Cancers of the Pancreas and Biliary Tract: Epidemiological Considerations'

[CANCER RESEARCH35,3437-3446,November1975] Cancers of the Pancreas and Biliary Tract: Epidemiological Considerations'

Joseph F. Fraumeni, Jr. Epidemiology Branch, National Cancerinstitute, NIH, Bethesda,Maryland 20014

Summary special promise in laying the groundwork for prevention of these tumors. The epidemiological patterns for pancreatic and biliary cancers reveal more differences than similarities. Pancreatic carcinoma is common in western countries, although 2 Only limited information is available on the epidemiology Polynesian groups (New Zealand Maoris and native Ha and etiology of pancreatic and biliary tract cancers. Studies waiians) have the highest rates internationally. In the into the origins of these tumors have cleanly lagged behind United States the disease is rising in frequency, predominat investigations of other tumors which are perceived as more ing in males and in blacks. The rates are elevated in urban prevalent, menacing, or fashionable for study. areas, but geographic analysis uncovered no clustering of contiguous counties except in southern Louisiana. The Pancreatic Cancer origin of pancreatic cancer is obscure, but a twofold increased risk has been documented for cigarette smokers Pancreatic neoplasms are more common than is generally and diabetic patients. Alcohol, occupational agents, and appreciated. Among deaths from malignant neoplasms in dietary fat have been suspected, but not proven to be risk the United States, pancreatic cancer is fourth on the list, factors. Except for the rare hereditary form of pancreatitis, with about 18,000 people dying each year.2 This number is there are few clues to genetic predisposition. exceeded only by the 62,000 annual deaths from lung In contrast, the reported incidence of biliany tract cancer cancer, 45,000 deaths from colonectal cancer, and 29,000 is highest in Latin American populations and American deaths from breast cancer. The 1-year relative survival rate Indians. The tumor predominates in females around the is about 8%, and the 5-year rate is about 2% (3), so that the world, except for Chinese and Japanese who show a male level of mortality is a good measure of incidence. This excess. In the United States the rates are higher in whites review is concerned with exocnine pancreatic carcinomas; than blacks, and clusters of high-risk counties have been islet cell carcinomas and other tumors comprise a very small found in the north central region, the southwest, and fraction of pancreas cancer. Appalachia. The distribution of biliary tumors parallels that Demography. There are a number of peculiarities in the of cholesterol gallstones, the major risk factor for biliary distribution of pancreatic cancer that serve as leads to cancer. Insights into biliary cancinogenesis depend upon nutritional and other etiobogical factors. Geographic differ clarification of lithogenic influences, such as pregnancy, ences are pronounced, with the frequency greatest in obesity, and hyperlipoproteinemia, exogenous estrogens, western or industrial countries. This pattern has been familial tendencies, and ethnic-geographic factors that may correlated with the prevalence of â€œwesternâ€•diseasessuch as reflect dietary habits. Noncalculous risk factors for biliary breast cancer, colorectal cancer, and myocandial infarction cancer include ulcerative colitis, clonorchiasis, Gardner's (75). Chant 1 illustrates the international variation, with 16 syndrome, and probably certain industrial exposures. countries selected from the publication, Cancer Incidence in Within the biliary tract, tumors of the gallbladder and Five Continents (16). The rank order is determined by the bile duct show epidemiological distinctions. In contrast to male incidence, which exceeds the female rate except for the gallbladder cancer, bile duct neoplasms predominate in Latins in El Paso, Colombians, and the Bantu in South males; they are less often associated with stones and more Africa. Although the disease is common in the western often with other risk factors. In some respects, bile duct and countries, the male rates are highest among the Maonis in pancreatic tumors are alike. The male predominance of New Zealand, followed by the native Hawaiians and the both tumors, an association between cholecystectomy and black Americans. The female rates are highest among the pancreatic cancer, and other considerations have prompted native Hawaiians, followed by the Latins in El Paso and the the notion that the same biliary carcinogens may affect the Maoris in New Zealand. It is noteworthy that 2 groups of bile duct, ampulla of Vater, or, by neflux, the pancreatic Polynesian descent, the New Zealand Maonis and native duct. Various epidemiological and interdisciplinary ap Hawaiians, are especially prone to this tumor. The lowest proaches are needed to further clarify the origins of biliary rates in both sexes are reported for Nigeria and Bombay. tract and pancreatic cancers, but nutritional studies hold Table 1 presents United States mortality statistics, 1950

I Presented at the Conference on Nutrition in the Causation of Cancer, May 19 to 22, 1975, Key Biscayne, Fla. 2 Epidemiology Branch, National Cancer Institute, unpublished data.

