klammer and Max (1983),34 14/20 patients had features suggestive of inflammatory lesions. Shukla et al, (1985)1 reported pain in 85 percent, nausea and vomiting in 25 percent and fever in 15 percent of their cases.
Maringhini et al (1987)23 followed 2583 patients of calculus and inflammation and found that 5 patients developed GBC, representing a three-fold rise in the risk, though this rise was only significant in men than women. Cholelithiasis and chronic cholecystitis was most common preoperative diagnosis (28%). Yamaguchi and Enjoji (1988)25 found that 77 percent of their patients had a history suggestive of cholelithiasis or calculus 10disease while gallstones were detected only in 62 percent cases. Silk et al, (1989)35 found pain in 55/62 patients while nausea was present in 32/62 and vomiting in 25/62 patients. Chao and Greager (1991)13 reviewed data from University of Illinois College of Medicine at Chicago and found pain to be the commonest presetting feature in 54 percent of the cases. All the patients in their series had a preoperative diagnosis of GBC. In the series of 100 cases from Queen Mary Hospital in Hong Kong 60 percent of the patients were misdiagnosed as having calculus cholecystitis or cholecystitis.43 Out of 54 patients at Temuco, Chile 50 underwent cholecystectomy with preoperative diagnosis of calculus cholecystitis.38 Friedman et al, (1993)43 reported a 76-year-old male presenting with cholelithiasis which on histology was found to harbor primary lymphoma of the gallbladder. Deehan et al, (1993)44 reviewed 27 cases of carcinoid tumor of the gallbladder while describing two additional cases 16/29 presented as cholelithiasis.
Calcification of the wall of the gallbladder, so-called porcelain gallbladder, is believed to be end-stage of chronic cholecystitis. Frequency of development of carcinoma in these patients is 12.5-61 percent.45 In past 15 years, 11 instances of carcinoma arising in calcified gallbladder have been reported.174546 As majority of these patients contain stone it is difficult to access the isolated role of this variant of cholelithiasis in neoplastic transformation.
 
Xanthogranulomatous Cholecystitis
Lipids accompanying with bile pigments enters into the connective tissues of gallbladder wall resulting into inflammatory process. This lipid is sometimes oxidized to a chrome lipid and the resultant condition is called Ceroid granuloma47 or ceroid like histolytic granuloma48 or fibroxanthogranulomatous inflammation.59 These terms have now been replaced by xanthogranulomatous cholecystitis (XGC) a descriptive term first used by McCoy et al, (1976).50 The incidence of XGC is reported to range from 0.7 percent in Illinois51 to 1.8 percent is Sheffield52 with Japan having an intermediate rate of 1.2 percent among routine cholecystectomy specimen.48 Recent reports from Japan claim an incidence of 9 percent.53
XGC not only mimics carcinoma in various ways, but there appears to be a possible association between the two.54 GBC was over represented in a series of patients from Sheffield, with XGC55 and the condition was more frequent than expected in a series from Manchester.57 The reason for this observation is not clear. However, it may simply be that XGC of a particular duration or degree may be responsible. Or it could be that the tissue disruption by carcinoma facilitates the entry of bile into stroma.56,57 The 11association, nevertheless, is important as both lesions are represented within same specimen and there is always a possibility of overlooking the carcinoma altogether. Dixit et al, (1999)58 reported 32 cases of XGC and incidence of about 9 percent in routine cholecystectomy specimen and found carcinoma associated in one. This may be a chance observation. Apart from series from Manchester no one else has actually found on association between the two. United kingdom is a low incidence area, and its possible that etiology may be varying in low and high incidence areas.
 