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to 1969, for 5 racial groups.2 In both sexes blacks have Table I higher rates than whites. Among Japanese Americans, the A verage annual age-adjusted mortality rates (per /00,000) for male rate exceeds the level in blacks, while the female rates pancreas cancer in the United States by sex and race, for Japanese and Chinese Americans are lower than in 1950 to 1969 whites. American Indians have the lowest figure reported in MalesFemalesWhite9.635.83Black10.406.23Amerind6.666.03Chinese8.873.59Japanese10.645.68 males, but the female rate exceeds the level in whites (12). All racial groups show a male predominance. Factors underlying these racial differences are unclear, but an environmental influence is suggested by the much higher mortality reported for pancreatic cancer in Japanese Amen cans than in Japan (24). This shift is complicated, however, by the lack of stepwise progression; the migrants themselves have higher rates than the United States-born Japanese. A similar effect of migration within the United States is reflect in part inaccuracies in the reporting of census and suggested by a cancer mortality survey in Ohio; blacks born mortality data in the older black population. The time in the south, where the risk of pancreas cancer is low, have trends since 1950 show a 2.2-fold increase in black males, substantially higher rates than Ohio-born blacks (42). These compared to 1.9 in black females, 1.3 in white males, and trends indicate that migration from a low-risk to a high-risk 1.2 in white females. The predominance of blacks with this environment may pose an added risk, and raise the possi tumor appeared in the late 1950's and has progressively bility of a multifactorial etiology (e.g., early nutritional increased. Case-control studies of pancreas cancer in the deficits followed by dietary excesses). Another group predis black population would help identify causal factors. The posed to pancreas cancer are Jews, particularly Jewish disease is on the increase in other western countries and in women, in both the United States and Israel (76). Japan, and only part of the climb can be attributed to Chant 2 illustrates the age patterns of mortality from improvements in diagnosis and reporting (34). pancreatic cancer in the United States. The rates in blacks In contrast to the substantial international variation in predominate until age 65 and then plateau, while the rates in pancreatic cancer, geographic differences within the United whites continue to climb. This cross-over effect is seen in States are limited. Recent analyses of United States cancer reported mortality statistics for other tumors, and may mortality at the county level reveal that the highest rates for

3438 CANCER RESEARCH VOL.35

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pancreatic cancer are in metropolitan areas (46). When plotted on maps (47), the areas with excessive mortality among white males or females do not cluster in a manner signifying strong occupational or other geographically re lated factors (Chart 3). An exception may be an aggregation of pancreatic cancer identified in white males from the southern part of Louisiana, where 24 of the 64 counties in the state have rates in the top 10% of the country. The geographic variation in the United States is consistent with the urban predominance of this tumor, due partly to the availability of medical services (34, 76). Most studies also indicate a positive relation to lower socioeconomic class Chart 3. Geographic variation in mortality from pancreas cancer by United States county, white males (top) and females (bottom), 1950 to (32), although the gradient is not nearly as great as for 1969. Counties are shaded according to 5 levels: (a) significantly high rates, cancers of the stomach or cervix. and in top 10%of all United States county rates; (b) significantly high Incidence data from the 1969 to 197 1 Third National rates, but not in upper decile; (c) in upper decile, but not significant; (d) not Cancer Survey (6) reveal that pancreatic cancer predomi significantly different from total United States rate; and (e) significantly nates in blacks and in males (Chart 4). The age-specific lower than total rate in the United States. incidence curves show that, for both sexes, the rates in blacks are consistently higher than in whites except for the 140 . I' oldest age group. The tumor increases progressively with I â€˜(WILES age, being very rare under age 30. However, a recent report 120 . WIIITESâ€” I @ suggests that, in Japanese children, the tumor may occur l@ 6LACKS â€”â€”â€” excessively (72). Pancreatic tumors are thought to be uncommon in domestic animals. From a total of about 10,500 confirmed neoplasms reported to the Veterinary Medical Data Pro gram of the National Cancer Institute, 54 were pancreatic @@ 40 %FE'IALES carcinomas (56). There were 42 tumors in dogs, represent ing 1% of all canine tumors, 9 in cats, 2 in cattle, and 1 in a horse.

@ The Environment. Although the demographic features of .@ I 1y ;@h1@t@1 pancreatic cancerpoint to an environmental influence,none havebeensingledout with certainty. Someagents,however, Chart 4. Averageannualage-specificincidencerates(per100,000)for have fallen under suspicion. pancreas cancer by sex and race, Third National Cancer Survey, 1969 to Tobacco. Retrospective and prospective surveys indicate 1971. an approximately 2-fold increased risk of pancreatic cancer in cigarette smokers (76). A cause-and-effect relation is differential exists for this cancer among nonsmokers (25). A suggested by a dose-response gradient in risk, and by relationship to cigar smoking was recently noted, but needs autopsy studies of smokers showing hyperplastic changes in confirmation (76). the pancreaticduct. Cigarette smoking seemsto accountfor Alcohol. A retrospective survey of S3 patients with the male preponderance of pancreatic cancer, since no sex pancreatic cancer in Veterans Administration hospitals in

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New Orleans revealed that 65% had moderate or heavy research into the causes of one disorder may help to solve alcohol intake (10), but subsequent studies in other areas the other. have not confirmed this relationship. However, since the Endocrinopathy. An autopsy study of patients with death rates for pancreas cancer in males are elevated in pancreatic cancer revealed a high frequency of ovarian many Louisiana counties, attention should be given to the corticostromal and endometrial hyperplasia, as well as types of alcoholic beverages consumed by patients. neoplasms of the breast, ovary, and uterus (64). This Occupation. Industrial agents have been repeatedly sus constellation was thought to reflect excessive pituitary pected, particularly since chemicals can induce pancreatic activity in the form of gonadotrophic hormones, but the cancer in laboratory animals (40). Yet the evidence so far is findings remain to be confirmed. fragmentary. Occupational exposure to @-naphthylamine Pancreatitis. It has been suggested by clinical observa and benzidine were linked to pancreatic cancer (44), but the tions that chronic pancreatitis predisposes to pancreatic number of cases is too small to be conclusive. A survey of cancer(76), but the evidencefor a causal relationship is not death certificates of chemists belonging to the American convincing. However, about 20% of patients with a rare Chemical Society revealed an increased relative frequency syndrome, called hereditary pancreatitis, have pancreatic of pancreatic cancer (35), but specific chemical exposures cancer at autopsy (2). Only about 20 families have been could not be traced. Working in metal industries has been reported, about one-half showing pancreatic cancer in 1or 2 linked to this tumor (18), and a recent study of death members. In some families, hereditary pancreatitis affects certificates in the state of Washington pointed to a hazard one member, while pancreatic cancer strikes another, associated with aluminum milling, primarily potroom work suggesting different manifestations of the same genetic ens exposed to coal tar pitch derivatives (50). defect. In some patients, hyperlipemia is prominent and Diet. Some aspect ofthe western type ofdiet is implicated may contribute to the pancreatitis and perhaps the cancer. by the international patterns of pancreatic cancer (76). In Other Genetic Syndromes. Familial occurrences of pan Japan, the climbing rates for pancreatic cancer have been creatic cancer are very rare. In one family without signs of linked to consumption of a western diet, particularly meat, hereditary pancreatitis, 4 sibs developed pancreatic canci but the observations are very preliminary. The greatest noma (39). Other evidence of genetic susceptibility is difference between the Japanese and American diet may be sketchy. Ataxia telangiectasia is a recessively inherited in fat intake, and a positive correlation has been reported immunodeficiency syndrome that predisposes to cancer, between pancreatic cancer mortality and per capita fat mainly lymphoma, and to diabetes. Pancreatic cancer has consumption in various countries (76). No association with not been reported in homozygous patients, perhaps since body weight has been found. few survive to a susceptible age, but was thought to be ex Microbes. In laboratory animals, pancreatic sarcomas cessive in a preliminary survey of heterozygous relatives but not carcinomas have been produced by the Rous (69). For completeness, mention should be given to pan sarcoma virus (55). In man, certain common viruses may creatic islet cell tumors, which are usually benign and some damage the exocrine and endocrine portions of the pancreas times part of the inherited syndrome of multiple endocrine and are suspected of playing an important role in the adenomatosis (30). The tumors occasionally arise from a development of diabetes (67). Research into the viral â€œnon-$â€•cellthat secretes a gastrin-like hormone resulting etiology of diabetes may have important implications to in gastric hypersecretion and recurrent peptic ulcers of the pancreatic carcinogenesis. small bowel (Zollinger-Ellison syndrome). The Host. A few conditions appear to predispose to Gallbladder Disease. A suggestiveassociation has been pancreatic cancer, implicating host susceptibility to this reported betweencholecystectomyand subsequentdevelop tumor'. ment of pancreatic cancer, particularly in women (76). Diabetes. Best evidence for a predisposing disease is Furthermore, pancreatic cancer has shown geographic diabetes, particularly diabetic females whose risk of pan correlations with cholesterol type of gallstones, and similar creatic cancer is estimated at 2-fold (3 1). No other cancer is ities in sex ratio to bile duct cancers. These findings were consistently reported to occur excessively with diabetes. The among the considerations prompting Wynder et al. (76) to mechanism of the association remains to be clarified; some hypothesize that the bile contains carcinogens that affect the workers suggest that diabetes is only a prodromal sign of the bile duct and ampulla of Vater, and reflux into the neoplasm. However, the excess risk of pancreatic cancer pancreatic duct. This notion is consistent with the prepon extends many years after diagnosis of the diabetes (3 1), and derance of tumors at the head of the pancreas and the pathological studies of patients dying with diabetes have association of tumors with hyperplastic and preneoplastic revealed hyperplastic changes in the pancreatic duct (65). In changes nearby in the pancreatic duct (65). addition, the various population groups with a high rate of pancreatic cancer (the Maoris, Hawaiians, Jews, American Biliary Tract Cancer Indians, and blacks) are also particularly prone to diabetes (17, 45, 57, 74). A declining sex ratio with increasing age has A special handicap to the study of biliary tract cancer has been reported for both diabetes and pancreatic cancer, but been the failure of the International Classification of not for other tobacco-related or digestive tumors (34). These Diseases to distinguish between cancers of the liver and relationships taken together suggest that the 2 diseases biliary system until the 7th revision in 1958. Since then, share metabolic and nutritional determinants, so that about 4500 deaths from cancers of the biliary tract have