Inflammatory Bowel Disease
The association of ulcerative colitis (UC) and biliary tract diseases is well known. A less frequent lesion is carcinoma of the extrahepatic biliary tract which is 5-10 times more frequent among them than in general population.59,60 The first report of biliary tract tumor and UC occurring in same patient was made by Parker and Kendell in 1954. Majority of these carcinomas arise in bile duct but about eight cases have been reported in gallbladder. In 1974, Ritchie et al,60 reported another case of GBC in patients of documented ulcerative colitis and suggested that these tumors are approximately 10 times more frequent in UC then in general population. First case demonstrating an association of UC was reported by Herzog and Goldblum (1996),61 Simms etal, (1994) 62 added another case to it. Stauffer et al, (1966)63 reported 2 cases and since then 1 case each has been reported by Warren et al, (1968),64 Stauffer et al, (1965),63 Ham (1968),65 Morowitz (1971)66 and Ritchie et al, (1974).60 The review of literature suggests that important factors in history are length of colitis symptoms and length of clinical involvement. Proctocolectomy in no way precludes the development of this tumor, neither the preceding or associated hepaticobiliary disease a necessary prerequisite for developing this tumor.
Thus, GBC in association with UC may have a different pathogenesis than is usually encountered. A causative role of altered bile salt metabolism is only speculative.
 
Blood Groups
In 1953, Aird et al,67 first reported an association between blood group ‘A’ and gastric cancer, since then numerous other reports have documented an association of blood group A and various other cancers including salivary gland, colon, uterus, ovary, pancreas, kidney, bladder and cervix. Juvonen and Niemela (1992)68 studied 171 patients with cholelithiasis and found no association with any blood group although patients with blood group ‘A’ were found to have multiple stones. The first study on blood group association with GBC was carried out at University Hospital, Varanasi12 and it showed a significant association of blood group A (χ2=2.8) and AB (χ2=39.0) with GBC69 compared to high prevalence of ‘O’ and ‘B’ blood groups in general population. No association could be demonstrated in patients with gallstones.
The increased risk of developing gastric and colonic cancer has been explained by expression of Forssmann antigen in patients with these cancers. This antigen is similar to blood group ‘A’ antigen. Due to this similarity, antibodies to blood groups ‘A’ also attack cancerous and pre-cancerous cells expressing Forssmann antigen there by checking their growth. Patients with blood group ‘A’ and ‘AB’ lacks antibodies to ‘A’ and hence, are more prone to development of cancer. Similar mechanism has also been implicated in gallbladder carcinogenesis in these patients. Another proposed mechanism is presence of genes associated with expression of factor or factors that confer a favorable prognosis, closely related to genes responsible for expression of blood group antigens and these may be inherited together. This study definitely demonstrates a positive association with blood group ‘A’ and ‘AB’ but to label it as a risk-factor, further casecontrol studies an blood group antigenic determination in tumor tissue are required as well, to elucidate this relationship further.
 
Racial and Ethnic Factors
A high prevalence GBC is seen in certain population groups. Its incidence in southwest American Indians has been estimated to be six times that of non-Indian population70 and carcinoma was found in 4.5 to 6.0 percent of all patients undergoing biliary tract surgery.71 Richenbach (1967)70 also observed that the incidence of gallstones in this population was twice that of American whites. Among the Navajo tribe of southwest American Indians a death certificate study revealed a low incidence of malignant diseases72 while these findings were contradicted in autopsy studies.73 Among this Navajo tribe along with Pima Indians the GBC was found to be very high.70,74
An epidemiological study undertaken by Hart et al, (1972)31 in Israel revealed the overall incidence to be 2.7/100,000. The incidence was higher in European born females who migrated to Israel, even though the incidence of GBC is low in Europeper se, Karin (1972)75 reported a high incidence of gallbladder malignancies in Japanese population. IARC data,14 collected from population based cancer registries, showed the highest incidence to be in Chilean population followed by Polish, Israel, Japanese and Scandinavian population. Shukla et al, (1985)1 reported a high incidence from India. Indian Cancer Registry data (ICMR 1991)15 showed the incidence of gallbladder cancer to be 10/100,000 female population in North India, thus making it third highest after Chile and Poland. The striking 13factor is almost negligible presence of this disease in South India. Shukla et al, (1995) 1 also showed a high incidence in eastern Uttar Pradesh.
A possible explanation is offered in form of dietary difference among population group however Richenbach (1967)70 contradicted it by reporting differences in diet of various south western American Indian tribes (Hesse, 1964).73 Similarly the diet of eastern Uttar Pradesh and western Bihar is quite different from Kashmir in India, still there is a strikingly high gallbladder cancer incidence in these two provinces. It seems that racial and ethnic factors do play a part in gallbladder carcinogenesis however the exact mechanism is yet not clear.
 