3440 CANCER RESEARCH VOL.35

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been reported yearly in the United States. A significant Table 2 fraction of these tumors appear to be causally related to A verageannualage-adjustedmortality rates(per I00JXXI)for biliarv tract gallstones, so that the epidemiological features of both cancer in the United States by sex and race, 1958 to 1967

diseases require attention. MalesFemalesWhite1.782.87Black1.131.57Amerind4.929.84Chinese2.782.30Japanese4.073.87 Demography. The descriptive epidemiology of biliany tract cancer is rather different from that of pancreas cancer. Chart 5 illustrates the international variation, with 16 countries again selected from the publication, Cancer Incidence in Five Continents (16). The rank order is determined by the female incidence, which exceeds the male rate in most countries. Although the numbers of cases in some registries are small, the highest rates in females are gallstone-related diseases endemic in this population ( I2, reported for Rhodesian Africans, Colombians, and El Paso 61). Another ethnic group with an abnormally high risk of Latins. In males, the rates are high also in Japan and in the gallbladder cancer is the Mexican American females, Hawaiian Japanese and Chinese. At the other end of the reported to be very prone to gallstones before 40 years of scale is the low incidence for both sexes in the South age (7, 71). Ethnic differences within other nations have African Bantu, Nigerians, and New Zealand Maoris. been reported. For example, in Israel, gallbladder cancer Mortality statistics for the United States, 1958 to 1967, and gallstones are more common in European-born women permit a breakdown of biliary tract cancers by racial group than the Asian or African-born, while no ethnic differences (Table 2). In both sexes, the American Indians have the could be detected in males with these diseases (26). highest rates, and the blacks have the lowest. The figures for Chart 6 illustrates the age patterns of mortality from Japanese Americans also exceed those for whites. The rate biliary tract cancer in the United States, showing the for male ChineseAmericans is higher than in whites, but the predominance in whites compared to blacks, and the female female rate is lower. The usual female predominance of excess in both races. The level of mortality in each race is biliary tract tumors is seen among whites, blacks, and similar until age 55, when the rates for blacks start to American Indians, but the ChineseandJapaneseAmericans plateau, while the rates for whites continue to climb. The show a male predominance. The excessive risk of gallblad time trends over the limited interval, 1958 to 1967, revealed der cancer in American Indians is part of a spectrum of little change, except for a declining mortality in white