Familial and/or Genetic Causes
The greater risk of developing same cancer in first degree relatives of breast, stomach, colon and prostate cancer is well established.76 Patients suffering from GBC are known to develop second malignancy in 15 percent and family history of other organ cancer is present in 33 percent cases.10
The first report of familial occurrence of GBC was by Devor and Buechesy in 1979,77 from the two families of Hispanic New Mexicans. The only other report is by Trobjer et al, (1982)78 from Brazil. Although three cases of familial linkage has been reported till date the exact role of genetic factors in causation of GBC are still not clear.
 
Abnormal Pancreatic Biliary Duct Union
Anomalous junction of the pancreaticobiliary duct system is a congenital defect defined as the union of the pancreatic and biliary ducts located outside the duodenal wall. Pancreatic juice refluxes into common bile duct or bile juice regurgitate into pancreatic duct because the action of the sphincter muscle does not affect the union functionally. This gives rise to many complications such as cholangitis, gallstones, biliary cancers, pancreatitis and pancreatolithiasis.79
This high incidence of malignancies in anomalous pancreaticobiliary union was probably first brought to attention by Uchimura etal, (1982)80 and Komi et al, (1982)81 in two independent studies. The high incidence of GBC has been noted by many authors.82-88 The incidence of malignant changes has been reported to be as high as 15-40 percent. In the Japanese literature in past decade 34 cases have been reported. Aoki et al, (1987)85 analyzed 569 patients with anomalous pancreaticobiliary duct system and found 131 patients (23%) with associated biliary tract malignancy, 93 (71%) had GBC. All these patients presented in advanced (Nevin’s V)89 stage and only 2 survived for > 3 years. The association of gallstones with this anomaly was found to be low especially if cancer too was associated. The literature 14on this association is scares from other areas of high endemicity and till date from all centers is available it will be difficult to establish it as a cause, however, the association is too strong to neglect.
 
Chemical Carcinogens
The chemical similarity of carcinogens methyl cholanthrene to naturally occurring bile acids has led to speculation that GBC could be caused by such chemical transformationin vivo. Methyl cholanthrene per se has not been identified as such in bile of patients with GBC but the hypothesis stayed.13, 21, 34, 91
Fortner and others had been able to induce GBC by implanting pellets of chemicals into gallbladder of cats and dogs.91-93 Simmers and Podolak (1963)94 failed to produce carcinoma by inserting methyl cholanthrene pellets into the gallbladder of guinea pigs, establishing a significant species difference.
Introduction of foreign body in gallbladder is also known to cause carcinogenesis. Petrov and Krotkina (1947)95 induced GBC by inserting glass rods in guinea pig gallbladder. Feeding numerous other chemicals including O-amino toluene and various nitrosoamines has induced GBC. 8, 41,96-98
Kowalewski and Todd (1971)99 reviewed the probable multifactorial etiology of the disease. GBC was induced in 68 percent of hamsters who had cholesterol pallets inserted into the gallbladder and were subsequently fed on dimethylnitrosamine, while only 6 percent of controls fed on carcinogen alone developed cancer. Enomoto and coworkers (1974)97 too showed that a gallstone inducing diet greatly augments the carcinogenic effect of various chemicals.
Cryer and Krissanne (1979)100 linked biliary tract cancer to Benzidine, 3,3-dichloro benzidine and M-toluendiamine. GBC has been induced in animals with N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide, O-aminoazotlouene and aflatoxin B1.101 California Tumor Registry review of 1,808 cases of gallbladder and bile duct cancers found a significant association between GBC and workers in rubber, automobile, wood furnishing and metal fabricating industries. Kelly and Chamberlain8 found 27.6 percent of their cases of GBC from Akron City Hospital, Ohio, to be employed by rubber industries while 17 percent were unemployed and in 31.9 percent employment was not known. Since Akron is home of four major rubber companies, the fact that 27.6 percent of the patients were employed in rubber industries may be a coincidence. A larger epidemiological case-control study is needed to explain the role of chemical or occupational exposure in gallbladder carcinogenesis.15
 