NOVEMBER 1975 3441

while Appalachian communities have been identified at high risk ofgallstone disease (59). It is not clear why high rates of WHITES biliary tract cancer aggregate in the north-central area. BLACKSâ€”â€”â€” However, the geographic pattern of this tumor throughout the country resembles that of stomach cancer, with aggrega tions based largely on ethnic correlations.2 Incidence data from the Third National Cancer Survey (6) separate gallbladder cancer from other biliary tract neoplasms, which are primarily extrahepatic bile duct carcinomas. As shown in Table 3, the age-adjusted mci dence rates for tumors at both locations are generally higher in whites than blacks. In both races, the women are more likely, and the men less likely, to develop gallbladder cancer compared with bile duct cancers. Gallbladder cancer is twice as common in women than men, while bile duct Chart 6. Average annual age-specific mortality rates (per 100,000) for neoplasms have a 60% male predominance. Further studies biliary tract cancer in the United States by sex and race, 1958 to 1967. of Japanese and Chinese Americans are needed to see whether the male excess of biliary tract cancers results from a predominanceof bile duct tumors. Chart 8 shows the age-specific incidence rates for gall bladder and other biliary tumors in white males and females. In all categories, the risk increases steadily with age, with a consistent excess of females with gallbladder cancer and males with bile duct cancer. Gallbladder cancer is known to be more common in married than single women, with an increasing risk associated with an increas ing number of pregnancies (36, 37). In contrast to the situation in humans, biliary tract neoplasms and gallstones are seldom observed in domestic animals. From the 13,000 confirmed tumors of domestic

Table3 A verageannual age-adjusted incidencerates (per 100,000)for gallbladder andother biiary cancers,bysexandrace, Third National CancerSurvey, 1969 to 1971

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females from 3.20 to 2.68/100,000 population.2. 5 The geographic distribution in mortality from biliary ,

tract cancer at the county level shows clusters of areas with _t III elevated rates in the north-central region, the southwest, and 5 15 25 35 45 55 65 75 85+ Appalachia (Chart 7). The variation is more pronounced in Chap 8. Averageannual age-specificincidencerates (per 100,000)for females than males. The cluster in the southwest can be gallbladder and other biliary cancers, white males and females, Third attributed to the predisposition of Mexican Americans, National Cancer Survey, 1969to 1971.