Free Radicals
In the mammalian cell, molecular oxygen is essential for energy production through oxidative phosphorylation and detoxification. Cell death will rapidly ensue in the absence of oxygen. Under normal circumstances most of the molecular oxygen acts as terminal 4-electron acceptor while undergoing tetravalent reduction to water within intracellular cytochrome oxide reductive system (Reaction 1.1).
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Reaction 1.1: Tetravalent reduction of oxygen to form water
During this normal reduction a series of univalent reductions take place (Reaction 1.2) where only one electron is transformed at a time. This gives rises to highly reactive free radical intermediates, which if not handled properly by cytochrome system, may present an immediate and severe threat to the integrity of the cell.
The reactive oxygen species (ROS) generated there off may cause oxidative damage to enzymes, nucleic acid, cytoplasmic and membrane proteins and the cellular lipids largely present in cellular membrane.102
Carbon tetrachloride (CCl4) and halogenoalkanes are most common chemical pollutants produced by industries and automobiles. These can be absorbed through skin or ingested through water and produce hepatotoxicity in virtually all species. The hepatotoxicity of halogenoalkanes involves reductive dehalogenation by cytochrome p450, of hepatic microsome mixed function oxidoreductive system to form tetrachloromethyl (CCl.3) and trichloromethyl peroxy (CCl3O.2) radicals.103-107
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Reaction 1.2: Electron reduction of oxygen with formation of intermediate free radicals (Reproduced with permission from Shukla VK et al, J Surg Oncol 1994;56:255-262. © 1994 Wiley Liss Inc.)
Although a consensus on direct proof of generation of carbon tetrachloride free radicals has not yet been reached, indirect evidence of the microsomal formation of16the same is overwhelming.108 Free radical induce carcinogenesis is thought to occur in two stages. First, the initiation stage during which a physical, chemical or biologic agent directly cause an irreversible alternation in molecular structure of DNA. In second, the promotion stage, the expression of the genes that regulate the cell growth and differentiation is altered.109110
Recent experiments strongly suggests that free radicals are active in both promotion as well as initiation stage of cancer, making it an important etiological agent in carcinogenesis.111112
 
Lipid Peroxidation Products
Polyunsaturated fatty acids (PUFA) are more vulnerable to free radical attack. This oxidative damage is termed as lipid peroxidation and causes reduction in membrane fluidity and permeability beside producing highly genotoxic and tumorigenic lipid peroxidation products.104108, 112-118 Linolenic (C 18:2) and Arachidonic acid (C 20:4) contain number of ethylene-interrupted double bonds, which are in particular, prone to hydrogen abstraction. This process is autocatalytic chain reaction (Reactions 1.3 and 1.4) however, it can be halted by the action of free radical scavenger molecules.113-115,120 -129
The NADPH cytochrome p450 electron transport chain present in the liver microsomal mitochondria acts as electron donor and promote generation of free radicals thereby initiating lipid peroxidation. Of various lipid peroxide products 4-hydroxy nonenal (HNE) has a high neoplastic and tumorigenic potential.130-138 Shukla et al, (1994)115 have shown an increase in concentration of HNE in gallbladder. A further significant decrease in concentration PUFA has been observed in patients with GBC,112 leading to speculation that increase lipid peroxidation along with non-functioning of the gallbladder may give rise to an increased concentration of carcinogenic lipid peroxidation products (e.g. HNE) in gallbladder which retain for long time and in high concentration may be responsible for malignant transformation (Fig. 1.5).
 