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animals reported to the Veterinary Medical Data Program not be explained by obesity, impaired glucose tolerance, on of the National Cancer Institute, only 2 arose in the serum cholesterol. Further studies of these relationships are gallbladder and 4 in the bile duct (2 1). However, a cluster of urgently needed. biliary tract tumors was reported in 5 bears from 1 grotto in A high rate of gallstones was observed recently in an the San Diego Zoo (19). autopsy survey of men on an experimental senum-choles Gallstones. In western countries, the major component of terol-lowering diet (68). The diet was low in cholesterol and gallstones is cholesterol. In the United States about 15 saturated fat, and high in polyunsaturated fat and plant million people have stones, and only a small fraction of sterol content. This finding raises the possibility that them develop biliary tract tumors (29). When various series measures to lower serum cholesterol may act by increasing of gallbladder cancer are combined, however, stones are its biliary excretion and subsequent precipitation as stones. detected in about 75% of surgical cases and 90% of autopsy Estrogen Therapy. Recent studies by the Boston Col cases, while the percentage of bile duct cancers with stones laborative Drug Surveillance Program demonstrate that the is usually less than 30%. Furthermore, the frequencies of risk of surgery for gallbladder disease, including gallstones, gallstones and gallbladder cancer run in parallel from one is increased 2-fold following p.o. contraceptive therapy (8) population to another (26). Both conditions share epidemio and 2.5-fold following postmenopausal estrogen therapy (9). logical characteristics to a remarkable degree, so it is likely The findings are consistent with the female preponderance that cholesterol stones or the underlying metabolic pattern and parity effect of gallbladder cancer, and with the play a major part in the pathogenesis of biliany tumors. capacity of estrogens to increase the saturation of bile with Further studies are needed on the risk estimates of biliany cholesterol (28, 38, 54). tract neoplasms following stones, and the identification of flea! Disease. A predisposition to gallstones has been variables and mechanisms contributing to the risk. The observed among patients with regional entenitis, and other information would help in assessing prospects for control diseases or resection of the terminal ileum (27). The ling these tumors, such as cholecystectomy for people with mechanism may involve interruption of the enterohepatic â€œsilentâ€•stones, and the possible use of stone-dissolving circulation of bile salts. agents. immune Deficiency. Immunological determinantsof It is generally thought that persons prone to cholesterol stones are suggested by a recent survey of 50 patients with stones have a liver cell defect that produces â€œlithogenicâ€•bile late-onset immunological deficiency ( 15). Twelve developed with precipitation of cholesterol. Some workers postulate gallstones (24%), significantly more than the 9.4% found in that the bile is supersaturated with cholesterol (63), while a matched control series. The pathogenic mechanism is others suggest that a reduction of bile salts or phospholipids unclear, but might underlie the relationship previously leads to a relative excess and precipitation of cholesterol noted between biliary tract disease and immunoproliferative (38). Whatever mechanisms are involved, the risk factors neoplasms (77). for cholesterol stones seem relevant to the origins of biliary Familial Tendency. A tendency to sibship aggregation is tract cancer. demonstrated by surveys of patients with gallstones (73), Age, Sex, and Parity. The population-based survey of and in some families a Mendelian trait has been suspected. Framingham, Mass., revealed that the incidence of gall A laboratory marker of susceptibility is suggested by the stone disease rises steadily with age and is twice as common discovery of lithogenic bile from a high frequency of normal in women than men (22). The sex difference starts at sisters of young white women with gallstones (14). puberty and is related only in part to the elevated risk of Ethnicity and Locale. The frequency of gallstones is gallbladder disease with increasing pregnancies (5, 22, 53). greater in whites than blacks in the United States ( I3). Probably mediated by hormonal factors, pregnancy may American Indians comprise the most susceptible group. By impair gallbladder motility on produce bile relatively rich in screening of medical records, and by cholecystognaphy, a cholesterol (28, 49). survey of Pima Indians uncovered gallbladder disease â€˜in Obesity. Several studies indicate that patients with gall nearly one-half of the population (61). In American Indians stones are overweight and have a greater skinfold thickness with stones, the hepatic bile is supersaturated with choles when compared with controls (5, 22). However, in Pima terol (63), but the influence of genetic or environmental Indians, who are very prone to gallbladder disease, a factors in the production of this defect cannot be distin relationship to body weight was not detected, perhaps since guished. This lithogenic potential of bile precedes gallstone this population as a whole tends to obesity (61). formation, since it has been found in normal Chippewa Diet and Hyperlipoproteinemia. Various observations in Indian women who are at very high risk ofdeveloping stones man and experimental animals have suggested an influence (70). of dietary fats, carbohydrates, or total calories in the Another â€œclusterâ€•ofgallbladder disease in the United development of gallstones (62), but the results are not States exists in white residents of eastern Kentucky and conclusive. One investigation detected an increase in biliary rural Appalachia (59), where the prevalence rate is 4 times cholesterol concentration in persons with increased caloric that in Framingham, and is only slightly lower than in Pima and protein intake (62). The cholesterol levels in the serum Indians. In this area the disease primarily affects parous of patients are unremarkable, but a recent study uncovered rural women of low socioeconomic status, and may be gallbladder disease in 41% of males and 68% of females with related to dietary habits including excessive intake of fats, type IV hyperlipoproteinemia (20). This association could meats, and cholesterol. Dietary fats have been correlated