Secondary Bile Acids
Interest in the hypothesis that bile acids are possible precursor of carcinogenic aromatic hydrocarbons has now faded. Though there is a large body of evidence that bile acids are tumor promoters and co-mutagens, can cause dysplastic changes in colonic mucosa and are strongly implicated as tumor promoters in colon carcinogenesis.139-145 They are also reported to influence the growth and morphology of cultured human fibroblasts99 and promote hepatoma formation in rats. Shukla etal, (1993)146 reported a significantly high level of secondary bile acids in patients with GBC compared to controls and subjects with cholelithiasis, in Varanasi, suggesting a possible role in gallbladder carcinogenesis.
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Reaction 1.3: Reaction showing production of peroxides as a result of free radical injury to fatty acids(Reproduced with permission from Shukla VK et al, J Surg Oncol 1994 ; 56 : 255-262. © 1994 Wiley Liss Inc.)
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Reaction 1.4: Production of lipid peroxidation products. Mechanism of the formation of hydroxyalkenals by peroxidation of polyunsaturated fatty acids (PUFA) linolenic acid (C 18:2) (Reproduced with permission from Pandey etal, J Surg Oncol 1995 ; 59 : 31-34 © 1995 Wiley-Liss)
The production of tumor promoters and initiators insitu in the digestive tract is well established and has been implicated in stomach, large bowel, urinary bladder and cervical carcinogenesis, gallbladder being no exception. The role of aerobic and anaerobic bacteria in biliary tract diseases is previously studied.147 Among aerobes Escherichia coli, other coliform bacilli and Enterococci are frequently cultured, while Clostridium perfringens is most common anaerobe along with gram positive cocciBacillus fragileslactobacilli and actionmycetes.148-150 Pandey et al, (1995)151 showed an increased degradation of primary bile acids to secondary bile acids in patients of carcinoma of the gallbladder with positive cultures.
18
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Figure 1.5: Hypothesis depicting the direct and free radical mediated gallbladder carcinogenesis. (Reproduced with permission from Pandey et al. Eur J Cancer Prev 2000; 9: 165-172. © 2000 Harcourt Brace Pub.)
As gallbladder carcinoma is common in Varanasi region, so are the stones and two-third of these stones are mixed stones, these observations strongly suggest that bacterial degradation of primary bile acids in gallbladder may be responsible for gallbladder carcinogenesis (Fig. 1.5).
 
Chronic Bacterial Infection
Samy and MacBin (1995)152 carried out bile cultures in 366 patients undergoing biliary tract surgery and found bacteriologic positivity in 73 (20%) of the cases. E. coli was the commonest organism cultured in 45 percent followed by Streptococci in 16.4 percentCl. welchii in 15 percent and Klebsiella and Streptococcusfecalis in 10 percent each.
The proposed mechanism of action is by virtue of degradation of bile salts by bacteria’s leading to carcinogenesis.153 Kinoshita and Gelboin (1978)154 showed that during glucuronidase action on biliary glucuronide, a highly active intermediate is formed which binds to DNA and so is potentially carcinogenic.
Pandey et al, (1995)151 explored their role in gallbladder carcinogenesis further in a case-control study. They carried out analysis of bile for bile acids and simultaneously performed bile cultures. Results of their study showed a significantly high level of secondary bile acids among culture positive patients compared to those, which were culture negative (P=0.001). 19These results strongly suggested a role of bacterial degradation of bile acids as a possible mechanism of carcinogenesis.151
 
Typhoid Carrier State
The association of typhoid carrier state and GBC was first reported by Axelord in 1978.155 An year later Welton et al,156 reported results of a case-control study of deceased typhoid carriers registered by New York city Health Department between 1922 and 1975. They matched 471 carriers with 942 controls for sex, age at death, year of death, brought in which the carrier died and where they were born. They found that chronic typhoid carriers die of hepatobiliary cancers six times more often than matched controls this difference was statistically significant (P<0.001). They suggested that it is the chronic typhoid infection along with gallbladder stasis that is probably responsible for producing gallbladder carcinogenesis. An observation supporting the hypothesis of Lowenfels (1978).153 Walten et al, further suggested that use of carcinogens in treatment may be responsible for some of their cases as local irradiation was being used for curing carrier states in 1909 and 1937.157
Mellemgaard (1988)158 studied 219 persons of typhoid carrier state registered with Serum Institute. They found that among those who died from the cancer, incidence was similar to that of general population. Of the 28/219 dying of cancer, three deaths were due to hepatobiliary cancer (one each of hepatocellular, adenocarcinoma gallbladder and adenocarcinoma of the bile duct) yielding a relative risk of 3.85 (90% confidence interval 1.05-9.94).
Caygill et al, (1994, 1995)159,160 studied the cancer risk in chronic typhoid and paratyphoid carriers of Aberdeen typhoid outbreak and communicable diseases (Scotland) unit records and found a large excess of GBC mortalities [167.0, 95% confidence interval (54.1–389)]. They suggested:
  1. Progression to chronic carrier status and not typhoid infection per secarriers the excess cancer risks.
  2. The risk is not only for hepatobiliary but also other bile related cancers.
  3. With in the hepatobiliary cancers the main risk appears in the gallbladder.
The findings of Caygill et al, (1995)160 suggested the need for effective eradication of chronic carriage either by antibiotics or by surgery, as the risk of developing GBC is too high to neglect. Carcinogenesis in chronic typhoid carriers is preventable and every measure should be taken to prevent this dreaded complication.
These all were the retrospective studies of mortality among carriers. Singh et al, (1995 and 2000),161-165 carried out a cross-sectional prospective study to detect the incidence of typhoid carriage in patients with GBC and gallstones. 20They found 27.4 percent incidence of carriers in GBC while it was 8.9 percent in stones and 5 percent in age and sex matched normal healthy controls. Carrier state represented an increased risk of 7.19 times for developing GBC compared to controls. Again a risk too high to neglect. They suggested that Salmonella typhii probably by their virtue of degradation of primary to secondary bile acids produces carcinogenesis,161-165 refuting the earlier hypothesis of Caygill that Salmonella carrier state is associated with high incidence of mixed infection which may be responsible for carcinogenesis.164 This is discussed in detailed by Caygill etal elsewhere in this book.
 
Heavy Metals
The incidence of gallbladder cancer in the gangetic plain rises from Varanasi to Patna in Bihar, a belt of 300 km. This region lie downstream on Ganges which is the main source of drinking, irrigation and bathing water in these parts and also receives untreated domestic sewage and industrial and agricultural waste. The main source of pollution is the tanneries upstream in Kanpur which uses heavy metal based compounds for leather tanning. High concentration of cadmium has been reported in sewage, irrigation water and vegetables grown in this area. The heavy metal concentrations recorded are much higher than WHO recommendations. Metals especially cadmium, are excreted by liver and concentrate in gallbladder, and are known carcinogens.166,167
To investigate the association of toxic heavy metals with GBC Shukla et al, (1998)168 carried out a case-control study. The results showed significantly higher biliary concentrations of cadmium, chromium and lead in the bile of cancer patients when compared to biliary concentrations among patients with gallstones. However, no association was made with the drinking water and food heavy metal levels. Again this could be attributed to reduce gallbladder contractility and increased emptying time.
 