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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1975 American Association for Cancer Research. J. F. Fraumeni, Jr. also with the predominance ofgallstones in railroad workers References from northern India, compared with southern India (41), and with the rising incidence of cholesterol gallstones in 1. Akwari, 0. E., Van Heerden, J. A., Foulk, W. T., and Baggenstoss@A. Japan (52). H. Cancer of the Bile Ducts Associated with Ulcerative Colitis. Ann. Other Risk Factors. Although gallstones represent the Surg.,181:303-309,1975. most important risk factor in biliary tract cancers, particu 2. Appel, M. F. Hereditary Pancreatitis. Review and Presentation of an larly of the gallbladder, there is a need to seek other risk Additional Kindred. Arch. Surg., 108: 63-65, 1974. 3. Baylor, S. M., and Berg, J. W. Cross-Classification and Survival factors that are responsible for the tumors developing in the Characteristics of 5,000 Cases of Cancer of the Pancreas. J. Surg. absence of stones or that may interact with stones to Oncol., 5: 335â€”358,1973. produce tumors. 4. Belamaric, J. Intrahepatic Bile Duct Carcinoma and C. Sinensis Occupation. Environmental chemicals were implicated in Infection in Hong Kong. Cancer, 31: 468â€”473,1973. 1970, when an epidemiological survey of rubber workers 5. Bernstein, R. A., Werner, 1. H., and Rimm, A. A. Relationship of suggested an excess of cancers arising in the gallbladder and Gallbladder Disease to Parity, Obesity, and Age. Health Serv. Rept., bile ducts (43). From occupational mortality statistics in 88: 925-936, 1973. California, gallbladder and bile duct cancers were promi 6. Biometry Branch, National Cancer Institute. The Third National nent among automotive and rubber plant workers, while Cancer Survey Advanced Three-Year Report, 1969-7 1 Incidence. bile duct cancers alone were increased in workers from the Department of Health, Education, and Welfare Publication 75â€”637. aircraft, chemical, and wood-finishing industries (33). These Bethesda, Md.: NIH, 1975. 7. Bornstein, F. P. Gallbladder Carcinoma in the Mexican Population of preliminary observations are based on small numbers, but the Southwestern United States. Pathol. Microbiol., 35: 189-191, are consistent with the capacity of various chemicals, 1970. including those used in the rubber industry, to produce liver 8. Boston Collaborative Drug Surveillance Programme. Oral Contracep and biliary tract tumors in laboratory animals. tives and Venous Thromboembolic Disease, Surgically Confirmed Ulcerative Colitis. It has been estimated that in patients Gallbladder Disease, and Breast Tumours. Lancet, 1: 1399-1404, 1973. with ulcerative colitis the risk of biliary tract tumors is 9. Boston Collaborative Drug Surveillance Program. Surgically Con about 10 times greater than in the general population (60). firmed Gallbladder Disease, Venous Thromboembolism, and Breast Usually arising in the extrahepatic bile ducts, the tumors Tumors in Relation to Postmenopausal Estrogen Therapy. New Engl. develop in about 1% of colitis patients. In a recent series J. Med., 290: 15-19, 1974. 10. Burch, G. E., and Ansari, A. Chronic Alcoholism and Carcinoma of from the Mayo Clinic, the biliary tumors with colitis the Pancreas.A Correlative Hypothesis. Arch. Intern. Med., 122. appeared 3 decades earlier than usual, but did not appear 273-275,1968. influenced by the extent, severity, or form of treatment of I I. Cannon, M. M., and Leavell, B. S. Multiple Cancer Types in One the colitis ( I). However, in a study from St. Mark's Family. Cancer, 19: 538-540, 1966. Hospital in London, the tumors occurred more often in 12. Creagan, E. T., and Fraumeni, J. F., Jr. Cancer Mortality among patients with total colitis of long duration (60). The tumors American Indians, 1950- 1967. J. NatI. Cancer Inst., 49: 959-967, arise without gallstones or the usual hepatobiliary manifes 1972. tations of colitis (e.g., cholangitis), so that the pathogenic 13. Cunningham, J. A., and Hardenbergh, F. E. Comparative Incidence of mechanisms are obscure. Cholelithiasis in the Negro and White Races. Arch. Intern. Med., 97: Clonorchiasis. Intrahepatic bile duct cancer (cholangio 68-72, 1956. 14. Danzinger, R. G., Gordon, H., Schoenfield, L. J., and Thistle, J. L. carcinoma) is endemic among Chinese in some pants of Lithogenic Bile in Siblings of Young Women with Cholelithiasis. Asia, and results from infection by the liver fluke, Clonor Mayo Clin. Proc., 47: 762-766, 1972. chis sinensis (4). 15. Diaz-Buxo, J. A., Hermans, P. E., and Elveback, L. R. 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Joseph F. Fraumeni, Jr.

Cancer Res 1975;35:3437-3446.

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