Metallothionein over Expression
Metallothionein (MT) are sulfur rich, low molecular weight intracellular metal binding proteins with a possible role in human carcinogenesis of some cancers. These proteins are typically found in liver and kidney and also in heart, testes and brain. They bind to heavy metals through clusters of thiolate bonds. Their primary function is in regulation of trace metal metabolism, storage of these ions in the liver and as a protective mechanism against heavy metal toxicity.169-172 Other functions include control of intracellular redox potential, a role as a free radical scavenger and protection against ionizing radiation.173 MT over expression has been found to be associated with resistance to anticancer drugs174 and thus it serves as a 21marker for prognosis in cancer.175,176 Experimental studies in animals reveal that normal tissue deficient in MT are more prone to cadmium induced carcinogenesis.171,172
Shukla et al, (1998)177 studied the immunohistochemical expression of metallothionein in 27 cases of GBC and compared it with 8 cases of chronic cholecystitis and 7 normal gallbladder. MT expression was significantly higher in cases with GBC (70.4%) compared to chronic cholecystitis (25%) and it was absent in normal gallbladder. They concluded that increase MT expression in GBC may represent an increased exposure to heavy metals, and may play an important role in carcinogenesis as heavy metal exposure is known to cause cancer. It may also be relevant to poor prognosis and chemotherapy resistance seen in these cases.177
 
Benign Tumors of Gallbladder
Benign tumors of gallbladder, although rare, are implicated in malignant transformation. Christensen and Ishak (1970)178 reported a series describing 180 cases of benign and pseudotumors of the gallbladder. Among these were 24 polyps, 18 adenomatous hyperplasia, 73 adenomyomatous hyperplasia, 51 adenomata. The clinical presentation was essentially similar to that of cholecystitis with majority presenting with right quadrant pain. None of the case in their series was associated with cancer. They concluded that there is no evidence to suggest that these lesions have greater malignant potential than adjacent gallbladder mucosa.
Interest in polyp-cancer sequence was rejuvenated in 1990s by Aldridge and Bismuth.179 They suggested that increased use of ultrasound would invariably lead to increased detection of benign lesions, which were thought to be of little significance in past decades180 and were thought to be unlikely to undergo malignant changes. They suggested that if GBC is to be detected and treated early some questions like:
  1. Which benign gallbladder lesions are likely to undergo malignant changes?
  2. What is their incidence? and
  3. Should all gallbladder polyp constitute an indication for cholecystectomy? need be addressed.
Much of the controversy surrounding malignant transformation still continues. However the report of Christensen and Ishak (1970)178 suggested that adenomyomatosis might be a pre-malignant lesion. The evidence for malignant transformation comes from the study of Kozuka et al, (1982)180 who reviewed gallbladder histology in 1605 cases and found 11 benign adenomas, seven of these adenomas showed malignant changes. The transformation from benign to malignant was traceable histologically. They 22 further noticed that all adenomas showing malignant change were over 12 mm in diameters.
Adenomyomatosis in the gallbladder is characterized by extension of mucosa into and through a thickened muscular wall (Rokitansky-Aschoff sinuses) and is described by variety of names like diverticular disease of gallbladder, adenomyoma, cholecystitis glandularis proliference and cholecystitis cystica. Reports from Japan181,182 France183,184 have described five patients with malignant association.
The incidence of gallbladder adenomas in general population is unknown, however, the incidence in cholecystectomy specimen is one percent in most of the reports suggesting an incidence of 0.002-0.016 percent of the population per year.179 In India there are no reports on incidence of benign tumors in population, however, Pandey et al, (1996)185 in ultrasonographic screening among 610 healthy subjects with no history of gallbladder disease, found 2 (0.3%) case of gallbladder polyps.
Spigelman et al, (1990)186 studied the mutagenicity of bile on duodenal adenomas among patients with familial adenomatous polyposis and found it to be more mutagenic than healthy controls. They concluded that bile is an important factor in malignant transformation of benign lesions. This is discussed in detailed elsewhere.
 
Altered Gallbladder Motility
Altered gallbladder motility is less talked about as a probable cause of gallbladder cancer. However, it has been extensively studied in patients with cholelithiasis.187-191 The cholesterol nucleation theory gives further strength to this observation. Altered gallbladder motility has been observed during pregnancy192,193 in patients administered female sex hormones193,194 and among patients on parental nutrition195-197 other studies in patients with gallstones too have been found altered gallbladder motility.198-203 However, there are no reports in patients with gallbladder cancer and its exact significance is not known.
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